U.S. patent application number 15/954863 was filed with the patent office on 2019-03-21 for implantable medical devices comprising bio-degradable alloys.
The applicant listed for this patent is Bio DG, Inc.. Invention is credited to Gordon F. JANKO, Herbert R. RADISCH, Thomas A. TROZERA.
Application Number | 20190083683 15/954863 |
Document ID | / |
Family ID | 42312210 |
Filed Date | 2019-03-21 |
United States Patent
Application |
20190083683 |
Kind Code |
A1 |
JANKO; Gordon F. ; et
al. |
March 21, 2019 |
IMPLANTABLE MEDICAL DEVICES COMPRISING BIO-DEGRADABLE ALLOYS
Abstract
The invention provides medical devices comprising high-strength
alloys which degrade over time in the body of a human or animal, at
controlled degradation rates, without generating emboli. In one
embodiment the alloy is formed into a bone fixation device such as
an anchor, screw, plate, support or rod. In another embodiment the
alloy is formed into a tissue fastening device such as staple. In
yet another embodiment, the alloy is formed into a dental implant
or a stent.
Inventors: |
JANKO; Gordon F.; (Poway,
CA) ; RADISCH; Herbert R.; (San Diego, CA) ;
TROZERA; Thomas A.; (Del Mar, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bio DG, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
42312210 |
Appl. No.: |
15/954863 |
Filed: |
April 17, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15222527 |
Jul 28, 2016 |
|
|
|
15954863 |
|
|
|
|
14059331 |
Oct 21, 2013 |
|
|
|
15222527 |
|
|
|
|
13553645 |
Jul 19, 2012 |
8591672 |
|
|
14059331 |
|
|
|
|
12684081 |
Jan 7, 2010 |
8246762 |
|
|
13553645 |
|
|
|
|
61143378 |
Jan 8, 2009 |
|
|
|
61168554 |
Apr 10, 2009 |
|
|
|
61260363 |
Nov 11, 2009 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C22C 38/50 20130101;
A61L 31/022 20130101; C22C 38/44 20130101; A61C 8/0012 20130101;
A61L 31/148 20130101; A61B 17/064 20130101; C22C 38/52 20130101;
A61B 17/866 20130101; C22C 38/58 20130101; A61B 2017/00004
20130101; C22C 38/48 20130101; A61B 17/8085 20130101; C22C 38/04
20130101; A61F 2/82 20130101; A61B 17/84 20130101; A61F 2210/0004
20130101 |
International
Class: |
A61L 31/02 20060101
A61L031/02; C22C 38/50 20060101 C22C038/50; C22C 38/48 20060101
C22C038/48; C22C 38/04 20060101 C22C038/04; C22C 38/44 20060101
C22C038/44; A61B 17/84 20060101 A61B017/84; C22C 38/52 20060101
C22C038/52; A61L 31/14 20060101 A61L031/14; C22C 38/58 20060101
C22C038/58 |
Claims
1. An implantable medical device comprising a biodegradable alloy,
wherein the alloy is substantially austenite in structure, and
wherein the alloy has an average grain size in the range of about
0.5 microns to about 20 microns or a surface to volume ratio for
individual grains of, on average, greater than 0.1 .mu..sup.-1.
2. The implantable medical device of claim 1, wherein the average
grain size is about 0.5 microns to about 5.0 microns.
3. The implantable medical device of claim 1, wherein the average
grain size is about 1.0 micron to about 2.0 microns.
4. The implantable medical device of claim 1, wherein the surface
to volume ratio for individual grains is, on average, greater than
1.0 .mu..sup.-1.
5. The implantable medical device of claim 1, wherein the
implantable device is a bone screw, bone anchor, tissue staple,
craniomaxillofacial reconstruction plate, fastener, reconstructive
dental implant, or stent.
6. The implantable medical device of claim 1, wherein the alloy
comprises an austenite promoting component and a corrosion
resisting component, and wherein the total amount of the austenite
promoting component in the alloy is greater than about 10% and the
total amount of the corrosion resisting component is about 0.5% to
about 10%.
7. The implantable medical device of claim 1, wherein the alloy
contains less than about 0.1% nickel and less than about 0.1%
vanadium.
8. The implantable medical device of claim 1, wherein the alloy
contains less than about 4% chromium.
9. The implantable medical device of claim 1, wherein the alloy
contains less than about 6% cobalt.
10. The implantable medical device of claim 1, wherein the alloy
contains less than about 0.1% nickel, less than about 0.1%
vanadium, less than about 4% chromium, and less than about 6% of
cobalt.
11. The implantable medical device of claim 1, wherein the alloy
comprises an austenite promoting component comprising manganese,
cobalt, platinum, palladium, iridium, aluminum, carbon, nitrogen,
silicon, or any combination thereof, and wherein % platinum+%
palladium+% iridium+0.5*(% manganese+% cobalt)+30*(% carbon+%
nitrogen) is greater than about 12%.
12. The implantable medical device of claim 1, wherein the alloy
comprises a corrosion resisting component comprising chromium,
molybdenum, tungsten, tantalum, niobium, titanium, zirconium,
hafnium, or any combination thereof, and wherein % chromium+%
molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(% titanium+%
zirconium+% hafnium) is about 0.5% to about 7%.
13. The implantable medical device of claim 1, wherein the alloy
comprises an austenite promoting component comprising manganese,
cobalt, platinum, palladium, iridium, aluminum, carbon, nitrogen,
silicon, or any combination thereof, wherein % platinum+%
palladium+% iridium+0.5*(% manganese+% cobalt)+30*(% carbon+%
nitrogen) is greater than about 12%, and wherein the alloy
comprises a corrosion resisting component comprising chromium,
molybdenum, tungsten, tantalum, niobium, titanium, zirconium,
hafnium, or any combination thereof, wherein % chromium+%
molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(% titanium+%
zirconium+% hafnium) is about 0.5% to about 7%.
14. The implantable medical device of claim 1, wherein the device
is coated with a therapeutic agent.
15. The implantable medical device of claim 1, wherein the device
is coated with a biodegradable hydrogel.
16. The implantable medical device of claim 1, wherein the device
comprises a geometry that maximizes the surface to mass ratio.
17. The implantable medical device of claim 1, wherein the device
comprises a hollow opening or passageway.
18. An implantable medical device comprising a biodegradable alloy,
wherein the alloy is substantially martensite in structure and
comprises iron, carbon, a corrosion resisting component, and an
austenite promoting component.
19. The implantable medical device of claim 18 which contains about
65% to about 75% iron, about 0.1% to about 0.3% carbon, about 2.0%
to about 6.0% of a corrosion resisting component, and about 20% to
about 30% of an austenite promoting component.
20. A container containing the implantable medical device of claim
1 and an instruction for using the implantable medical device for a
medical procedure.
21. A container containing the implantable medical device of claim
18 and an instruction for using the implantable medical device for
a medical procedure.
Description
[0001] The present invention is a continuation of U.S.
Non-Provisional Ser. No. 15/222,527, filed on Jul. 28, 2016, which
is a continuation of U.S. Non-Provisional application Ser. No.
14/059,331, filed on Oct. 21, 2013, which is a continuation of U.S.
Non-Provisional application Ser. No. 13/553,645, filed on Jul. 19,
2012, now U.S. Pat. No. 8,591,672, which is a continuation of U.S.
Non-Provisional application Ser. No. 12/684,081, filed on Jan. 7,
2010, now U.S. Pat. No. 8,246,762, which claims priority from U.S.
Provisional Application Nos. 61/143,378, filed on Jan. 8, 2009,
61/168,554, filed on Apr. 10, 2009, and 61/260,363, filed on Nov.
11, 2009. The contents of each of the aforementioned applications
are expressly incorporated herein by reference in their
entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to biodegradable materials
useful for manufacturing implantable medical devices, specifically
biodegradable compositions comprising metal alloys that can provide
high strength when first implanted and are gradually eroded and
replaced with body tissue.
BACKGROUND OF THE INVENTION
[0003] Medical devices meant for temporary or semi-permanent
implant are often made from stainless steel. Stainless steel is
strong, has a great deal of load bearing capability, is reasonably
inert in the body, does not dissolve in bodily fluids, and is
durable, lasting for many years, if not decades. Long lasting
medical implants, however, are not always desirable. Many devices
for fixing bones become problematic once the bone has healed,
requiring removal by means of subsequent surgery. Similarly, short
term devices such as tissue staples have to be removed after the
tissue has healed, which limits their use internally.
[0004] Attempts to generate biodegradable materials have
traditionally focused on polymeric compositions. One example is
described in U.S. Pat. No. 5,932,459, which is directed to a
biodegradable amphiphilic polymer. Another example is described in
U.S. Pat. No. 6,368,356, which is directed to biodegradable
polymeric hydrogels for use in medical devices. Biodegradable
materials for use in bone fixation have been described in U.S. Pat.
No. 5,425,769, which is directed to CaSO.sub.4 fibrous collagen
mixtures. And U.S. Pat. No. 7,268,205 describes the use of
biodegradable polyhydroxyalkanoates in making bone fasteners such
as screws. However, none of the biodegradable polymeric materials
developed to date have demonstrated sufficient strength to perform
suitably when substantial loads must be carried by the material,
when the material is required to plastically deform during
implantation, or when any of the other native characteristic of
metal are required from the material. For example, the
polyhydroxyalkanoate compositions described in U.S. Pat. No.
7,268,205 do not have sufficient strength on their own to bear
weight and must be augmented by temporary fixation of bone
segments. In addition, biodegradable polymeric materials tend to
lose strength far more quickly than they degrade, because the
portions of the material under stress tend to be more reactive,
causing preferential dissolution and breakdown at load-bearing
regions.
[0005] Metals, particularly steels, are thus preferred for the
construction of many medical implants. The performance
characteristics of steel closely match the mechanical requirements
of many load bearing medical devices. Although ordinary steel
compounds, unlike stainless steel, will degrade in biological
fluids, they are not suitable for use in biodegradable implantable
medical devices. This is because ordinary steels do not degrade in
a predictable fashion, as one molecule or group of molecules at a
time, which can be easily disposed of by the body. Rather, because
of their large-grain structures, ordinary steels tend to break down
by first degrading at grain boundaries, causing fissures and
separations in the medical device, followed by rapid loss of
strength and integrity and particulation. Particulation of the
medical device is extremely dangerous because it allows small
pieces of the device to leave the area of implantation and become
lodged in other tissues, where they can cause serious injury
including organ failure, heart attack and stroke. The use of
ordinary steels in implantable medical devices is also complicated
by the fact that ordinary steels typically contain alloying
elements that are toxic when released in the body.
[0006] There remains a need in the field to develop implantable
medical devices that have desirable characteristics associated with
steel but are also biodegradable.
SUMMARY OF THE INVENTION
[0007] The invention is based, in part, on the discovery that
certain metal alloys having, e.g., a fine-grain, substantially
austenite structure will biodegrade over time without forming
emboli. The invention is also based, in part, on the discovery that
certain metal alloys having, e.g., a substantially martensite
structure will biodegrade over time without forming emboli. Such
alloys are useful for making biodegradable, implantable medical
devices.
[0008] Accordingly, in one aspect, the invention provides
implantable medical devices comprising a biodegradable alloy that
dissolves gradually from its exterior surface. In certain
embodiments, the rate of dissolution from the exterior surface of
the alloy is substantially uniform across smooth portions of the
exterior surface (e.g., substantially planar, concave, or convex
surfaces). In certain embodiments, the alloy has a fine-grain,
substantially austenite structure. In related embodiments, the
alloy has a substantially austenite structure that does not
preferentially degrade at grain boundaries. In other embodiments,
the alloy has a substantially martensite structure.
[0009] In certain embodiments, the implantable medical devices
comprise an alloy that is substantially austenite in structure and
has an average grain size of about 0.5 microns to about 20 microns.
For example, in certain embodiments, the average grain size is
about 0.5 microns to about 5.0 microns, or about 1.0 micron to
about 2.0 microns. In certain embodiments, the implantable medical
devices comprise an alloy that is substantially austenite in
structure, wherein the surface to volume ratio of individual grains
is, on average, greater than 0.1 .mu..sup.-1. For example, in
certain embodiments, the surface to volume ratio of individual
grains is, on average, greater than 1.0 .mu..sup.-1.
[0010] In certain embodiments, the implantable medical devices
comprise an alloy that is an iron alloy (e.g., a steel). For
example, in certain embodiments, the alloy contains about 55% to
about 80% iron. In certain embodiments, the alloy contains at least
two non-iron elements, wherein each of said at least two non-iron
elements is present in an amount of at least about 0.5%, and
wherein the total amount of said at least two elements makes up
greater than about 20% of the alloy. In certain embodiments,
greater than about 5% of the alloy consists of elements other than
iron, chromium, nickel, and carbon. In certain embodiments, the
implantable medical devices comprise an alloy that contains less
than about 0.1% nickel. In certain embodiments, the alloy contains
less than about 0.1% vanadium. In certain embodiments, the alloy
contains less than about 4.0% chromium. In certain embodiments, the
alloy contains less than about 6.0% cobalt. In certain embodiments,
the alloy contains less than about 0.1% nickel, less than about
0.1% vanadium, less than about 4.0% chromium, and less than about
6.0% cobalt. In certain embodiments, the alloy contains less than
about 0.1% of each of the elements in the set consisting of
platinum, palladium, iridium, rhodium, rhenium, rubidium, and
osmium. In certain embodiments, the alloy contains less than about
0.01% of phosphorus.
[0011] In certain embodiments, the implantable medical devices
comprise an alloy that comprises an austenite promoting component.
In certain embodiments, the amount of austenite promoting component
in the alloy is greater than about 10%. In certain embodiments, the
austenite promoting component comprises one or more elements
selected from the list consisting of manganese, cobalt, platinum,
palladium, iridium, aluminum, carbon, nitrogen, and silicon. In
certain embodiments, the austenite promoting component comprises
one or more elements selected from the list consisting of
manganese, cobalt, platinum, palladium, iridium, carbon, and
nitrogen, wherein % platinum+% palladium+% iridium+0.5*(%
manganese+% cobalt)+30*(% carbon+% nitrogen) is greater than about
12% (e.g., greater than about 14%, about 16%, about 18%, about 19%,
or about 20%).
[0012] In certain embodiments, the implantable medical devices
comprise an alloy comprising a corrosion resisting component. In
certain embodiments, the amount of corrosion resisting component in
the alloy is less than about 10% (e.g., about 0.5% to about 10%).
In certain embodiments, the corrosion resisting component comprises
one or more elements selected from the list consisting of chromium,
molybdenum, tungsten, tantalum, niobium, titanium, zirconium, and
hafnium. In certain embodiments, the corrosion resisting component
comprises one or more elements selected from the list consisting of
chromium, molybdenum, tungsten, tantalum, niobium, titanium,
zirconium, and hafnium, wherein % chromium+% molybdenum+%
tungsten+0.5*(% tantalum+% niobium)+2*(% titanium+% zirconium+%
hafnium) is about 0.5% to about 7% (e.g., about 6.0%, about 5.5%,
about 5.0%, about 4.5%, about 4.0%, about 3.5%, or about 3.0%).
[0013] In certain embodiments, the alloy comprises an austenite
promoting component and a corrosion resisting component. In certain
embodiments, the amount of austenite promoting component in the
alloy is greater than about 10% and the amount of corrosion
resisting component in the alloy is about 0.5% to about 10%.
[0014] In certain embodiments, the implantable medical device is a
high tensile bone anchor (e.g., for the repair of separated bone
segments). In other embodiments, the implantable medical device is
a high tensile bone screw (e.g., for fastening fractured bone
segments). In other embodiments, the implantable medical device is
a high strength bone immobilization device (e.g., for large bones).
In other embodiments, the implantable medical device is a staple
for fastening tissue. In other embodiments, the implantable medical
device is a craniomaxillofacial reconstruction plate or fastener.
In other embodiments, the implantable medical device is a dental
implant (e.g., a reconstructive dental implant). In still other
embodiments, the implantable medical device is a stent (e.g., for
maintaining the lumen of an opening in an organ of a human or
animal body).
[0015] In certain embodiments, the implantable medical device
comprises a geometry that maximizes the surface to mass ratio. For
example, in certain embodiments, the implantable medical device
comprises one or more openings (e.g., recesses) in the surface of
the device or one or more passageways through the device.
[0016] In certain embodiments, the implantable medical device
further comprises a therapeutic agent. In certain embodiments, the
therapeutic agent is coated upon the surface of the device. In
other embodiments, the therapeutic agent is incorporated into the
body of the device (e.g., into the pores of the alloy from which
the implantable medical device was made, into a recess in the
surface of the device, or in a passageway through the device).
[0017] In certain embodiments, the implantable medical device
further comprises a biodegradable gel. In certain embodiments, the
biodegradable gel is coated upon the surface of the device. In
other embodiments, the biodegradable gel is incorporated into the
body of the device (e.g., into the pores of the alloy from which
the implantable medical device was made, into a recess in the
surface of the device, or in a passageway through the device). In
certain embodiments, the biodegradable gel comprises a therapeutic
agent.
[0018] In another aspect, the invention provides a container
containing an implantable medical device of the invention. In
certain embodiments, the container further comprises an instruction
(e.g., for using the implantable medical device for a medical
procedure).
[0019] The invention and additional embodiments thereof will be set
forth in greater detail in the detailed description that
follows.
DETAILED DESCRIPTION OF THE INVENTION
[0020] As used herein, the term "percentage" when used to refer to
the amount of an element in an alloy means a weight-based
percentage. "Weighted percentages" of corrosion resisting and
austenite promoting components, however, are calculated in a manner
such that the weighted percentages do not necessarily correspond to
the actual weight-based percentages.
[0021] The object of the present invention is to provide medical
devices for temporary implantation in the body of a subject (e.g.,
a human or animal subject), wherein the devices are made using a
biodegradable alloy. The biodegradable alloy is one that is not a
stainless steel, but instead undergoes reactions involving normal
body chemistry to biodegrade or bio-absorb over time and be removed
by normal body processes. It is another object of the invention to
provide implantable medical devices made using a biodegradable
alloy that is non-toxic and/or non-allergenic as it is degrading
and being processed by the body. It is yet another object of the
invention to provide implantable medical devices made using a
biodegradable alloy that has little or no magnetic susceptibility
and does not distort MRI images.
[0022] The invention is thus based, in part, on the discovery that
certain alloys having, e.g., a fine-grain, substantially austenite
structure will biodegrade over time without forming emboli. These
austenite alloys exhibit little or no magnetic susceptibility and
can be made non-toxic and/or non-allergenic by controlling the
amounts of various metals (e.g., chromium and nickel) incorporated
into the alloys. The invention is also based, in part, on the
discovery that certain alloys having, e.g., a substantially
martensite structure will biodegrade over time without forming
emboli. These martensite alloys can also be made non-toxic and/or
non-allergenic by controlling the amounts of various metals (e.g.,
chromium and nickel) incorporated into the alloys. The alloys may
be incorporated into a variety of implantable medical devices that
are used to heal the body of a subject (e.g., a human or other
animal), but become unnecessary once the subject is healed. The
alloys can be used, for example, to make biodegradable, implantable
medical devices that require high strength, such as bone fasteners
for weight-bearing bones. The alloys can also be used to make
biodegradable, implantable medical devices that require ductility,
such as surgical staples for tissue fixation.
[0023] Accordingly, in one aspect, the invention provides
implantable medical devices comprising a biodegradable alloy that
dissolves from its exterior surface. As used herein, the term
"alloy" means a mixture of chemical elements comprising two or more
metallic elements. Biodegradable alloys suitable for making
implantable medical devices of the invention can be, for example,
iron alloys (e.g., steels). In certain embodiments, the iron alloys
comprise about 55% to about 65%, about 57.5% to about 67.5%, about
60% to about 70%, about 62.5% to about 72.5%, about 65% to about
75%, about 67.5% to about 77.5%, about 70% to about 80%, about
72.5% to about 82.5%, or about 75% to about 85% iron. The iron
alloys further comprise one or more non-iron metallic elements. The
one or more non-iron metallic elements can include, for example,
transition metals, such as manganese, cobalt, nickel, chromium,
molybdenum, tungsten, tantalum, niobium, titanium, zirconium,
hafnium, platinum, palladium, iridium, rhenium, osmium, rhodium,
etc., or non-transition metals, such as aluminum. In certain
embodiments, the iron alloys comprise at least two non-iron
metallic elements. The at least two non-iron elements can be
present in an amount of at least about 0.5% (e.g., at least about
1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 4.0%,
about 5.0%, or more). In certain embodiments, the iron alloys
comprise at least two non-iron metallic elements, wherein each of
said at least two non-iron elements is present in an amount of at
least about 0.5%, and wherein the total amount of said at least two
elements is at least about 15% (e.g., at least about 17.5%, about
20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%,
about 35%, about 37.5%, or about 40%). The biodegradable alloys can
also comprise one or more non-metallic elements. Suitable
non-metallic elements include, for example, carbon, nitrogen, and
silicon. In certain embodiments, the iron alloys comprise at least
about 0.01% (e.g., about 0.01% to about 0.10%, about 0.05% to about
0.15%, about 0.10% to about 0.20%, about 0.15% to about 0.25%, or
about 0.20% to about 0.30%) of at least one non-metallic
element.
[0024] Biodegradable alloys suitable for use in the implantable
medical devices of the invention are designed to degrade from the
outside inward, such that they maintain their strength for a
greater portion of their life and do not particulate or embolize.
Without intending to be bound by theory, it is believed that this
is accomplished by providing an alloy structure that either has no
appreciable reactive grain boundaries, forcing degradation to take
place at the surface molecular layer, or by providing a very fine
grain alloy that acts as a homogeneous, grain free material. In
certain embodiments, the rate of dissolution from an exterior
surface of a suitable biodegradable alloy is substantially uniform
at each point of the exterior surface. As used herein in this
context, "substantially uniform" means that the rate of dissolution
from a particular point on an exterior surface is +/-10% of the
rate of dissolution at any other point on the same exterior
surface. As persons skilled in the art will appreciate, the type of
"exterior surface" contemplated in these embodiments is one that is
smooth and continuous (i.e., substantially planar, concave, convex,
or the like) and does not include sharp edges or similar such
discontinuities, as those are locations where the rate of
dissolution is likely to be much higher. A "substantially" planar,
concave, or convex surface is a surface that is planar, concave,
convex, or the like and does not contain any bumps, ridges, or
grooves that rise above or sink below the surface by more than 0.5
mm.
[0025] Steel alloys have iron as their primary constituent.
Depending upon a combination of (i) the elements alloyed with the
iron and (ii) the historical working of the alloy, steels can have
different structural forms, such as ferrite, austenite, martensite,
cementite, pearlite, and bainite. In some instances, steels having
the same composition can have different structures. For example,
martensite steel is a form of high tensile steel that can be
derived from austenite steel. By heating austenite steel to between
1750.degree. F. and 1950.degree. F., and then rapidly cooling it to
below the martensite transition temperature, the face centered
cubic structure of the austenite steel will reorient into a body
centered tetragonal martensite structure, and the martensite
structure will freeze into place. Martensite steel does not have
appreciable grain boundaries, and thus provides no primary
dissolution path to the interior of the steel. The result is a slow
dissolution from the outside, without the formation of emboli.
Metallurgical examination of martensitic material will show
"pre-austenitic grain boundaries," places where the austenite grain
boundaries once existed, but these are nonreactive traces of the
former structure.
[0026] Accordingly, in certain embodiments, the biodegradable
implantable medical devices of the invention comprise an alloy
(e.g., an iron alloy) having a substantially martensite structure.
As used herein, the term "substantially martensite structure" means
an alloy having at least 90% martensite structure. In certain
embodiments, the alloy has at least 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, 99%, 99.5%, 99.8%, 99.9% or more martensite
structure.
[0027] The martensite alloy can have the composition of any alloy
described herein. For example, in certain embodiments, the
martensite alloy is formed from an austenite alloy described
herein. In certain embodiments, the martensite alloy comprises
carbon, chromium, nickel, molybdenum, cobalt, or a combination
thereof. For example, in certain embodiments, the martensite alloy
comprises (i) carbon, (ii) chromium and/or molybdenum, and (iii)
nickel and/or cobalt. In certain embodiments, the martensite alloy
comprises about 0.01% to about 0.15%, about 0.05% to about 0.20%,
about 0.10% to about 0.25%, about 0.01% to about 0.05%, about 0.05%
to about 0.10%, about 0.10% to about 0.15%, or about 0.15% to about
0.20% carbon. In certain embodiments, the martensite alloy
comprises about 0.1% to about 6.0%, about 1.0% to about 3.0%, about
2.0% to about 4.0%, about 3.0% to about 5.0%, or about 4.0% to
about 6.0% chromium. In certain embodiments, the martensite alloy
comprises about 0.1% to about 6.0%, about 0.5% to about 2.5%, about
1.0% to about 3.0%, about 1.5% to about 3.5%, about 2.0% to about
4.0%, about 2.5% to about 4.5%, about 3.0% to about 5.0%, about
3.5% to about 5.5%, or about 4.0% to about 6.0% molybdenum. In
certain embodiments, the martensite alloy comprises about 5.0% to
about 9%, about 6.0% to about 10%, about 7.0% to about 11%, about
8.0% to about 12%, about 9.0% to about 13%, about 10% to about 14%,
or about 11% to about 15% nickel. In certain embodiments, the
martensite alloy comprises about 5.0% to about 10%, about 7.5% to
about 12.5%, about 10% to about 15%, about 12.5% to about 17.5%, or
about 15% to about 20% cobalt.
[0028] In certain embodiments, the martensite alloy contains about
2.0% to about 6.0%, about 3.0% to about 7.0%, about 3.5% to about
7.5%, about 4.0% to about 8.0%, about 4.5% to about 8.5%, or about
5.0% to about 9.0% of a corrosion resisting component. In certain
embodiments, the martensite alloy contains about 2.5%, about 3.0%,
about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, or
about 6.0% of a corrosion resisting component. In certain
embodiments, the corrosion resisting component is calculated as a
sum of the percentages of corrosion resisting elements (e.g.,
chromium, molybdenum, tungsten, tantalum, niobium, titanium,
zirconium, hafnium, etc.) in the alloy. In other embodiments, the
corrosion resisting component is calculated as a weighted sum of
the corrosion resisting elements in the alloy. In certain
embodiments, individual elements in the weighted sum are weighted
according to their corrosion resisting efficacy, as compared to
chromium. In certain embodiments, the weighted % corrosion
resisting component is determined according to the formula: %
chromium+% molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(%
titanium+% zirconium+% hafnium).
[0029] In certain embodiments, the martensite alloy contains at
least about 10%, about 15%, about 18%, about 20%, about 22%, or
about 24% of a austenite promoting component. For example, in
certain embodiments, the martensite alloy contains about 10% to
about 20%, about 15% to about 25%, about 20% to about 30%, about
25% to about 35%, about 30% to about 40% of an austenite promoting
component. In certain embodiments, the martensite alloy comprises
about 22%, about 23%, about 24%, about 25%, about 26%, about 27%,
or about 28% of an austenite promoting component. In certain
embodiments, the austenite promoting component is calculated as a
sum of the percentages of austenite promoting elements (e.g.,
nickel, manganese, cobalt, platinum, palladium, iridium, aluminum,
carbon, nitrogen, silicon, etc.) in the alloy. In other
embodiments, the austenite promoting component is calculated as a
weighted sum of all the austenite promoting elements in the alloy.
In certain embodiments, individual elements in the weighted sum are
weighted according to their austenite promoting efficacy, as
compared to nickel. In certain embodiments, the weighted %
austenite promoting component is calculated according to the
formula: % nickel+% platinum+% palladium+% iridium+0.5*(%
manganese+% cobalt)+30*(% carbon+% nitrogen).
[0030] In certain embodiments, the martensite alloy comprises about
2.0% to about 4.0%, about 3.0% to about 5.0%, or about 4.0% to
about 6.0% of a corrosion resisting component, and about 10% to
about 20%, about 15% to about 25%, about 20% to about 30%, about
25% to about 35%, or about 30% to about 40% of an austenite
promoting component. For example, in certain embodiments, the
martensite alloy comprises about 3.0% to about 5.0% of a corrosion
resisting component and about 20% to about 30% of an austenite
promoting component. In certain embodiments, the corrosion
resisting and austenite promoting components are calculated as sums
of the percentages of corrosion resisting and austenite promoting
elements, respectively. In other embodiments, the corrosion
resisting and austenite promoting components are calculated as
weighted sums of the corrosion resisting and austenite promoting
elements, respectively.
[0031] While martensite alloys have the desirable characteristic of
lacking grain boundaries, austenite alloys are particularly useful
for medical implants because of their low magnetic susceptibility,
which can be useful where the alloy is exposed to a strong magnetic
field. It is desirable for medical implants to have low magnetic
susceptibility because they may be used in patients that would have
future need of Magnetic Resonance Imaging (MRI), which utilizes
very high magnetic fields. A magnetic reactive alloy in a strong
magnetic field can experience heating, causing local tissue stress
and damage to tissue surrounding the implant. Magnetic reactive
implants also distort MRI images, making them unreadable. In
addition, austenite alloys can provide certain mechanical benefits,
since they undergo larger plastic deformations between their
elastic limit (yield point) and ultimate failure, as compared to
martensite alloys. For example, whereas a martensite alloy may have
a maximum elongation of about 16% to 20%, an austenite alloy can
have a maximum elongation of about 50% to 60%.
[0032] Thus, in certain embodiments, the biodegradable implantable
medical devices of the invention comprise an alloy (e.g., an iron
alloy) having a substantially austenite structure. As used herein,
the term "substantially austenite structure" means at least 85%
austenite structure. In certain embodiments, the alloy has at least
88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%,
99.8%, 99.9% or more austenite structure. In certain embodiments,
the austenite alloy has substantially no martensite or ferrite
structure. As used herein , the term "substantially no martensite
or ferrite structure" means less than 5% (e.g., less than 4%, 3%,
2%, 1%, 0.5%, 0.2%, 0.1%, or 0.05%) martensite or ferrite
structure. In certain embodiments, the austenite alloy is
characterized by a maximum elongation of about 40% to about 65%
(e.g., about 50% to about 60%).
[0033] Austenitic steels have grains with defined boundaries of
irregular shape. Since austenite is a face centered cubic
structure, the grains tend to be cubic when viewed perpendicular to
a major lattice plane. In austenite alloys having either very low
carbon or very low chromium, it is possible to create a structure
with a fine grain size (e.g., about 0.5 to about 5.0 microns on a
side). A cubic austenite grain of 2.5 microns has a total surface
area of 37.5 square microns and a volume of 15.625 cubic microns,
for a surface to volume ratio of 2.4 .mu..sup.-1 and a total mass
of 0.12 micrograms. Because of the extremely small mass of the
grain, the grain material reacts as quickly as the grain boundary
material when placed in a biological environment, allowing the
alloy to shed material from the outside. This, in turn, prevents
weakening of the material bulk along grain boundaries and grain
separation from the material bulk of the alloy. As the size of
grains increase, however, the ratio of surface to volume decreases.
Each grain becomes bigger, taking longer to be absorbed, making it
more likely that dissolution will take place along grain
boundaries, penetrating deeper into the alloy's material bulk and
thereby reducing the strength of the alloy.
[0034] Accordingly, the rate of biodegradation of austenite alloys
can be altered by controlling the grain size and surface to volume
ratio of the individual grains. As the grain size increases, with a
commensurate decrease in the surface-to-volume ratio,
biodegradation progresses faster toward the center of the device,
increasing the total biodegradation rate. However, too large a
grain size can cause separation of grains and adverse effects.
[0035] In certain embodiments, the austenite alloy has an average
grain size of about 0.5 microns to about 20 microns on each side.
For example, in certain embodiments, the average grain size is
about 0.5 microns to about 5.0 microns, about 2.5 microns to about
7.5 microns, about 5.0 microns to about 10 microns, about 7.5
microns to about 12.5 microns, about 10 microns to about 15
microns, about 12.5 microns to about 17.5 microns, or about 15
microns to about 20 microns on each side. In certain embodiments,
the average grain size is about 0.5 to about 3.0 microns, or about
1.0 micron to about 2.0 microns on each side. In certain
embodiments, the austenite alloy has a structure wherein the
surface to volume ratio of individual grains is, on average,
greater than 0.1 .mu..sup.-1. For example, in certain embodiments,
the surface to volume ratio of individual grains is, on average,
greater than 0.2 .mu..sup.-1, 0.3 .mu..sup.-1, 0.4 .mu..sup.-1, 0.5
.mu..sup.-1, 0.6 .mu..sup.-1, 0.7 .mu..sup.-1, 0.8 .mu..sup.-1, 0.9
.mu..sup.-1, 1.0 .mu..sup.-1, 1.5 .mu..sup.-1, 2.0 .mu..sup.-1, 2.5
.mu..sup.-1, 3.0 .mu..sup.-1, 3.5 .mu..sup.-1, 4.0 .mu..sup.-1, 4.5
.mu..sup.-1, 5.0 .mu..sup.-1, 6.0 .mu..sup.-1, 7.0 .mu..sup.-1, 8.0
.mu..sup.-1, 9.0 .mu..sup.-1, 10.0 .mu..sup.-1, 11.0 .mu..sup.-1,
12.0 .mu..sup.-1, 13.0 .mu..sup.-1, 14.0 .mu..sup.-1, 15.0
.mu..sup.-1, or more.
[0036] Austenite grain sizes of about 0.5 microns to about 20
microns can be achieved by successive cycles of mechanical working
to break down the alloy, followed by thermal recrystallization. The
mechanical working of materials, whether done at cold temperatures
(i.e. room temperature to 200.degree. C.) or at elevated
temperatures, causes strain-induced disruption of the crystal
structure, by physically forcing the alloy into a new shape. The
most common method of mechanical working of metals is by reducing
the thickness of a sheet of metal between two high pressure rolls,
causing the exiting material to be substantially thinner (e.g.,
20%-60% thinner) than the original thickness. Other methods such as
drawing can also be employed. The process of mechanically working
metals breaks down larger, contiguous lattice units into different
structures. More importantly, it stores substantial strain-induced
energy into distorted lattice members, by straining lattice
structure distances to higher energy arrangements. Subsequent
low-temperature recrystallization, which takes place at about 0.35
to about 0.55 times the absolute melting temperature of the alloy,
allows the lattice structure to undergo rearrangements to a lower
energy condition, without changes to overall macro dimensions. To
accommodate lattice rearrangement without gross changes in
dimensions, the size of individual lattice sub-units, or grains, is
reduced, releasing substantial strain energy by breaking the
lattice into smaller sub-units, and producing a finer grain
structure. The process of mechanical working followed by
recrystallization can be repeated serially, producing finer and
finer grains.
[0037] In certain embodiments, the austenite alloy comprises
carbon. For example, in certain embodiments, the alloy comprises
about 0.01% to about 0.10%, about 0.02% to about 0.12%, about 0.05%
to about 0.15%, about 0.07% to about 0.17%, about 0.10% to about
0.20%, about 0.12% to about 0.22%, or about 0.15% to about 0.25%
carbon. In certain embodiments, the austenite alloy comprises one
or more (e.g., two or more) elements selected from the list
consisting of nickel, cobalt, aluminum, and manganese. In certain
embodiments, the alloy comprises about 2.0% to about 6.0%, about
3.0% to about 7.0%, about 4.0% to about 8.0%, or about 5.0% to
about 9.0% nickel. In other embodiments, the alloy comprises
substantially no nickel. In certain embodiments, the alloy
comprises about 10% to about 20%, about 15% to about 20%, about 15%
to about 25%, about 18% to about 23%, about 20% to about 25%, or
about 20% to about 30% cobalt. In certain embodiments, the alloy
comprises less than about 5.0% (e.g., less than about 4.5%, about
4.0%, about 3.5%, about 3.0%, or about 2.5%) manganese. In certain
embodiments, the alloy comprises about 0.5% to about 1.5%, about
1.0% to about 2.0%, or about 1.5% to about 2.5% manganese. In other
embodiments, the alloy comprises about 1.0% to about 8.0%, about
6.0% to about 10%, about 8.0% to about 12%, or about 10% to about
14% manganese. In certain embodiments, the austenite alloy
comprises one or more (e.g., two or more) elements selected from
the list consisting of chromium, molybdenum, and tantalum. In
certain embodiments, the alloy comprises about 0.5% to about 1.5%,
about 1.0% to about 2.0%, about 1.5% to about 2.5%, or about 2.0%
to about 3.0% chromium. In other embodiments, the alloy comprises
substantially no chromium. In certain embodiments, the alloy
comprises about 0.5% to about 1.5%, about 1.0% to about 2.0%, about
1.5% to about 2.5%, or about 2.0% to about 3.0% molybdenum. In
certain embodiments, the alloy comprises about 1.0% to about 3.0%,
about 2.0% to about 4.0%, about 3.0% to about 5.0%, or about 4.0%
to about 6.0% tantalum. In certain embodiments, the austenite alloy
comprises (i) carbon, (ii) at least two elements selected from the
list consisting of nickel, cobalt, aluminum, and manganese, and
(iii) at least two elements selected from the list consisting of
chromium, molybdenum, and tantalum.
[0038] Aside from the pattern of dissolution, the rate of
dissolution and the release of potentially toxic elements need to
be controlled in alloys used to make implantable medical devices of
the invention. The particular elements used to make up an alloy
help determine the physical and chemical properties of the
resulting alloy. For example, adding small amounts of carbon to
iron changes the structure of the iron, creating steel that is
greatly increased in hardness and strength, while changing the
plasticity relative to iron. Similarly, stainless steels are
fabricated by adding elements to the iron that decrease corrosion
(i.e., corrosion resisting components), such as chromium and
molybdenum. A stainless steel that resists corrosion in a
biological system can contain, for example, 18% chromium and 1%
molybdenum. Titanium, niobium, tantalum, vanadium, tungsten,
zirconium, and hafnium likewise provide a protective effect that
slows down the rate of degradation of steel in a biologic
system.
[0039] A stainless steel that does not break down in the intended
biological system is typically not suitable for use in a
biodegradable implant. Thus, alloys having large quantities of
corrosion resisting elements, such as chromium, molybdenum,
titanium, and tantalum, usually cannot be used to make
biodegradable implantable medical devices of the invention.
However, small quantities of such corrosion resisting elements are
useful for controlling the biodegradation rate of suitable alloys.
Accordingly, in certain embodiments, an alloy useful for making a
biodegradable implantable medical device of the invention (e.g., an
austenite alloy) contains at least about 0.5%, about 1.0%, about
1.5%, about 2.0%, about 2.5%, about 3.0%, or about 3.5%, but less
than about 15%, about 12%, about 11%, about 10%, about 9.0%, about
8.0% or about 7.0% of a corrosion resisting component. For example,
in certain embodiments, the alloy contains about 1.0% to about
7.0%, about 2.0% to about 8.0%, or about 3.0% to about 9.0% of a
corrosion resisting component. In certain embodiments, the alloy
(e.g., austenite alloy) contains about 3.0%, about 3.5%, about
4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%,
or about 7.0% of a corrosion resisting component. In certain
embodiments, the corrosion resisting component is calculated as a
sum of the percentages of corrosion resisting elements (e.g.,
chromium, molybdenum, tungsten, tantalum, niobium, titanium,
zirconium, hafnium, etc.) in the alloy. In other embodiments, the
corrosion resisting component is a weighted sum of all the
corrosion resisting elements in the alloy. For example, in certain
embodiments, individual elements in the weighted sum are weighted
according to their corrosion resisting efficacy, as compared to
chromium. In certain embodiments, the weighted % corrosion
resisting component is determined according to the formula: %
chromium+% molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(%
titanium+% zirconium+% hafnium).
[0040] Corrosion resisting elements, such as chromium and
molybdenum, are ferrite promoting and tend to cause steel to form a
ferritic structure. To overcome such ferrite promotion and achieve
an austenite structure, austenite promoting elements can be added
to the alloy. Austenite promoting elements include, for example,
nickel, manganese, cobalt, platinum, palladium, iridium, aluminum,
carbon, nitrogen, and silicon. Accordingly, in certain embodiments,
an alloy (e.g., an austenite alloy) useful for making an
implantable medical device of the invention contains an austenite
promoting component. In certain embodiments, the alloy contains
about 10% to about 20%, about 15% to about 25%, about 20% to about
30%, about 25% to about 35%, or about 30% to about 40% of an
austenite promoting component. In certain embodiments, the alloy
contains at least about 10%, about 12%, about 14%, about 16%, about
18%, about 20%, about 22%, about 24%, about 26%, about 28%, or
about 30% of an austenite promoting component. In certain
embodiments, the austenite promoting component is calculated as a
sum of the percentages of austenite promoting elements (e.g.,
nickel, cobalt, manganese, platinum, palladium, iridium, aluminum,
carbon, nitrogen, silicon, etc.) in the alloy. In other
embodiments, the austenite promoting component is a weighted sum of
the austenite promoting elements in the alloy. In certain
embodiments, individual elements in the weighted sum are weighted
according to their austenite promoting efficacy, as compared to
nickel. In certain embodiments, the weighted % austenite promoting
component is calculated according to the formula: % nickel+%
platinum+% palladium+% iridium+0.5*(% manganese+% cobalt)+30*(%
carbon+% nitrogen). In certain embodiments, the alloy contains a
weighted % austenite promoting component of about 15% to about 25%
(e.g., about 16%, about 17%, about 18%, about 19%, about 20%, about
21%, about 22%, about 23%, about 24%, or about 25%). In certain
embodiments, the alloy contains an unweighted % austenite promoting
component of about 25% to about 35% (e.g., about 28%, about 29%,
about 30%, about 31%, about 32%, about 33%, about 34%, or about
35%).
[0041] In certain embodiments, an alloy (e.g., an austenite alloy)
useful for making an implantable medical device of the invention
contains less than about 5.0% (e.g., about 0.1% to about 2.5%,
about 0.5% to about 3.0%, about 1.0% to about 3.5%, about 1.5% to
about 4.0%, or about 2.0% to about 4.5%) of platinum, iridium, and
osmium, either individually or in total. In certain embodiments,
the alloy contains substantially no platinum, palladium, or
iridium. As used herein, "substantially no" platinum, palladium, or
iridium means that the alloy contains less than 0.1% of platinum,
palladium, or iridium. In certain embodiments, the alloy contains
substantially none platinum, palladium, and iridium. In certain
embodiments, the alloys contain less than about 0.05%, or about
0.01% of each of platinum, palladium, or iridium. In certain
embodiments, the alloys contain less than about 0.05%, or less than
about 0.01%, of each of platinum, palladium, and iridium. In other
embodiments, the total amount of platinum, iridium, and osmium in
the alloy is about 5.0% or greater, and the alloy further comprises
at least one additional metal element other than iron, manganese,
platinum, iridium, and osmium (e.g., at least about 0.5% or more of
said at least one additional metal element). In certain
embodiments, the at least one addition metal element is a corrosion
resisting element (e.g., chromium, molybdenum, tungsten, titanium,
tantalum, niobium, zirconium, or hafnium) or a austenite promoting
element selected from the group consisting of nickel, cobalt, and
aluminum.
[0042] Biodegradable alloys implanted in a human or animal body
need to be relatively non-toxic because all of the elements in the
alloys will eventually be dissolved into body fluids. Nickel is
often used to stabilize an austenitic crystal structure. However,
many people have nickel allergies and cannot tolerate nickel ions
in their systems. Having nickel as part of a biodegradable alloy
guarantees that all of the nickel in the alloy will eventually be
absorbed by the host's body, which can cause complications in a
nickel sensitive individual. Likewise, chromium, cobalt, and
vanadium have some toxicity in the human body, and should be
minimized in a biodegradable alloy. Accordingly, in certain
embodiments, an alloy useful for making a biodegradable implantable
medical device of the invention (e.g., an austenite alloy) contains
less than about 9.0%, about 8.0%, about 7.0%, about 6.0%, about
5.0%, about 4.0%, about 3.0%, about 2.5%, about 2.0%, about 1.5%,
about 1.0%, or about 0.5% of each of nickel, vanadium, chromium,
and cobalt. In certain embodiments, the alloy contains
substantially no nickel. As used here, the phrase "substantially no
nickel" means that the alloy contains 0.1% or less nickel. In
certain embodiments, the alloy contains less than about 0.05%, less
than about 0.02%, or less than about 0.01% nickel. In certain
embodiments, the alloy contains substantially no vanadium. As used
here, the phrase "substantially no vanadium" means that the alloy
contains 0.1% or less vanadium. In certain embodiments, the alloy
contains less than about 0.05%, less than about 0.02%, or less than
about 0.01% vanadium. In certain embodiments, the alloy contains
less than about 4.0% chromium (e.g., less than about 3.0%, about
2.0%, or about 1.5%). In certain embodiments, the alloy contains
substantially no chromium. As used here, the phrase "substantially
no" chromium means that the alloy contains 0.1% or less chromium.
In certain embodiments, the alloy contains less than about 0.05%,
less than about 0.02%, or less than about 0.01% chromium. In
certain embodiments, the alloy contains less than about 6.0% (e.g.,
less than about 5.0%, about 4.0%, about 3.0%, about 2.0%, or about
1.0%) cobalt.
[0043] To remove or minimize toxic elements from the alloys used to
created the biodegradable implantable medical devices of the
invention, the toxic elements can be replaced with non-toxic
counterparts. For example, since nickel is used as an austenite
promoting element, it can be replaced with other austenite
promoting elements, such as manganese, cobalt, platinum, palladium,
iridium, aluminum, carbon, nitrogen, and silicon. Similarly, since
chromium is used as a corrosion resisting element, it can be
replaced with other corrosion resisting elements, such as
molybdenum, tungsten, titanium, tantalum, niobium, zirconium, and
hafnium. However, not all alloy substitutions are equivalent. For a
corrosion resisting effect, molybdenum is as effective as chromium,
while niobium and tantalum are only half as effective as chromium,
and titanium is twice as effective as chromium. For austenite
promoting effect, manganese and cobalt are only half as effective
as nickel, while carbon is 30 times more effective than nickel, and
nitrogen is 25-30 times more effective than nickel. Accordingly, in
certain embodiments, a biodegradable alloy is rendered
non-allergenic or less allergenic by replacing one part of nickel
with two parts manganese, one part of manganese and one part of
cobalt, or two parts of cobalt. In other embodiments, a
biodegradable alloy is rendered non-toxic or less toxic by
replacing one part of chromium with one part of molybdenum, half a
part of titanium, or two parts of tantalum or niobium. In certain
embodiments, the total percentage of nickel, cobalt and manganese
is from about 10% to about 20%, about 15% to about 25%, or about
20% to about 30%, about 25% to about 35%, or about 30% to about
40%, wherein the percentage of nickel is less than about 9.0%,
about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.0%, or
about 3.0%. In other embodiments, the total percentage of chromium
and molybdenum is from about 1.0% to about 7.0%, about 2.0% to
about 8.0%, about 3.0% to about 9.0%, or about 4.0% to about 10%,
wherein the amount of chromium is less than about 2.0%, about 1.5%,
about 1.0%, or about 0.5%.
[0044] Additional elements that can be included in alloys useful
for making biodegradable, implantable medical devices of the
invention include rhodium, rhenium, and osmium. In certain
embodiments, the amount of rhodium, rhenium, or osmium in the alloy
is less that about 5.0% (e.g., about 0.1% to about 2.5%, about 0.5%
to about 3.0%, about 1.0% to about 3.5%, about 1.5% to about 4.0%,
or about 2.0% to about 4.5%). In certain embodiments, there is
substantially no rhodium, rhenium, or osmium in the alloy. As used
herein, "substantially no" rhodium, rhenium, or osmium means that
the alloy contains less than about 0.1% of rhodium, rhenium, or
osmium. In certain embodiments, there is substantially none
rhodium, rhenium, and osmium in the alloy. In certain embodiments,
the alloy contains less than about 0.05%, or less than about 0.01%,
of rhodium, rhenium, or osmium. In certain embodiments, the alloy
contains less than about 0.05%, or less than about 0.01%, of each
of rhodium, rhenium, and osmium.
[0045] In certain embodiments, when one or more elements selected
from the group consisting of platinum, palladium, iridium, rhodium,
rhenium, and osmium is present in an alloy useful for making
biodegradable, implantable medical devices of the invention, the
amount of manganese in the alloy is less than about 5.0% (e.g.,
less than about 4.5%, about 4.0%, about 3.5%, about 3.0%, or about
2.5%). In other embodiments, when one or more elements selected
from the group consisting of platinum, palladium, iridium, rhenium,
rubidium, and osmium is present in the alloy and the amount of
manganese in the alloy is about 5.0% or greater (e.g., about 5.0%
to about 30%), then the alloy further comprises at least one
additional metal element. In certain embodiments, the at least one
addition metal element is a corrosion resisting element (e.g.,
chromium, molybdenum, tungsten, titanium, tantalum, niobium,
zirconium, or hafnium) or a austenite promoting element selected
from the group consisting of nickel, cobalt, and aluminum.
[0046] In certain embodiments, alloys useful for making
biodegradable, implantable medical devices of the invention contain
substantially no rubidium or phosphorus. As used herein,
"substantially no" rubidium or phosphorus means less than 0.1% of
rubidium of phosphorus. In certain embodiments, the alloys contain
substantially none rubidium and phosphorus. In certain embodiments,
the alloys contain less than about 0.05%, or less than about 0.01%,
of rubidium or phosphorus. In certain embodiments, the alloys
contain less than about 0.05%, or less than about 0.01%, of each of
rubidium and phosphorus.
[0047] In certain embodiments, the present invention provides
biodegradable implantable medical devices comprising a range of
biodegradable alloys (e.g., austenitic alloys) that are acceptably
non-allergenic, non-toxic, have little or no magnetic
susceptibility, and provide a useful range of degradation rates.
The following are exemplary boundaries defining alloys useful in
the biodegradable implantable medical devices of the present
invention: [0048] substantially no nickel; [0049] substantially no
vanadium; [0050] less than about 6.0% chromium; [0051] less than
about 10% cobalt; [0052] a corrosion resisting component of less
than about 10% (e.g., about 0.5% to about 10%); and [0053] an
austenite promoting component of at least about 10% (e.g., about
10% to about 40%).
[0054] In certain embodiments, the alloys contain about 55% to
about 80% iron. For example, in certain embodiments, the alloys
contain about 55% to about 65%, about 60% to about 70%, about 65%
to about 75%, about 70% to about 80% iron. In certain embodiments,
the amount of chromium is less than about 4.0% and the amount of
cobalt is less than about 6.0%. In certain embodiments, the amount
of chromium is less than about 2.0% and the amount of cobalt is
less than about 4.0%. In certain embodiments, the corrosion
resisting component is less than about 8.0% (e.g., about 0.5% to
about 8.0%) and the austenite promoting component is greater than
about 12%. In certain embodiments, the corrosion resisting
component is less than less than about 7.0% (e.g., about 0.5% to
about 7.0%) and the austenite promoting component is greater than
about 14%. In certain embodiments, the corrosion resisting
component is less than about 6.0% (e.g., about 0.5% to about 6.0%)
and the austenite promoting component is greater than about 16%. In
certain embodiments, the corrosion resisting and austenite
promoting components are calculated as sums of the percentages of
corrosion resisting and austenite promoting elements, respectively.
In other embodiments, the corrosion resisting and austenite
promoting components are calculated as weighted sums of the
corrosion resisting and austenite promoting elements, respectively.
In certain embodiments, the weighted % corrosion resisting
component is determined according to the formula: % chromium+%
molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(% titanium+%
zirconium+% hafnium). In certain embodiments, the weighted %
austenite promoting component is calculated according to the
formula: % nickel+% platinum+% palladium+% iridium+0.5*(%
manganese+% cobalt)+30*(% carbon+% nitrogen). In certain
embodiments, the alloys contain less than about 5.0% manganese
(e.g., less than about 4.5%, about 4.0%, about 3.5%, about 3.0%, or
about 2.5%). In certain embodiments, the alloys contain one or more
elements selected from the group consisting of platinum, palladium,
iridium, rhodium, rhenium, and osmium. In certain embodiments, the
alloys contain about 0.5% to about 5.0% of one or more elements
selected from the group consisting of platinum, palladium, iridium,
rhodium, rhenium, and osmium. In certain embodiments, the alloys
contain substantially none of the elements selected from the group
consisting of platinum, palladium, iridium, rhodium, rhenium, and
osmium. In certain embodiments, the alloys contain substantially
none of the elements selected from the group consisting of rubidium
and phosphorus.
[0055] The degradation of an entire implant is a function of the
mass of the implant as compared to its surface area. Implants come
in many different sizes and shapes. A typical coronary stent, for
example, weighs 0.0186 grams and has a surface area of 0.1584
square-inches. At a degradation rate of 1 mg/square-inch/day, a
coronary stent would loose 50% of its mass in 30 days. In
comparison, a 12 mm long cannulated bone screw weighs 0.5235 g and
has a surface area of 0.6565 square-inches. At the same degradation
rate of 1 mg/square-inch/day, the cannulated screw will loose half
of its mass in 363 days. Thus, as persons skilled in the art will
readily appreciate, it is desirable to have biodegradable alloys
that have a range of degradation rates to accommodate the variety
of implants used in the body of a subject.
[0056] In addition, the biodegradation rate of the implantable
medical devices of the present invention are significantly
influenced by the transport characteristics of the surrounding
tissue. For example, the biodegradation rate of an implant placed
into bone, where transport to the rest of the body is limited by
the lack of fluid flow, would be slower than a vascular stent
device that is exposed to flowing blood. Similarly, a biodegradable
device embedded in tissue would have slower degradation rate than a
device exposed to flowing blood, albeit a faster degradation rate
than if the device was embedded in bone. Moreover, different ends
of a medical device could experience different rates of degradation
if, for example, one end is located in bone and the other end is
located in tissue or blood. Modulation of biodegradation rates
based on the location of the device and ultimate device
requirements is thus desirable.
[0057] In order to control the dissolution rate of a medical device
independent of the geometric shape changes that occur as the device
degrades, several techniques have been developed. The first method
to alter the dissolution profile of a metallic device is to alter
the geometry of the device such that large changes in surface area
are neutralized. For example, the surface to mass ratio can be
increased or maximized. A substantially cylindrical device, which
would lose surface area linearly with the loss of diameter as the
device degrades, could have a concentric hole drilled through the
center of the device. The resulting cavity would cause a
compensating increase in surface area as alloy was dissolved from
the luminal surface of the device. As a result, the change in
surface area as the device degrades over time--and thus the change
in rate of degradation--would be minimize or eliminated. A similar
strategy of creating a luminal space (e.g., a luminal space that
has a shape similar to the outer surface of the device) could be
implemented with essentially any type of medical device.
[0058] Because biodegradation rates are partially a function of
exposure to bodily fluid flow, biodegradation rates can be modified
by coating (e.g., all or part of) the biodegradable implantable
medical device with a substance that protects the alloy surface.
For example, biodegradable hydrogels, such as disclosed in U.S.
Pat. No. 6,368,356, could be used to retard exposure of any parts
of a device exposed to mobile bodily fluids, thereby retard
dissolution and transport of metal ions away from the device.
Alternatively, medical devices can be constructed with two or more
different alloys described herein, wherein parts of the device that
are exposed to mobile bodily fluids are made from more corrosion
resistant alloys (i.e., alloys comprising higher amounts of a
corrosion resisting component), while parts of the device imbedded
in bone or tissue are made from less corrosion resistant alloys. In
certain embodiments, the different parts of the device can be made
entirely from different alloys. In other embodiments, parts of the
device exposed to mobile bodily fluids can have a thin layer or
coating of an alloy that is more corrosion resistant than the alloy
used to make the bulk of the device.
[0059] It is frequently desirable to incorporate bioactive agents
(e.g., drugs) on implantable medical devices. For example, U.S.
Pat. No. 6,649,631 claims a drug for the promotion of bone growth
which can be used with orthopedic implants. Bioactive agents may be
incorporated directly on the surface of an implantable medical
device of the invention. For example, the agents can be mixed with
a polymeric coating, such as a hydrogel of U.S. Pat. No. 6,368,356,
and the polymeric coating can be applied to the surface of the
device. Alternatively, the bioactive agents can be loaded into
cavities or pores in the medical devices which act as depots such
that the agents are slowly released over time. The pores can be on
the surface of the medical devices, allowing for relatively quick
release of the drugs, or part of the gross structure of the alloy
used to make the medical device, such that bioactive agents are
released gradually during most or all of the useful life of the
device. The bioactive agents can be, e.g., peptides, nucleic acids,
hormones, chemical drugs, or other biological agents, useful for
enhancing the healing process.
[0060] As persons skilled in the art will readily recognize, there
are a wide array of implantable medical devices that can be made
using the alloys disclosed herein. In certain embodiments, the
implantable medical device is a high tensile bone anchor (e.g., for
the repair of separated bone segments). In other embodiments, the
implantable medical device is a high tensile bone screw (e.g., for
fastening fractured bone segments). In other embodiments, the
implantable medical device is a high strength bone immobilization
device (e.g., for large bones). In other embodiments, the
implantable medical device is a staple for fastening tissue. In
other embodiments, the implantable medical device is a
craniomaxillofacial reconstruction plate or fastener. In other
embodiments, the implantable medical device is a dental implant
(e.g., a reconstructive dental implant). In still other
embodiments, the implantable medical device is a stent (e.g., for
maintaining the lumen of an opening in an organ of an animal
body).
[0061] Powdered metal technologies are well known to the medical
device community. Bone fasteners having complex shapes are
fabricated by high pressure molding of a powdered metal in a
carrier, followed by high temperature sintering to bind the metal
particles together and remove the residual carrier. Powdered metal
devices are typically fabricated from nonreactive metals such as
316LS stainless steel. The porosity of the finished device is
partially a function of the metal particle size used to fabricate
the part. Because the metal particles are much larger and
structurally independent of the grains in the metal's crystal
structure, metal particles (and devices made from such particles)
can be made from alloys of any grain size. Thus, biodegradable
implantable medical devices of the invention can be fabricated from
powders made from any of the alloys described herein. The porosity
resulting from the powdered-metal manufacturing technique, can be
exploited, for example, by filling the pores of the medical devices
with biodegradable polymers. The polymers can be used to retard the
biodegradation rates of all or part of the implanted device, and/or
mixed with bioactive agents (e.g., drugs) that enhance the healing
of the tissue surrounding the device. If the porosity of the
powdered metal device is filled with a drug, the drug will be
delivered as it becomes exposed by the degradation of the device,
thereby providing drug to the tissue site as long as the device
remains present and biodegrading.
[0062] In certain embodiments, the implantable medical device is
designed for implantation into a human. In other embodiments, the
implantable medical device is designed for implantation into a pet
(e.g., a dog, a cat). In other embodiments, the implantable medical
device is designed for implantation into a farm animal (e.g., a
cow, a horse, a sheep, a pig, etc.). In still other embodiments,
the implantable medical device is designed for implantation into a
zoo animal.
[0063] In another aspect, the invention provides a container
containing an implantable medical device of the invention. In
certain embodiments, the container is a packaging container, such
as a box (e.g., a box for storing, selling, or shipping the
device). In certain embodiments, the container further comprises an
instruction (e.g., for using the implantable medical device for a
medical procedure).
[0064] The following examples are intended to illustrate, but not
to limit, the invention in any manner, shape, or form, either
explicitly or implicitly. While the specific alloys described
exemplify alloys that could be used in implantable medical devices
of the invention, persons skilled in the art will be able to
readily identify other suitable alloys in light of the present
specification.
EXAMPLES
Example 1
[0065] A "condition A" martensitic steel composed of 0.23% carbon,
3.1% chromium, 11.1% nickel, 1.2% molybdenum, 13.4% cobalt and
70.97% iron was obtained from Carpenter Steel. The steel was heat
treated it in a reducing atmosphere at 1250.degree. C. for 12
hours, followed by slow cooling. Afterwards, the material was
tested for Rockwell Hardness, yielding a hardness range of 31-32 on
the Rockwell C scale. The steel was then cut into pieces of various
dimensions: [0066] (1) 0.514'' width by 0.0315'' length by 0.020''
thick, having a surface to volume ratio of about 167.4 and weighing
about 48.2 mg; [0067] (2) 0.514'' width by 0.0315'' length by
0.050'' thick, having a surface area to volume of about 107.4 and
weighing about 119.8 mg; and [0068] (3) 0.514'' width by 0.0315''
width by 0.500'' thick, having a surface to volume ratio of about
71.4 and weighing about 1207.7 mg.
[0069] Each piece of steel was immersed in 10 ml of human blood at
37.degree. C. under gentle rocking. At one week intervals the
pieces were retrieved, weighed and tested for Rockwell hardness.
The test pieces demonstrated a degradation rate matching the linear
formula L=0.74S, where L is the loss in milligrams per day and S is
the total surface area. No loss in hardness of the material was
apparent up the point that the material thickness became too thin
to measure, demonstrating that material loss was from the exterior
surfaces with no degradation of the interior material.
Example 2
[0070] An austenite steel comprising 0.1% carbon, 0.45% manganese,
and 99.45% iron and having no contaminating elements greater than
0.05% was obtained from a commercial source. The alloy was etched
and tested for grain size and Rockwell hardness. The alloy was then
cut into several pieces having dimensions of about 0.5'' wide by
about 0.5'' long by about 0.005'' thick.
[0071] The pieces of austenite steel were tested for hardness and
then immersed in 10 CC of blood at 37.degree. C. with gentile
agitation. The pieces were removed at weekly intervals, weighed,
tested for hardness and re-immersed in fresh blood for the next
period. The resulting dissolution into the blood samples followed
the linear formula L=1.05S, where L is the loss in milligrams per
day and S is the total surface area. No loss of hardness was
apparent up to the point that material thickness became too thin to
make a hardness measurement.
[0072] In both of the above experiments, the dissolution rate was
largely a function of the total surface area which, due to the
shape of the test pieces, changed very little throughout the
experiment. In device shapes more consistent with practical
implants, the surface of the device will be reduced in surface area
as the device is dissolved and replaced with body tissues. The
reduction in surface area will reduce the rate of metal loss,
causing the ultimate loss curve to be a geometric function of the
remaining device surface area. Thus, as persons skilled in the art
will readily appreciate, rate of loss of an implanted device will
largely be a function of the geometry of the device.
Example 3
[0073] Some examples of austenite alloys suitable for use in
implantable medical devices of the invention are as follows:
[0074] Alloy 1:
TABLE-US-00001 Carbon 0.1% Nickel 6.0% Cobalt 20.0% Manganese 1.0%
Chromium 2.0% Molydbenum 2.0% Iron 68.9%
[0075] Alloy 2:
TABLE-US-00002 Carbon 0.1% Nickel 6.0% Cobalt 20.0% Manganese 8.0%
Chromium 2.0% Tantalum 4.0% Iron 59.9%
[0076] Alloy 3:
TABLE-US-00003 Carbon 0.1% Nickel 0.0% Cobalt 20.0% Manganese 10.0%
Molydbenum 2.0% Tantalum 4.0% Iron 63.9%
[0077] Alloy 4:
TABLE-US-00004 Carbon 0.08% Nickel 0.0% Manganese 28.0% Titanium
3.0% Iron 68.92%
[0078] As persons skilled in the art will readily appreciate, the
foregoing alloys may contain some impurities that cause the actual
percentages of each element in the alloy to be slightly lower than
shown above.
Example 4
[0079] Thin flat samples approximately 0.5 inches square and 0.05
inches thick were prepared from a martensitic steel composed of
0.23% carbon, 3.1% chromium, 11.1% nickel, 1.2% molybdenum, 13.4%
cobalt, and the balance iron. The flat shape was chosen so that
there would be very little change in surface area as the samples
degraded. The samples were cleaned and weighed. All samples were
then immersed in buffered saline at 37.degree. C. with slow orbital
shaking. Half of the samples were allowed to oxidize in air,
forming protective chromium oxides on the surface prior to
immersion, and the other half were immersed immediately after
cleaning. Samples were removed at intervals between one week and
136 days dried and weighed. Samples that were immersed immediately
after cleaning experienced a constant weight loss of 1.1 mg per
square inch per day over the study period. Samples that were
oxidized prior to immersion experienced a weight loss of 0.6 mg per
day per square inch of surface. The protective effect of chromium
oxide reduced the degradation rate by approximately 50%.
Example 5
[0080] An austenitic alloy composed of 0.08% carbon, 18% manganese,
5% cobalt, 0.5% molybdenum, 1% tantalum, and 2% chromium was
melted, upset forged and hot rolled to approximately 0.094 inches
thick. The alloy had a hardness of approximately Rockwell C 45.
Samples were immersed in buffered saline at 37.degree. C. with slow
orbital shaking. The samples were periodically rinsed, dried and
weighed for a three month period. The samples experienced a
constant weight loss of 1.07 mg per square inch per day.
Example 6
[0081] An austenitic alloy composed of 0.08% carbon, 18% manganese,
5% cobalt, 0.5% molybdenum, 1% tantalum, and 2% chromium was
melted, upset forged and hot rolled to approximately 0.094 inches
thick. The alloy was further annealed at 1800.degree. F., after
which the alloy had a hardness of approximately Rockwell C 25.
Samples were immersed in buffered saline at 37.degree. C. with slow
orbital shaking. The samples were periodically rinsed, dried and
weighed for a three month period. The samples experienced a
constant weight loss of 0.92 mg per square inch per day.
Example 7
[0082] An austenitic alloy composed of 0.08% carbon, 18% manganese,
5% cobalt, 0.5% molybdenum, 1% niobium, and 2% chromium was melted,
upset forged and hot rolled to approximately 0.094 inches thick.
The alloy had a hardness of approximately Rockwell C 45. Samples
were immersed in buffered saline at 37.degree. C. with slow orbital
shaking. The samples were periodically rinsed, dried and weighed
for a three month period. The samples experienced a constant weight
loss of 1.08 mg per square inch per day.
Example 8
[0083] An austenitic alloy composed of 0.08% carbon, 18% manganese,
5% cobalt, 0.5% molybdenum, 1% niobium, and 2% chromium was melted,
upset forged and hot rolled to approximately 0.094 inches thick.
The alloy was further annealed at 1800.degree. F., after which the
alloy had a hardness of approximately Rockwell C 25. Samples were
immersed in buffered saline at 37.degree. C. with slow orbital
shaking. The samples were periodically rinsed, dried and weighed
for a three month period. The samples experienced a constant weight
loss of 0.98 mg per square inch per day.
[0084] Although the invention has been described with reference to
the presently preferred embodiments, it should be understood that
various changes and modifications, as would be obvious to one
skilled in the art, can be made without departing from the spirit
of the invention. Accordingly, the invention is limited only by the
following claims.
* * * * *