U.S. patent application number 15/358636 was filed with the patent office on 2017-03-16 for bioerodible magnesium alloy microstructures for endoprostheses.
The applicant listed for this patent is Boston Scientific SciMed, Inc.. Invention is credited to Dennis A. Boismier, Charles Deng, Jacob Drew Edick, Torsten Scheuermann, Jonathan S. Stinson, Louis Toth, Jan Weber.
Application Number | 20170072112 15/358636 |
Document ID | / |
Family ID | 50156984 |
Filed Date | 2017-03-16 |
United States Patent
Application |
20170072112 |
Kind Code |
A1 |
Stinson; Jonathan S. ; et
al. |
March 16, 2017 |
BIOERODIBLE MAGNESIUM ALLOY MICROSTRUCTURES FOR ENDOPROSTHESES
Abstract
A bioerodible endoprosthesis includes a bioerodible magnesium
alloy. The bioerodible magnesium alloy has a microstructure
including equiaxed Mg-rich solid solution-phase grains having an
average grain diameter of less than or equal to 5 microns and
second-phase precipitates in grain boundaries between the equiaxed
Mg-rich solid solution-phase grains. The beta-phase precipitates
have an average longest dimension of 0.5 micron or less. The
microstructure can be produced by one or more equal-channel
high-strain processes.
Inventors: |
Stinson; Jonathan S.;
(Plymouth, MN) ; Boismier; Dennis A.; (Shorewood,
MN) ; Edick; Jacob Drew; (Minneapolis, MN) ;
Scheuermann; Torsten; (Munich, DE) ; Toth; Louis;
(Rogers, MN) ; Weber; Jan; (Maastricht, NL)
; Deng; Charles; (Chanhassen, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boston Scientific SciMed, Inc. |
Maple Grove |
MN |
US |
|
|
Family ID: |
50156984 |
Appl. No.: |
15/358636 |
Filed: |
November 22, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14178869 |
Feb 12, 2014 |
|
|
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15358636 |
|
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61765412 |
Feb 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 2/82 20130101; A61L
31/022 20130101; C22F 1/06 20130101; A61L 31/14 20130101; C22C
23/02 20130101; A61L 31/148 20130101 |
International
Class: |
A61L 31/02 20060101
A61L031/02; C22F 1/06 20060101 C22F001/06; C22C 23/02 20060101
C22C023/02; A61F 2/82 20060101 A61F002/82; A61L 31/14 20060101
A61L031/14 |
Claims
1. A bioerodible endoprosthesis comprising: a bioerodible magnesium
alloy comprising magnesium and one or more additional alloying
elements, wherein the alloy has a microstructure comprising
equiaxed Mg-rich solid solutionphase grains having an average grain
diameter of less than or equal to 5 microns and continuous or
discontinuous second-phase precipitates in grain boundaries between
the Mg-rich solid solution-phase grains, the second-phase
precipitates having an average longest dimension of 0.5 micron or
less.
2. The endoprosthesis of claim 1, wherein the second-phase
precipitates are primarily centered upon the gran boundaries and do
not extend into a Mg-rich solid solution phase grain interior by
more than 1 micron from the grain boundary when viewed at
200-500.times. magnification on a metallography plane.
3. The endoprosthesis of claim 1, wherein the equiaxed Mg-rich
solid solution phase grains have an average grain diameter of less
than or equal to 1 micron and the second-phase precipitates have an
average longest dimension of 0.2 microns or less.
4. The endoprosthesis of claim 1, wherein less than 50% of the
equiaxed Mg-rich solid solution-phase grains have twin bands.
5. The endoprosthesis of claim 1, wherein less than 15% of the
equiaxed Mg-rich solid solution-phase grains have twin bands.
6. The endoprosthesis of claim 1, wherein the bioerodible magnesium
alloy includes beta-phase precipitates outside the grain
boundaries, wherein at least 50% of the total amount of beta-phase
precipitates are located in grain boundaries between the equiaxed
Mg-rich solid solution-phase grains.
7. The endoprosthesis of claim 1, wherein the bioerodible magnesium
alloy includes beta-phase precipitates outside the grain
boundaries, wherein at least 65% of the total amount of beta-phase
precipitates are located in grain boundaries between the equiaxed
Mg-rich solid solution-phase grains.
8. The endoprosthesis of claim 1, wherein the bioerodible magnesium
alloy includes beta-phase precipitates outside the grain
boundaries, wherein at least 80% of the total amount of beta-phase
precipitates are located in grain boundaries between the equiaxed
Mg-rich solid solution-phase grains.
9. The endoprosthesis of claim 1, wherein the alloy has an elastic
modulus of between 39 GPa and 44 GPa, a 0.2% offset yield strength
of between 150 MPa and 350 MPa, an ultimate tensile strength of
between 250 MPa and 400 MPa, and a tensile reduction in area of at
least 30%
10. The endoprosthesis of claim 1, wherein the bioerodible
magnesium alloy comprises aluminum.
11. The endoprosthesis of claim 10, wherein the second-phase grain
boundary precipitates comprise Mg.sub.17Al.sub.12.
12. The endoprosthesis of claim 1, wherein the bioerodible
magnesium alloy comprises zinc, calcium, manganese, neodymium, tin,
yttrium, cerium, lanthanum, gadolinium, or a combination
thereof.
13. The endoprosthesis of claim 1, wherein the bioerodible
magnesium alloy comprises between 5 and 11 weight percent aluminum,
between 0.1 and 3.0 weight percent zinc, up to 0.3 weight percent
manganese, and between 0.6 and 1.5 weight percent neodymium, and
balance magnesium.
14. The endoprosthesis of claim 1, wherein the endoprosthesis is a
stent comprising a plurality of struts, wherein the struts have a
width to thickness ratio of less than 1.2.
15. The endoprosthesis of claim 1, wherein the endoprosthesis has a
surface finish having an R.sub.a surface roughness of less than 0.5
microns.
16. The endoprosthesis of claim 1, wherein the fully manufactured
non-sterile or sterile finished product bare bioerodible magnesium
alloy endoprothesis has a mass loss of less than 10% after 28 days
of continuous immersion in non-flowing, agitated Simulated Body
Fluid at 37.degree. C., where the Simulated Body Fluid has a volume
of at least 10 times an initial volume of the stent.
17. A method of processing a bioerodible magnesium alloy containing
at least 85 weight percent magnesium for a stent comprising:
forming an ingot or billet comprising a magnesium alloy, the
magnesium alloy comprising magnesium and one or more alloying
elements; and performing at least one high-strain process on the
ingot or billet to form a microstructure comprising equiaxed
Mg-rich solid solution-phase grains having an average grain
diameter of less than or equal to 5 microns and continuous or
discontinuous second-phase precipitates in grain boundaries between
the equiaxed Mg-rich solid solution-phase grains, the second-phase
precipitates having an average longest dimension of 0.5 micron or
less.
18. The method of claim 17, further comprising holding the ingot or
billet at a temperature of between the solvus and liquidus
boundaries of the phase diagram for at least 2 hours to homogenize
the ingot or billet before preforming the at least one high-strain
process on the ingot or billet.
19. The method of claim 17, wherein the at least one high-strain
process is an equal-channel high-strain process preformed at a
temperature of less than 400.degree. C.
20. The method of claim 19, wherein the ingot or billet is
processed through at least two equal-channel high-strain processes
at different temperatures, wherein a first equal-channel
high-strain process occurring at a first time is performed at a
higher temperature than a second equal-channel high-strain process
occurring at a second time after the first time, wherein the first
equal-channel high-strain process is performed at a temperature of
between 250.degree. C. and 400.degree. C. and the second
equal-channel high-strain process is performed at a temperature of
between 150.degree. C. and 300.degree. C.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 14/178,869, filed Feb. 12, 2014, which claims the benefit of
U.S. Provisional Application No. 61/765,412, filed Feb. 15, 2013,
the contents of which are herein incorporated by reference
TECHNICAL FIELD
[0002] This disclosure relates to microstructures for bioerodible
magnesium alloys used in endoprostheses and methods of producing
those microstructures.
BACKGROUND
[0003] Endoprostheses can be used to replace a missing biological
structure, support a damaged biological structure, and/or enhance
an existing biological structure. Frequently, only a temporary
presence of the endoprosthesis in the body is necessary to fulfill
the medical purpose. Surgical intervention to remove
endoprostheses, however, can cause complications and may not even
be possible. One approach for avoiding a permanent presence of all
or part of an endoprosthesis is to form all or part of the
endoprosthesis out of bioerodible material. The term "bioerodible"
as used herein is understood as the sum of microbial procedures or
processes solely caused by the presence of endoprosthesis within a
body, which results in a gradual erosion of the structure formed of
the bioerodible material.
[0004] At a specific time, the endoprosthesis, or at least the part
of the endoprosthesis that includes the bioerodible material, loses
its mechanical integrity. The erosion products are mainly absorbed
by the body, although small residues can remain under certain
conditions. A variety of different bioerodible polymers (both
natural and synthetic) and bioerodible metals (particularly
magnesium and iron) have been developed and are under consideration
as candidate materials for particular types of endoprostheses. Many
of these bioerodible materials, however, have significant
drawbacks. These drawbacks include the erosion products, both in
type and in rate of release, as well as the mechanical properties
of the material.
SUMMARY
[0005] A bioerodible endoprosthesis provided herein includes a
bioerodible magnesium alloy having a microstructure defined by
equiaxed Mg-rich solid solution-phase grains (i.e., alpha-phase
grains) having an average grain diameter of less than or equal to 5
microns and second-phase precipitates located in grain boundaries
between the equiaxed Mg-rich solid solution-phase grains. The
beta-phase precipitates can have an average longest dimension of
0.5 micron or less. Bioerodible magnesium alloys having the
microstructures provided herein can have improved mechanical
properties suitable for endoprostheses, such as stents.
[0006] A method of processing a bioerodible magnesium alloy for
endoprostheses provided herein can include the steps of forming an
ingot or billet of a magnesium alloy and performing at least one
high-strain process on the billet to form the grain and precipitate
morphology and size provided herein. In some cases, the processing
can include holding the ingot or billet at a temperature above the
solvus temperature (e.g., between 400.degree. C. and 450.degree.
C.) for at least 2 hours to homogenize the ingot or billet prior to
performing the at least one high-strain process. The at least one
high-strain process can be an equal-channel high-strain process and
can be conducted at a temperature of less than the solvus
temperature (e.g., a temperature below 400.degree. C.). In some
cases, multiple equal-channel high-strain processes are conducted
using subsequently lower temperatures.
[0007] Any suitable bioerodible magnesium alloy formulation capable
of having magnesium-rich solid solution grains and second-phase
precipitates that offer cathodic protection or promote the
formation of a protective film to the grains can be used in the
bioerodible endoprostheses provided herein. In some cases, the
bioerodible magnesium alloy includes aluminum, and
aluminum-containing beta-phase precipitates (e.g.,
Mg.sub.17Al.sub.12) are formed in the grain boundaries between the
equiaxed Mg-rich solid solution-phase grains. In some cases, the
bioerodible magnesium alloy can include aluminum, zinc, calcium,
manganese, tin, neodymium, yttrium, cerium, lanthanum, gadolinium,
or a combination thereof. For example, the bioerodible magnesium
alloy can include greater than 85 weight percent magnesium, between
5 and 11 weight percent aluminum, between 0.1 and 3.0 weight
percent zinc, less than or equal to 0.3 weight percent manganese,
and between 0.6 and 1.5 weight percent neodymium.
[0008] The endoprosthesis can also include a coating. In some
cases, the coating has a maximum thickness of 20 nm. In some cases,
the coating includes titanium oxide, aluminum oxide, or a
combination thereof. The endoprosthesis can also include a
therapeutic agent.
[0009] The endoprosthesis can be a stent.
[0010] One advantage of an endoprosthesis including a bioerodible
magnesium alloy having a microstructure provided herein is that the
resulting endoprosthesis' mechanical properties and degradation
rate can be tailored to maintain desired mechanical properties over
a desired period of time and an optimal bioerosion rate. A
bioerodible magnesium alloy having a microstructure provided herein
can have improved ductility as compared to similar alloys having
different microstructures.
[0011] 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
[0012] FIG. 1 is a perspective view of a representative stent.
[0013] FIGS. 2a and 2b depict metallographic images of etched AZ80
Mod alloy stents.
[0014] FIG. 3 depicts an exemplary microstructure provided
herein.
[0015] FIG. 4 depicts a phase diagram for a Magnesium-Aluminum
alloy.
[0016] FIGS. 5a-5d depicts exemplary Equal-Channel Angular
Extrusion dies.
DETAILED DESCRIPTION
[0017] A stent 20, shown in FIG. 1, is an example of an
endoprosthesis. Stent 20 includes a pattern of interconnected
struts forming a structure that contacts a body lumen wall to
maintain the patency of the body lumen. For example, stent 20 can
have the form of a tubular member defined by 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 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. Other examples of endoprostheses include covered stents and
stent-grafts.
[0018] At least one strut of stent 20 can be adapted to erode under
physiological conditions. In some cases, stent 20 is fully
bioerodible. Stent 20 can include a bioerodible magnesium-aluminum
alloy with relatively small concentrations of additional elements
having a microstructure defined by relatively equiaxed
magnesium-rich solid solution-phase grains having an average grain
diameter of less than or equal to 5 microns (longest dimension in a
metallography cross-section plane) and fine discontinuous or
continuous second-phase precipitates in grain boundaries between
the equiaxed Mg-rich solid solution-phase grains. A phase diagram
is shown in FIG. 4.
[0019] The beta-phase precipitates can have an average longest
dimension of 0.5 micron or less and are predominantly located in
grain boundaries rather than within grains (e.g., >50% of the
combined area of second-phase precipitates are on grain boundaries
in a given prepared metallography cross-section plane examined at
100-300.times. magnification). For example, FIG. 3 depicts an
exemplary microstructure provided herein. As shown in FIG. 3, a
majority of the second-phase precipitates (i.e., the beta-phase)
are located are located in grain boundaries rather than within the
Mg-rich solid solution-phase grains. Magnesium alloys having the
microstructures provided herein can have improved mechanical
properties suitable for endoprostheses, such as stents.
[0020] Although magnesium and magnesium alloys have been explored
as candidate materials for bioerodible endoprostheses in the past,
the mechanical properties of magnesium and magnesium alloys have
presented certain difficulties that make the use of a bioerodible
magnesium metal or alloy in certain endoprostheses, such as stents,
impractical. In particular, magnesium alloys can have a limited
ductility due to a lack of available slip planes in the Hexagonal
Close Packed (HCP) crystal lattice. Slip planes can accommodate
plastic deformation. Limited ductility can complicate certain uses
that rely upon plastic deformation. For example, limited ductility
can make stent crimping and stent expansion more complex due to an
increased probability of stent fractures during these plastic
deformations. Moreover, magnesium alloys typically have a lower
tensile strength than iron alloys (such as stainless steel alloys).
Bioerodible magnesium alloys having a microstructure provided
herein, however, can have improved ductility and tensile
strength.
[0021] Certain magnesium alloys were tested in order to identify
magnesium alloys having suitable bioerosion rates and ductility.
For example, L1c and WE43 (described in Table I below) were
prototyped and tested as stents, but found to have a bioerosion
rate that was too fast when subjected to in-vivo and in-vitro
testing. It is possible, however, that a L1c and/or WE43 alloy
having a microstructure provided herein would have a suitable
bioerodison rate for an endoprosthesis.
TABLE-US-00001 TABLE I Alloy Other Ex. Zn Zr Mn Y Nd Ca Ag Fe
Elements Mg L1c 2.87 .ltoreq.0.02 0.15 -- -- 0.22 0.10 0.0036 --
Balance WE43 Not 0.0-1.0 Not 2.0-6.0 1.5-4.5 Not Not Not 0.5-4.0 of
Balance specified specified specified specified specified other
rare earths metals; 0.0-0.3 Al
[0022] Certain modifications of the AZ80 alloy (see Table II below)
have also been developed in an attempt to find a magnesium alloy
having superior corrosion resistance to that of L1c, but also
having sufficient ductility. Although initial mechanical testing of
these AZ80 modified alloys showed an improvement in the mechanical
and corrosion properties as compared to L1c, AZ80 modified alloy
stents cracked and fractured at a nominal expanded diameter.
TABLE-US-00002 TABLE II Alloy Example Al Zn Mn Y Nd La Mg AZ80 7.5
0.5 0.2 -- -- -- Balance AZNd 7.3 0.6 0.1 -- 0.7 -- Balance AZY 7.4
0.6 0.1 0.5 -- -- Balance AZNdY 7.0 0.6 0.2 0.5 0.6 -- Balance AZM
7.3 0.6 0.4 -- -- -- Balance AZL 7.0 0.5 0.2 -- -- 1.2 Balance AE82
8.0 0.5 0.2 0.5 1.0 -- Balance
[0023] An analysis of the stents identified the presence of large
extrinsic intermetallic particles, e.g., oxide inclusions and
coarse Mg solid solution grain sizes, which are deleterious to
ductility. Low material ductility can result in stent cracking,
especially in balloon-expandable stents that are crimped onto a
balloon catheter, guided through a long tortuous path, and expanded
to fill the diameter of the artery. FIGS. 2A and 2B depict
metallographic images of etched AZ82 alloy stents. Referring to
FIG. 2A, the circled areas are the tensile and compression areas
near the strut peak of this nominally expanded stent. These circled
areas show twinning, cracking, and void nucleation. Referring to
FIG. 2B, voids are formed during the deformation. Magnesium having
the microstructure as shown in FIGS. 2A and 2B can be described as
having a coarse grain size with large secondary phase
precipitates.
[0024] The microstructures and processes provided herein eliminate
this root cause of low material ductility and stent cracking by
producing raw material alloy with much lower extrinsic inclusion
content (or at least much smaller inclusions) and stent material
with refined Mg solid solution grain size to randomize grain
texture, produce additional slip systems through grain size
refinement, and raise the activation energy needed to initiate a
crack due to the presence of a tortuous grain boundary network. The
microstructures and processes provided herein can be tailored to
manifest sufficient ductility in a balloon-expandable stent design
such that the Mg alloy stent would allow the stent to be crimped
onto a balloon catheter, wiggled through a long tortuous path, and
expanded to fill the diameter of the artery without fracturing.
[0025] The microstructure of a magnesium alloy is dependent on the
processing techniques and parameters. The grains (i.e., crystals)
of the alloy can align themselves with their basal planes parallel
to the direction of the processing material flow, which can result
in different mechanical properties in the direction of flow as
compared to the a direction perpendicular to the direction of flow.
In the case of extruding stent tubing including the alloys of Table
II, the resulting tube may have a strong preferred crystal
orientation, aligning the basal planes in the extrusion direction,
which produces increased ductility in the extrusion direction of
the tubing, but less ductility in a direction perpendicular to the
extrusion direction. The expansion of a stent, however, relies upon
the material having suitable ductility in all directions. A strong
grain texture with an unfavorable loading along the c-crystal axis
components of the grains causes twinning and void nucleation under
lower strains. The twinning with void nucleation shown in FIGS. 2A
and 2B can be the initiation of an eventual material failure. Stent
tube extrusion may also produce a randomized crystal structure with
no preferred orientation, which produces more isotropic mechanical
properties, but still suffers from the ductility issues discussed
above.
[0026] The microstructures provided herein can provide superior
ductility and other mechanical properties in multiple directions.
As shown in FIG. 3, the grain boundaries are decorated with
precipitates. The microstructures provided herein can be
characterized in a number of ways. In some cases, the
microstructures provided herein, when viewed at a 500.times. using
x-ray diffraction, have no more than 3% by area filled with
intermetallic ("IM") particles. In some case, the microstructures
provided herein have no more than 2% by area filled with IM
particles. In some cases, a maximum IM particle dimension will be
30 microns or less. In some cases, a maximum IM particle dimension
will be 20 microns or less, 10 microns or less, 5 microns or less,
or 1 micron or less.
[0027] The microstructures provided herein can include equiaxed
Mg-rich solid solution-phase grains with second-phase precipitates
located within smooth and equiaxed alpha-phase-grain boundaries. In
some cases, the equiaxed equiaxed Mg-rich solid solution-phase
grains have an average grain size of 20 microns or less, 15 microns
or less, 10 microns or less, 7.5 microns or less, 5 microns or
less, or 4 microns or less. In some cases, the equiaxed Mg-rich
solid solution-phase grains have an average grain size of between
0.1 microns and 10 microns, of between 0.5 microns and 5 microns,
or between 1 micron and 4 microns. In some cases, at least 90% by
volume of the beta phase particles can be found along alpha phase
grain boundaries. In some cases, the average beta phase individual
particle diameter or longest dimension is 5 microns or less, 3
microns or less, 1 micron or less, or 0.5 micron or less. In some
cases, the average beta phase individual particle diameter or
longest dimension is between 0.05 microns and 5 microns, between
0.1 microns and 3 microns, or between 0.2 microns and 1 micron. The
microstructure provided herein can have a reduced number of twin
bands. In some cases, less than 15% of the alpha grains will have
twin bands. In some cases, the number of alpha grains having twin
bands can be less than 10%, less than 5%, or less than 1% when the
stent is cut and crimped.
[0028] Microstructures provided herein can enhance ductility. The
microstructures provided herein can overcome the basal plane
alignment by randomizing grain orientations and result in isotropic
mechanical properties. Finer grains also yield increased grain
boundary areas, which can provide more grain boundary slip.
Refinement of precipitate diameter may also allow additional grain
boundary slip. Moreover, a homogenous dispersion of beta-phase
precipitates along the grain boundaries can maximize precipitation
strengthening and corrosion resistance. In some cases, the
precipitates can be substantially centered on the grain boundary
but be larger than the width of the grain boundary. For example,
the aluminum content of a magnesium alloy can react to form
corrosion resistant oxides at exposed grain boundaries to protect
each grain from corrosion. Moreover, smaller grains, each protected
by the formation of corrosion resistant oxides, can further slow
the corrosion of the overall structure of the bioerodible magnesium
alloys provided herein. Additionally, the beta-phase precipitates
can be fine enough so that they do not significantly impede
ductility.
[0029] A tubular body (e.g., stent tubing material) made from AZNd
alloy of the aim formulation shown in Table III, below, having a
microstructure provided herein can have an elastic modulus of
between 39 and 44 GPa, a 0.2% Offset Yield Strength of between 150
and 350 MPa, an ultimate tensile strength of between 225 and 400
MPa, a tensile reduction in area (RIA) of between 30% and 80%. In
some cases, stent tubing material provided herein can have a
tensile RIA of between 45% and 80%. In some cases, stent tubing
material provided herein can maintain its initial elastic modulus,
Yield Strength, ultimate tensile strength, and a tensile RIA within
+/-10% after storage of the tubing for 180 days at a temperature of
between 20.degree. C. and 25.degree. C. and a relative humidity of
less than 30%.
TABLE-US-00003 TABLE III Cu Fe Al Zn Mn Nd Si (ppm) (ppm) Batch
Specifi- 8 0.5 <0.2 1 -- <25 <25 1 cation XRF 8.80 0.55
0.10 0.68 0.031 23 24 OES 7.26 0.59 0.10 0.66 0.012 29 35 Batch
Specifi- 8 0.5 <0.2 1 -- <25 <25 2 cation XRF OES 8.2 0.43
0.23 0.65 ? ? ? Batch Specifi- 8 0.5 -- 1 -- <25 <25 3 cation
XRF 7.3 0.32 0.024 0.63 0.02 <10 26 OES
[0030] Bioerodible magnesium alloys having a microstructure
provided herein can be polished to have a smooth surface finish. In
some cases, an endoprosthesis provided herein can have a surface
including a bioerodible magnesium alloy having a surface roughness
R.sub.a of less than 0.5 microns, less than 0.4 microns, less than
0.3 microns, or less than 0.2 microns. Bioerodible magnesium alloys
having microstructure provided herein can have improved corrosion
resistance, which can provide a slower bioerosion rate. A stent
body of a bioerodible magnesium alloy having a microstructure
provided herein can have an in-vitro corrosion penetration rate of
less than 200 .mu.m/year after a period of 28 days of continuous
immersion in non-flowing, agitated Simulated Body Fluid (agitated
at 60 rpm) at 37.degree. C. where the Simulated Body Fluid ("SBF")
is present in an amount of at least 10 times the initial volume of
the stent material. The ingredients of SBF, which are added to
water, are shown in Table 4.
TABLE-US-00004 TABLE 4 SBF Ingredients Chemical Mass/Volume NaCl
5.403 g NaHCO.sub.3 0.504 g Na.sub.2CO.sub.3 0.426 g KCl 0.225 g
K.sub.2HPO.sub.4.cndot.3H.sub.2O 0.230 g MgCl.sub.2.cndot.6H.sub.2O
0.311 g 0.2M NaOH 100 mL HEPES 17.892 g CaCl.sub.2 0.293 g
Na.sub.2SO.sub.4 0.072 g
[0031] In some cases, the magnesium alloy includes aluminum. In
some cases, Mg.sub.17Al.sub.12 beta phases can precipitate in a
bioerodible magnesium alloy provided herein. Mg.sub.17Al.sub.12
beta phases can be less cathodic than phases that form from other
alloy systems, which can provide improved corrosion resistance
relative to alloys having more cathodic precipitates. The
precipitates can be more noble than the Mg grains and form a
corrosion-resistant barrier along grain boundaries and thereby
protect the grain interiors as a "grain coating." Aluminum can also
form native oxide layers along grain boundaries, which can act as a
protective layer for the grains and delay the onset of
intergranular corrosion. Smaller grain sizes can also reduce the
corrosion rate because corrosion must re-initiate past the
protective oxide layer for each grain corroded.
[0032] The microstructure provided herein can be formed by the
following material treatments: (a) solution treating a billet to
solutionize the second-phase precipitates that originally formed
during solidification of the alloy; (b) controlled cooling after
solutionizing to form a distribution of fine discontinuous or
continuous precipitates along grain boundaries; and (c)
thermomechanical deformation of the material after or during
cooling to refine the Mg-rich solid solution grain size and produce
a substantially equiaxed grain morphology.
[0033] For example, a billet of a bioerodible magnesium alloy can
be formed or machined into a solid or hollow rod, homogenized,
subjected to a high-strain process to refine the microstructure,
and then shaped or machined into stent tubing from which the stent
is manufactured into final dimensions (e.g., the dimensions of a
stent body).
[0034] Billets including a bioerodible magnesium alloy can be made
using any suitable process. For example, the billet can be of
bioerodible magnesium alloy having a diameter of between 2
centimeters and 1 meter. In some cases, aningot of a desired
bioerodible magnesium alloy can be made by conventional melting and
solidification in a mold (liquid casting), thixomolding (semi-solid
processing) or powder metallurgy (solid-processing). The ingot can
then be machined to the desired dimensions of the billet which will
serve as the feedstock for subsequent processing and shaping. In
some cases, a billet of a desired bioerodible magnesium alloy can
be formed without additional machining process. To form an
endoprosthesis (e.g., a stent body) out of the billet, the billet
can be converted into a rod or hollow tube having a smaller
diameter. In some cases, the ingot or billet is converted into a
rod or hollow tube after the ingot or billet is homogenized. In
some cases, the rod or hollow tube can have an outer diameter of
between 1 centimeter and 6 centimeters. In the case of a stent, a
hollow tube of a bioerodible magnesium alloy having a
microstructure provided herein can then be further reduced in
diameter and cut to form individual stent bodies, including
fenestrations between stent struts. In some cases, the stent struts
can have a width to thickness ratio of less than 1.2. In some
cases, the thickness of the hollow tube and the stent struts can be
between 80 microns and 160 microns.
[0035] An ingot or billet, in some cases, can be made by
thixomolding the elements of the bioerodible magnesium alloy.
Thixomolding involves mixing solid constituents into a portion of
the composition that is in a liquid phase and then cooling the
mixture to reach a fully solid state. Thixomolding can reduce the
number and size of brittle inter-metallic (IM) particles in the
alloy. For example, thixomolding can use a machine similar to an
injection mold. Room temperature magnesium alloy chips and chips of
the other alloy constituents can be fed into a heated barrel
through a volumetric feeder. The heated barrel can be filled with
an inert gas (e.g., argon) to prevent oxidation of the magnesium
chips. A screw feeder located inside the barrel can feed the
magnesium chips and other alloy constituents forward as they are
heated into a semi-solid temperature range. For example, the
mixture can be heated to a temperature of about 442.degree. C. The
screw rotation can provide a shearing force that can further reduce
the size of IM particles. Once enough slurry has accumulated, the
screw can move forward to inject the slurry into a steel die having
the shape of an ingot or billet.
[0036] An ingot or billet, in some cases, can be made by combining
the elements of the bioerodible magnesium alloy using powder
metallurgy. Powder metallurgy involves the solid-state sintering of
elemental or pre-alloyed powder particles. Using fine powders in a
sintering process can avoid the formation of coarse IM particles.
For example, fine powders of magnesium and other alloying
constituents can be blended into a homogenous mixture, pressed into
a desired shape (e.g., the shape of the ingot or billet), and
heated while compressed to bond the powders together. Sintering can
be conducted in an inert atmosphere (e.g., argon) to avoid
oxidation of the magnesium.
[0037] An ingot or billet including all of the desired elements of
a bioerodible magnesium alloy can be homogenized to reduce
elemental concentration gradients. The ingot or billet can be
homogenized by heating the ingot or billet to an elevated
temperature below the liquidus temperature of the alloy and holding
the ingot or billet at that temperature for period of time
sufficient to allow elemental diffusion within the ingot or billet
to reduce elemental concentration gradients within the ingot or
billet.
[0038] Homogenizing the ingot or billet can solutionize
intermetallic (IM) second-phase precipitate particles, because the
homogenization temperature is in excess of the phase boundary
(solvus temperature) between the high-temperature single, solid
phase (alpha) and two-phase field boundary on the Mg--Al phase
diagram. A follow-on solutioning treatment at the same or similar
position within the phase diagram can be used in some cases to
refine the precipitate structure. For example, a follow-on
solutioning treatment can be used if the homogenization treatment
cooling was not controlled sufficiently to tailor the second-phase
precipitate size and location. In some cases, the ingot or billet
is cooled rapidly after holding the ingot or billet at the elevated
temperature in order to form relatively fine IM second-phase
precipitates. For example, the ingot or billet can be cooled from
the elevated hold temperature via force gas cooling or liquid
quenching. The ingot or billet can be homogenized in an inert
atmosphere (e.g., in an argon atmosphere) or open atmosphere so
long as surface oxides are removed. In some cases, the ingot or
billet provided herein can be homogenized at a temperature of
between 400.degree. C. and 450.degree. C. In some cases, the ingot
or billet is held at a temperature of between 400.degree. C. and
450.degree. C. for at least 2 hours, at least 3 hours, or at least
4 hours. In some cases, the hold time at an elevated temperature is
between 4 hours and 24 hours. For example, a bioerodible magnesium
alloy ingot having a diameter of about 15 centimeters can be heated
to a temperature of 440.degree. C. for 6 hours to homogenize the
ingot, followed by quenching the ingot in a cooled argon gas
stream.
[0039] An ingot or billet can be subjected to one or more
high-strain processes to refine the microstructure into a
microstructure provided herein. In some cases, the high-strain
process(es) can include one or more equal-channel high-strain
processes. Equal-channel high-strain processes include
Equal-Channel Angular Extrusion ("ECAE") and Equal-Channel Angular
Pressing ("ECAP"). ECAE is an extrusion process that produces
significant deformation strain without reducing the cross sectional
area of the piece. ECAE can be accomplished by extruding the alloy
(e.g., a billet of the alloy) around a corner. For example, a
billet of a bioerodible magnesium alloy provided herein can be
forced through a channel having a 90 degree angle. The cross
section of the channel can be equal on entry and exit. The complex
deformation of the metal as it flows around the corner can produce
very high strains. In some cases, an ingot can be machined into a
billet having the exact dimensions of the channel of an ECAE die
prior to an ECAE process. Because the cross section can remain the
same, the billet can be extruded multiple times with each pass
introducing additional strain. With each ECAE process, the
orientation of the billet can be changed to introduce strain along
different planes. In some cases, an ECAE die can include multiple
bends. For example, FIGS. 5A-5D depict a variety of ECAE dies.
[0040] The ingot or billet provided herein can be extruded through
one or more ECEA dies (e.g., as depicted in FIGS. 5A-5D) at
temperatures lower than a homogenization temperature. Multiple
equal-channel high-strain extrusions can be performed at
subsequently lower temperatures. The equal-channel high-strain
processes can yield a fine grain size with fine beta-phase
precipitates (i.e., IM particles) that are primarily located along
the grain boundaries. In some cases, the dynamic recrystallization
of the grain refinement caused by successive equal-channel
high-strain extrusions at declining temperatures can introduce more
strain into the material and result in finer grain sizes as
compared to cold working and annealing steps. In some cases, an
ingot or billet is subjected to at least two ECAE processes at two
different sequentially-lower temperatures. In some cases, an ingot
or billet is subjected to at least three ECAE processes at
different sequentially-lower temperatures.
[0041] For example, a billet including a magnesium-aluminum alloy
can be processed through two ECAE processes, with the first ECAE
process occurring at a higher temperature than the second ECAE
process. Each process can occur through a simple ECAE die have a
single 90.degree. corner, such as that depicted in FIG. 5A. The
first ECAE process can be conducted at a temperature of between
250.degree. C. and 400.degree. C. to allow good diffusion of
aluminum to the grain boundaries where it can precipitate in the
form of Mg.sub.17Al.sub.12 beta phases. The Mg.sub.17Al.sub.12 beta
phases can be spherical and can have a diameter of about 1 micron
or less. Other beta phases can also move towards the grain
boundaries and precipitate there, depending on the particular alloy
composition. The first ECAE process can result in a microstructure
having an average grain diameter of 15 microns or less. A second
ECAE process can be done at a temperature of between 150.degree. C.
and 300.degree. C. The second ECAE process can further refine the
grain sizes and avoid coarsening. Because the first ECAE process
can be used to form Al-containing beta phases near the grain
boundaries, a lower temperature ECAE process can still allow
diffusion of Al- to the grain boundaries which form additional
secondary phase precipitate. The second ECAE process can produce an
average grain diameter of 5 microns or less. The beta-phase
precipitates can have an average diameter of 1 micron or less.
[0042] In the ECAE process shown in FIG. 5A, an ingot or
prior-worked billet 30a is extruded through a channel 31a including
two channel portions 32a, 33a of substantially identical
cross-sectional areas having the respective centerlines thereof
disposed at an angle 35a. As shown, angle 35a can be about
90.degree.. In some cases, angle 35a can be between 45.degree. and
170.degree., between 50.degree. and 160.degree., between 60.degree.
and 135.degree., between 70.degree. and 120.degree., between
80.degree. and 100.degree., or between 85.degree. and 95.degree..
Billet 30a can have any appropriate cross section and machined to
provide a snug fit into entry channel portion 32a. In some cases,
billet 30a can have a circular cross sectional shape. A ram 38a can
force billet 30a through channel 31a using an appropriate extrusion
ram pressure. The strain imposed on billet 30a is a function of
angle 35a.
[0043] In the ECAE process shown in FIG. 5B, an ingot or
prior-worked billet 30b is extruded through a channel 31b,
including three channel portions 32b, 33b, and 34b of substantially
identical cross-sectional areas having the respective centerlines
thereof disposed at angles 35b and 36b. As shown, angles 35b and
36b can be about 90.degree.. In some cases, angles 35b and 36b can
be between 45.degree. and 170.degree., between 50.degree. and
160.degree., between 60.degree. and 135.degree., between 70.degree.
and 120.degree., between 80.degree. and 100.degree., or between
85.degree. and 95.degree.. Billet 30b can have any appropriate
cross section and machined to provide a snug fit into entry channel
portion 32b. In some cases, billet 30b can have a circular cross
sectional shape, in other cases a square cross-sectional shape. A
ram 38b can force billet 30b through channel 31b using an
appropriate extrusion ram pressure. The strain imposed on billet
30b is a function of angles 35b and 36b.
[0044] In the ECAE process shown in FIG. 5C, an ingot or
prior-worked billet 30c is extruded through a channel 31c,
including three channel portions 32c, 33c, and 34c of substantially
identical cross-sectional areas having the respective centerlines
thereof disposed at angles 35c and 36c. As shown, angles 35c and
36c can be about 90.degree. and in separate planes. In some cases,
angles 35c and 36c can be between 45.degree. and 170.degree.,
between 50.degree. and 160.degree., between 60.degree. and
135.degree., between 70.degree. and 120.degree., between 80.degree.
and 100.degree., or between 85.degree. and 95.degree.. Billet 30c
can have any appropriate cross section and machined to provide a
snug fit into entry channel portion 32c. As shown, billet 30c can
have a circular cross sectional shape. A ram 38c can force billet
30c through channel 31c using an appropriate extrusion ram
pressure. The strain imposed on billet 30c is a function of angles
35c and 36c. Moreover, having the channel portions 32c, 33c, and
34c in different planes can impart shear forces along different
planes in a single pass.
[0045] In the ECAE process shown in FIG. 5D, an ingot or
prior-worked billet 30d is extruded through a channel 31d,
including three channel portions 32d, 33d, and 34d of substantially
identical cross-sectional areas having the respective centerlines
thereof disposed at angles 35d and 36d. As shown, angles 35d and
36d can be about 90.degree. and in opposite directions. In some
cases, angles 35d and 36d can be between 45.degree. and
170.degree., between 50.degree. and 160.degree., between 60.degree.
and 135.degree., between 70.degree. and 120.degree., between
80.degree. and 100.degree., or between 85.degree. and 95.degree..
Billet 30d can have any appropriate cross section and machined to
provide a snug fit into entry channel portion 32d. For example,
billet 30d can have a circular cross sectional shape. A ram 38d can
force billet 30d through channel 31d using an appropriate extrusion
ram pressure. The strain imposed on billet 30d is a function of
angles 35d and 36d.
[0046] The billet can be formed into a rod or hollow tube having a
reduced outer diameter after one or more high-strain processes.
Tube or rod drawing from the billet can occur in multiple steps,
with optional intermediate and final annealing steps, to reduce the
diameter. The drawing and annealing processes can be controlled to
preserve the microstructure formed in the one or more high-strain
processes. In some cases, the material is annealed at a temperature
of less than 300.degree. C. In some cases, the material is annealed
at a temperature of between 150.degree. C. and 300.degree. C.,
between 150.degree. C. and 250.degree. C., or between 150.degree.
C. and 200.degree. C. Annealing steps can be used to allow recovery
with limited recrystallization and avoid grain growth or changes in
precipitate volume fraction and morphology. Annealing steps can
also maintain a homogenous dispersion of beta-phase precipitates at
the grain boundaries.
[0047] Individual stent bodies can then be cut, including cutting
fenestrations between stent struts, using any suitable technique.
For example, the fenestrations can be cut using a laser.
[0048] Bioerodible magnesium alloys having a microstructure
provided herein can include magnesium alloyed with any suitable
combination of additional elements. In some cases, a bioerodible
magnesium alloy having a microstructure provided herein can include
aluminum. In some cases, a bioerodible magnesium alloy having a
microstructure provided herein can include zinc. In some cases, a
bioerodible magnesium alloy having a microstructure provided herein
can include calcium. In some cases, a bioerodible magnesium alloy
having a microstructure provided herein can include tin. In some
cases, a bioerodible magnesium alloy having a microstructure
provided herein can include manganese. In some cases, a bioerodible
magnesium alloy having a microstructure provided herein can include
neodymium. For example, a bioerodible magnesium alloy having a
microstructure provided herein can include at least 85 weight
percent magnesium, between 5 and 11 weight percent aluminum,
between 0.1 and 3 weight percent zinc, and between 0.05 and 0.3
weight percent manganese, between 0.6 and 1.5 weight percent
neodymium, up to 100 ppm copper, and up to 175 ppm iron. Other
possible bioerodible magnesium alloys include those listed in
Tables I and II above. Examples of other suitable bioerodible
magnesium alloys can be found in U.S. Patent Application
Publication No. 2012/0059455, which is hereby incorporated by
reference in its entirety, particularly the sections describing
particular bioerodible magnesium alloys.
[0049] A bioerodible magnesium alloy having a microstructure
provided herein can include a variety of different additional
elements. In some cases, the bioerodible magnesium alloy includes
less than 5 weight percent, in sum, of elements other than
magnesium, aluminum, zinc, and manganese. In some cases, the
bioerodible magnesium alloy includes less than 2 weight percent, in
sum, of elements other than magnesium, aluminum, zinc, and
manganese. The bioerodible magnesium alloy can consist essentially
of magnesium, aluminum, zinc, manganese, and neodymium. As used
herein, "consisting essentially of" means that the alloy can also
include impurities normally associated with the commercially
available forms of the constituent elements in amounts
corresponding to the amounts found in the commercially available
forms of the constituent elements. In some cases, the potential
impurity elements of iron, copper, nickel, gold, cadmium, bismuth,
sulfur, phosphorous, silicon, calcium, tin, lead and sodium are
each maintained at levels of less than 1000 ppm. In still other
embodiments, the potential impurity elements of iron, copper,
nickel, cobalt, gold, cadmium, bismuth, sulfur, phosphorous,
silicon, calcium, tin, lead and sodium are each maintained at
levels of less than 200 ppm. Iron, nickel, copper, and cobalt have
low solid-solubility limits in magnesium and can serve as active
cathodic sites and accelerate the erosion rate of magnesium within
a physiological environment. In still other embodiments, each of
iron, nickel, copper, and cobalt is maintained at levels of less
than 50 ppm. For example, each of the first five alloys listed in
Table II has no more than 35 ppm of iron.
[0050] Bioerodible magnesium alloys provided herein can optionally
include one or more rare earth metals. In some cases, the
bioerodible magnesium alloy includes between 0.1 and 1.5 weight
percent of a first rare earth metal. In some cases, the first rare
earth metal is yttrium, neodymium, lanthanum, or cerium. The
bioerodible magnesium alloy can also include between 0.1 and 1.5
weight percent of a second rare earth metal. For example, a
bioerodible magnesium alloy provided herein can include about 0.5
weight percent yttrium and 0.6 weight percent neodymium. In some
cases, the bioerodible magnesium alloy includes three or more rare
earth metals. In some cases, the total amount of rare earth metals
within the bioerodible magnesium alloy is maintained at a level of
less than 10.0 weight percent. In some cases, the total amount of
rare earth metals within the bioerodible magnesium alloy is
maintained at a level of less than 2.5 weight percent.
[0051] A coating can be applied over a bioerodible magnesium alloy
of an endoprosthesis provided herein. For example, a stent provided
herein can include a stent body formed of a bioerodible magnesium
alloy including a microstructure provided herein and a coating
overlying the surface of the stent body. A coating can slow or
delay the initial degradation of the bioerodible magnesium alloy
upon placement within a physiological environment by serving as a
temporary barrier between the Mg alloy and the environment. For
example, delaying the bioerosion processes can allow the body
passageway to heal and a stent to become endothelialized
(surrounded by tissues cells of the lumen wall) before the strength
of the stent is reduced to a point where the stent fails under the
loads associated with residing within a body lumen (e.g., within a
blood vessel). When an endothelialized stent fragments, the
segments of the stent can be contained by the lumen wall tissue and
are thus less likely to be released into the blood stream.
Endothelialization can also block the oxygen-rich turbulent flow of
the blood stream from contacting the endoprosthesis, thus further
reducing the erosion rate of the endoprosthesis. In some case, a
stent provided herein can include a coating that includes titanium
oxide, aluminum oxide, or a combination thereof. Examples of
suitable coatings can be found in U.S. Patent Application
Publication No. 2012/0059455, which is hereby incorporate by
reference in its entirety, particularly the sections describing
coatings formed by atomic layer deposition.
[0052] The stent can optionally include a therapeutic agent. In
some cases, the coating can include a therapeutic agent. In some
cases, the coating can include a polymer (e.g., a bioerodible
polymer). For example, a drug-eluting polymeric coating can be
applied to the stent body provided herein. In some cases, a stent
provided herein can be essentially polymer-free (allowing for the
presence of any small amounts of polymeric materials that may have
been introduced incidentally during the manufacturing process such
that someone of ordinary skill in the art would nevertheless
consider the coating to be free of any polymeric material). The
therapeutic agent may be any pharmaceutically acceptable agent
(such as a drug), a biomolecule, a small molecule, or cells.
Exemplary drugs include anti-proliferative agents such as
paclitaxel, sirolimus (rapamycin), tacrolimus, everolimus,
biolimus, and zotarolimus. Exemplary biomolecules include peptides,
polypeptides and proteins; antibodies; oligonucleotides; nucleic
acids such as double or single stranded DNA (including naked and
cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA,
small interfering RNA (siRNA), and ribozymes; genes; carbohydrates;
angiogenic factors including growth factors; cell cycle inhibitors;
and anti-restenosis agents. Exemplary small molecules include
hormones, nucleotides, amino acids, sugars, lipids, and compounds
have a molecular weight of less than 100 kD. Exemplary cells
include stem cells, progenitor cells, endothelial cells, adult
cardiomyocytes, and smooth muscle cells.
[0053] A stent provided herein can include one or more imaging
markers. Imaging markers can assist a physician with the placement
of the stent. Imaging markers can be radiopaque marks to permit
X-ray visualization of the stent.
[0054] Stent 20 can be configured for vascular, e.g., coronary and
peripheral vasculature or non-vascular lumens. For example, it can
be configured for use in the esophagus or the prostate. Other
lumens include biliary lumens, hepatic lumens, pancreatic lumens,
and urethral lumens.
[0055] Stent 20 can be of a desired shape and size (e.g., coronary
stents, aortic stents, peripheral vascular stents, gastrointestinal
stents, urology stents, tracheal/bronchial stents, and neurology
stents). Depending on the application, the stent can have a
diameter of between, e.g., about 1 mm to about 46 mm. In certain
embodiments, a coronary stent can have an expanded diameter of from
about 2 mm to about 6 mm. In some cases, a peripheral stent can
have an expanded diameter of from about 4 mm to about 24 mm. In
certain embodiments, a gastrointestinal and/or urology stent can
have an expanded diameter of from about 6 mm to about 30 mm. In
some cases, 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. The stent can be balloon-expandable,
self-expandable, or a combination of both (e.g., see U.S. Pat. No.
6,290,721).
[0056] Non-limiting examples of additional endoprostheses that can
include a bioerodible magnesium alloy including a microstructure
provided herein include stent grafts, heart valves, and artificial
hearts. Such endoprostheses are implanted or otherwise used in body
structures, cavities, or lumens such as the vasculature,
gastrointestinal tract, abdomen, peritoneum, airways, esophagus,
trachea, colon, rectum, biliary tract, urinary tract, prostate,
brain, spine, lung, liver, heart, skeletal muscle, kidney, bladder,
intestines, stomach, pancreas, ovary, uterus, cartilage, eye, bone,
joints, and the like.
[0057] All publications, patent applications, patents, and other
references mentioned herein are incorporated by reference herein in
their entirety.
[0058] Still further embodiments are within the scope of the
following claims.
* * * * *