Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
Biodegradable metallic micro-structures.
The present application is a continuation-in-part of US patent application
16/015,461 filed June 22, 2018, which is a continuation-in-part of US patent
application 14/398,521 filed March 11, 2014, now issued as US patent
10,028,847, which is a national phase entry of PCT application
PCT/0A2013/000445, filed May 2, 2013, which claimed priority from US
provisional patent application number 61/641,398 filed May 2, 2012. The
contents of all these patent applications is hereby incorporated by reference
in
its entirety.
FIELD OF THE INVENTION
[0001] The present invention relates to the field of medicine and is more
particularly concerned with biodegradable temporary structures such as stents,
membranes, mesh, clips, sutures and implants.
BACKGROUND
[0002] Obstructive coronary diseases may be caused by a stable or an unstable
plaque. An unstable atherosclerotic plaque is vulnerable to rupture and to
subsequent thrombogenic reaction, which can lead to sudden death. In general,
when the associated stenosis of a stable plaque reaches a certain threshold,
it
may cause a lack of myocardium perfusion and associated chest pain or angina
pectoris.
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[0003] Historically, the first endovascular mechanical treatment was
introduced in
1977 by Andreas Gruentzig who introduced the angioplasty balloon. Percutaneous
angioplasty was however associated with a phenomenon called restenosis.
Restenosis is essentially the re-obstruction of the vessel caused by vessel
recoil,
remodeling and hyperplasia. In order to treat the acute recoil and limit the
restenosis process, Palmaz-Schatz introduced a new medical implant, the stent,
in
1986. A new phenomenon was then observed, in-stent restenosis, or the re-
obstruction inside the stent. However, the restenosis rates associated with
balloon
angioplasty (40-60%) were greatly improved with the advent of stents in 1986
(20-
30%) which nevertheless still constitutes a relatively high rate. In order to
treat the
in-stent restenosis process, Drug Eluting Stents (DES) were introduced. DES
were
initially coated with antiproliferative and anti-thrombotic compounds. The
first DES
(Cypher, Cordis) was approved in Europe in 2002. DES initially were effective
in
limiting restenosis with reported rates between 0 and 16%. However, a few
years
following their introduction, a serious phenomenon was reported. Late
thrombosis
(reported by Camenzin on the "Black Sunday" in 2006) was demonstrated to be
associated with DES. It was subsequently shown that the rate of late
thrombosis
continues to increase with time following the implantation. This is phenomenon
is
of great concern since thrombosis is a life threatening event possibly leading
to
myocardium infarction.
[0004] The causes of late thrombosis are not fully elucidated but processes
like
chemical compound effect, chronic inflammation and vessel wall injury are
reported in the literature. Concerning chronic inflammation and vessel wall
injury, a
direct link was demonstrated between stent fracture and In-Stent Restenosis
(ISR)
and thrombosis. ISR is observed both with bare metal stents (BMS) and DES with
respective rates of 20-25% and 0-16.7%. The relation with DES fracture was
shown to be more frequent than previously thought. The reason is that most of
the
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time stent fracture is clinically silent. However, with imaging modalities,
the
reported incidence is 1-2% and pathologic investigations reported an incidence
of
29% with about 5% associated with adverse effects: inflammation, ulceration,
avulsion, ISR, thrombosis.
[0005] Furthermore, it was also shown that stent fractures are correlated with
anatomical location (tortuosity), with stent fractures more common in the
Right
Coronary Artery (RCA) with a rate of 57% than in the Left Anterior Descending
(LAD) with a rate of 34%, and stent design and lesion types. In addition,
stress
fractures are also strongly correlated with time: stents may get fully broken
over
long periods of time. For example, a few broken struts have been reported
after
implantation times of about 172 d and full stent fracture after implantation
times of
1800 d.
[0006] This problem is inherently a mechanical problem linked to the notion of
fatigue of material. Every material subjected to cyclic loading, such as heart
beats,
will fatigue and eventually fail. Possible solutions for stent design include
developing a superior material for manufacturing the stent for higher
longevity and
biodegradable stents. Indeed, a biodegradable stent would essentially
disappear
once it has performed its temporary scaffolding task and thus avoid being
subjected to cyclic fatigue.
[0007] It is with this perspective that the lgaki-Tamai stent, the first
polymeric
biodegradable stent made of poly-L-lactide polymer, was introduced in 2003.
Since
polymers have mechanical properties that are about 2 orders of magnitude lower
than metals, mechanical integrity problems were reported, including acute
recoil.
Given their relative weaker mechanical properties, larger struts are required
to
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ensure proper scaffolding of the vascular wall. The thicker struts, in turn,
may
cause more resistance to blood flow and may be too large to implant in many
blood vessels. Their capacity to properly scaffold plaques with calcification
was
also mentioned. In addition, larger struts were also associated with more
vessel
injuries, thus potentially leading to more vessel response and hyperplasia.
[0008] At about the same time, biodegradable metallic stents were
investigated.
The principle was to exploit the property of reactive metals to corrode for
biodegradation. The initial selected metal was magnesium. The concept of
biodegradation has been shown to work. However, there are several limitations
associated with the use of magnesium (WE magnesium). Similarly to polymers,
magnesium has mechanical properties that are much lower than the current super
alloys used for commercial stents (such as 316L stainless steel, L605 cobalt-
chromium alloy). As a consequence, thicker struts are also required, and these
are
associated with the same problems of possible flow disturbances and wall
injury.
Indeed, negative remodelling was recently demonstrated with the use of the
magnesium-based stent.
[0009] More recently, other reactive metal alloys were investigated, including
iron-
manganese alloys and electroformed iron. These alloys have relatively better
mechanical strength than magnesium-based alloys. However, the iron-manganese
alloys have quite large metallic grains (100 microns), which is an issue given
that a
stent strut dimension is below 100 microns. Electroformed irons have much
smaller grain sizes (2-8 microns) but have limited ductility. Furthermore,
control of
the degradation rate of these alloys is a challenging task.
[0010] Some stents, such as the stent proposed in US Patent 8,080,055 by
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Atanasoska et al. and issued December 20, 2011, use galvanic corrosion between
a core of a stent and a coating made of a different material to promote
degradation
of the stent in situ. However, such stents require thick struts having a
layered
structure. This structure also results in heterogeneous degradation as the
cathodic
layers will remain uncorroded and the anodic layer will also degrade non-
homogeneously.
[0011] Accordingly, there is a need in the industry to provide an improved
bioresorbable stent and other bioresorbable medical devices, along with
methods
of manufacturing such medical devices. An object of the present invention is
therefore to provide such devices and methods.
SUMMARY OF THE INVENTION
[0012] In a broad aspect, the invention provides a bioresorbable stent, the
bioresorbable stent comprising: a bioresorbable material, the bioresorbable
material being an intermixed particulate material including cathodic particles
and
anodic particles bound to each other. The anodic particles are made of an
anodic
material and the cathodic particles are made of a cathodic material, the
anodic and
cathodic materials forming a galvanic couple with the anodic material being
electropositive and the cathodic material being electronegative. The anodic
and
cathodic particles are present in a predetermined ratio in the bioresorbable
material. The anodic particles, cathodic particles and predetermined ratio are
such
that bioresorption of the stent is promoted by galvanic corrosion between the
anodic and cathodic materials.
[0013] For the purpose of this document, the terminology "stent" refers to
structures to be used during medical interventions, on humans or animals, to
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maintain open or to open a cavity in biological tissues. For example, a stent
could
be used, among other uses, to maintain an artery open. Stents therefore also
include devices referred to in the current literature as "scaffolds".
[0014] In some embodiments, the cathodic and anodic particles are
substantially
homogeneously dispersed in the bioresorbable material.
[0015] In some embodiments, the anodic and cathodic materials are metallic.
[0016] Typically, the anodic and cathodic materials are biocompatible.
[0017] In some embodiments, the anodic material is selected from the group
consisting of iron, iron alloys and vanadium and the cathodic material is
selected
from the group consisting of cobalt-chromium alloys, stainless steel,
tantalum,
titanium and platinum-steels.
[0018] In some embodiments, the anodic material and cathodic material are
selected from the group of couples consisting of iron/stainless steel and
iron/tantalum.
[0019] In some embodiments, the anodic and cathodic particles are from about 1
m to about 30 m in average size.
[0020] In some embodiments, the stent is bioresorbable at a predetermined
rate;
and the anodic particles, cathodic particles and predetermined ratio are
selected
such that the stent is bioresorbable at the predetermined rate due to galvanic
corrosion between the anodic and cathodic materials.
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[0021] In some embodiments, the bioresorbable material further includes rate
control particles made of a rate control material and dispersed in the
bioresorbable
material; and the rate control particles affect the galvanic corrosion to
change the
predetermined rate in accordance with a predetermined rate change.
[0022] In some embodiments, the rate control particles increase the
predetermined rate. In other embodiments, the rate control particles decrease
the
predetermined rate. For example, the rate control material is selected from
the
group consisting of: salts, acids, solid electrolytes, ceramics, dielectrics
and metal
oxides.
[0023] In some embodiments, the bioresorbable material is an annealed
material.
[0024] In some embodiments, the anodic and cathodic particles include grains
of
about 1 pm or less in average size. In some embodiments, the anodic and
cathodic particles include grains of about 4 pm or less in average size. In
some
embodiments, the anodic and cathodic particles include grains of about 10 pm
or
less in average size.
[0025] In some embodiments, the anodic and cathodic materials have bulk
specific weights that differ by about 50% or less. In some embodiments, the
anodic and cathodic materials have bulk specific weights that differ by about
20%
or less.
[0026] In some embodiments, the anodic and cathodic materials have hardnesses
that differ by about 50% or less. In some embodiments, the anodic and cathodic
materials have hardnesses that differ by about 20% or less.
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[0027] In some embodiments, the predetermined ratio is about 4:1 w/w (weight
to
weight) or more in the anodic particles with respect to the cathodic
particles. In
some embodiments, the predetermined ratio is about 8:1 w/w or more in the
anodic particles with respect to the cathodic particles. In some embodiments,
the
predetermined ratio is about 20:1 w/w or more in the anodic particles with
respect
to the cathodic particles.
[0028] In some embodiments, the cathodic material is stainless steel and the
anodic material is iron.
[0029] In some embodiments, the bioresorbable material is substantially non-
porous. For example, the bioresorbable material has a porosity of about 0.2%
or
less.
[0030] In some embodiments, the stent is entirely made of the bioresorbable
material. In other embodiments, the stent further comprises a non-
bioresorbable
portion.
[0031] In another broad aspect, the invention provides a method for
manufacturing a bioresorbable stent, the method comprising: providing an
anodic
powder including anodic particles made of an anodic material; providing a
cathodic
powder including cathodic particles made of a cathodic material, the anodic
and
cathodic materials forming a galvanic couple; mixing the anodic and cathodic
powders together in a predetermined ratio to obtain a mixed powder; cold
spraying
the mixed powder on a substrate to obtain a bioresorbable material; and
processing the bioresorbable material to form the bioresorbable stent. The
anodic
particles, cathodic particles and predetermined ratio are selected so that
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bioresorption of the stent is promoted by galvanic corrosion between the
anodic
and cathodic materials.
[0032] The specific details regarding some embodiments of the stent described
hereinabove apply to the present method.
[0033] In some embodiments, the method further comprises providing a
bioresorption rate control powder including rate control particles made of a
rate
control material. Mixing the anodic and cathodic powders together includes
also
mixing a rate control quantity of the bioresorption rate control powder with
the
anodic and cathodic powders to obtain the mixed powder. The bioresorption rate
control powder affects the galvanic corrosion to change the predetermined rate
in
accordance with a predetermined rate change.
[0034] In some embodiments, the substrate has a substantially planar form, or
cylindrical form, or thick plate form, or thin sheet form.
[0035] In some embodiments, processing the bioresorbable material to form the
bioresorbable stent includes taking a slice of a predetermined thickness of
the
bioresorbable material and shaping the slice to form the bioresorbable stent,
the
slice including substantially opposed slice first and second side edges.
[0036] In some embodiments, taking the slice of the predetermined thickness of
the bioresorbable material includes cutting the slice with electrical
discharge
machining methods (EDM). The EDM methods can be also used to cut the shape
of the final stent blank in a tubular form.
[0037] In some embodiments, processing the bioabsorbable material to form the
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tubular stent blanks includes CNC machining methods such as CNC Turning
operations or CNC Milling operations.
[0038] In some embodiments, taking the slice of the predetermined thickness of
the bioresorbable material includes cutting the slice with electrical
discharge
machining methods (EDM). The EDM methods can be also used to cut the shape
of the final stent blank in a tubular form.
[0039] In some embodiments, shaping the slice includes folding the slice to
form a
cylinder so that the slice first and second side edges are substantially
adjacent to
each other and welding the slice first and second side edges to each other.
[0040] In some embodiments, shaping the slice includes embossing the slice to
form a half-cylinder and welding a similar half-cylinder thereto to form a
complete
cylinder.
[0041] In some embodiments, shaping the slice to form the stent includes
forming
a substantially cylindrical stent blank and cutting out portions of the stent
blank to
define stent struts.
[0042] In some embodiments, cutting out portions of the stent blank includes
laser
cutting the portions of the stent blank under conditions maintaining the stent
blank
under an annealing temperature of the anodic and cathodic materials.
[0043] In some embodiments, cutting out portions of the stent blank includes
laser
cutting the portions of the stent blank using picosecond or femtosecond laser
equipment.
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[0044] In some embodiments, the method further comprises annealing the
bioresorbable material.
[0045] In some embodiments, the bioresorbable material is annealed under
conditions resulting in grains of the anodic and cathodic materials in the
anodic
and cathodic particles to remain below about 1 pm in average size. In some
embodiments, the bioresorbable material is annealed under conditions resulting
in
grains of the anodic and cathodic materials in the anodic and cathodic
particles to
remain below about 4 pm in average size. In some embodiments, the
bioresorbable material is annealed under conditions resulting in grains of the
anodic and cathodic materials in the anodic and cathodic particles to remain
below
about 10 pm in average size. In some embodiments, the bioresorbable material
is
dynamically annealed. In some embodiments, the bioresorbable material is
annealed at a temperature between 70% and 90% of a melting temperature of a
lowest melting temperature material selected from the anodic and cathodic
materials.
[0046] In some embodiments, the substrate is substantially planar and
processing
the bioresorbable material to form the bioresorbable stent includes cutting a
cylinder in the bioresorbable material and emptying the cylinder to form a
stent
blank.
[0047] In yet another broad aspect, the invention provides a bioresorbable
material, the bioresorbable material being an intermixed particulate material
comprising cathodic particles and anodic particles bound to each other. The
anodic particles are made of an anodic material and the cathodic particles are
made of a cathodic material, the anodic and cathodic materials forming a
galvanic
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couple. The anodic and cathodic particles are present in a predetermined ratio
in
the bioresorbable material. The anodic particles, cathodic particles and
predetermined ratio are such that bioresorption of the bioresorbable material
is
promoted by galvanic corrosion between the anodic and cathodic materials.
[0048] The specific details regarding some embodiments of the stent and the
bioresorbable material from which the stent is made as described hereinabove,
apply to some embodiments of the present bioresorbable material.
[0049] In yet another broad aspect, the invention provides an intermixed
particulate material comprising: cathodic particles and anodic particles bound
to
each other, the anodic particles being made of an anodic material and the
cathodic
particles being made of a cathodic material, the anodic and cathodic materials
forming a galvanic couple.
[0050] The specific details regarding some embodiments of the stent and the
bioresorbable material from which the stent is made, as described hereinabove,
apply to some embodiments of the present particulate material.
[0051] In yet another broad aspect, the invention provides a method for
manufacturing an intermixed particulate material, the method comprising:
providing an anodic powder including anodic particles made of an anodic
material;
providing a cathodic powder including cathodic particles made of a cathodic
material, the anodic and cathodic materials forming a galvanic couple; mixing
the
anodic and cathodic powders together in a predetermined ratio to obtain a
mixed
powder; and cold spraying the mixed powder on a substrate to obtain the
intermixed particulate material.
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[0052] The specific details regarding some embodiments of the stent and the
bioresorbable material from which the stent is made, as described hereinabove,
apply to some embodiments of the present method.
[0053] In yet another broad aspect, the invention provides a method for
manufacturing a bioresorbable medical device, the method comprising: providing
an anodic powder including anodic particles made of an anodic material;
providing
a cathodic powder including cathodic particles made of a cathodic material,
the
anodic and cathodic materials forming a galvanic couple; mixing the anodic and
cathodic powders together in a predetermined ratio to obtain a mixed powder;
cold
spraying the mixed powder on a substrate to obtain a bioresorbable material;
and
processing the bioresorbable material to form the bioresorbable medical
device.
The anodic particles, cathodic particles and predetermined ratio are such that
bioresorption of the stent is promoted by galvanic corrosion between the
anodic
and cathodic materials.
[0054] The specific details regarding some embodiments of the stent and the
bioresorbable material from which the stent is made, as described hereinabove,
apply to some embodiments of the present method.
[0055] In some embodiments, the medical device is selected from the group
consisting of stents, scaffolds, markers, anchors, clips, occluders, sutures,
surgical
devices and orthopedic support devices.
[0056] In yet another broad aspect, the invention provides a method of
implanting
a bioresorbable stent in a patient, the method comprising: determining a
desired
resorption rate of the bioresorbable stent based on the satisfaction of
predetermined criteria by the patient; selecting a patient stent from a set of
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predetermined stents, the predetermined stents being as defined above, the
patient stent having the desired resorption rate when implanted in the
patient; and
implanting the patient stent in the patient. In some embodiments, the method
further comprises resorbing the stent in the patient at the desired resorption
rate.
[0057] Advantageously, in some embodiments of the invention, a relatively
small
bioresorbable stent that is nevertheless strong and ductile enough can be
manufactured using the proposed material.
[0058] In yet another broad aspect, there is provided a method for
manufacturing
a bioresorbable stent, the method comprising: providing a mixed powder
including
anodic particles made of a metallic anodic material and cathodic particles
made of
a metallic cathodic material, the anodic and cathodic materials forming a
galvanic
couple; cold spraying the mixed powder on a substrate to obtain an amalgamated
material; forming a substantially tubular stent blank made of the amalgamated
material by machining the amalgamated material using electrical discharge
machining (EDM); removing selected portion of the stent blank to form the
stent;
wherein the anodic particles, cathodic particles and predetermined ratio are
selected so that bioresorption of the stent is promoted by galvanic corrosion
between the anodic and cathodic materials.
[0059] The material formed through cold-spray is an amalgamated material in
which the various particles contained in the mixed powder have been
amalgamated, or in other words stuck to each other, using cold spraying.
[0060] There may be provided a method further comprising removing the
amalgamated material from the substrate and annealing the amalgamated
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material removed from the substrate before forming the stent blank.
[0061] There may be provided a method wherein the amalgamated material is
annealed under conditions resulting in grains of the anodic and cathodic
materials
in the anodic and cathodic particles to remain below about 1 pm in average
size.
[0062] There may be provided a method wherein the amalgamated material is
annealed under conditions resulting in grains of the anodic and cathodic
materials
in the anodic and cathodic particles to remain below about 4 pm in average
size.
[0063] There may be provided a method wherein the amalgamated material is
annealed under conditions resulting in grains of the anodic and cathodic
materials
in the anodic and cathodic particles to remain below about 10 pm in average
size.
[0064] There may be provided a method wherein the amalgamated material is
annealed at a temperature below a sintering temperature of the amalgamated
material.
[0065] There may be provided a method wherein the amalgamated material is
annealed at a temperature between 70% and 90% of a melting temperature of a
lowest melting temperature material selected from the anodic and cathodic
materials.
[0066] There may be provided a method wherein the cathodic material is
stainless
steel and the anodic material is iron.
[0067] There may be provided a method wherein the amalgamated material is
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annealed at an annealing temperature of between 800 C and 1400 C for an
annealing duration of 30 minutes to 4 hours.
[0068] There may be provided a method wherein the annealing temperature is
between 1100 C and 1300 C and the annealing duration is between 1 and 3
hours.
[0069] There may be provided a method wherein the amalgamated material is
brought from room temperature to the annealing temperature at a predetermined
heating rate.
[0070] There may be provided a method wherein the predetermined heating rate
is between about 100 and about 400 C/hr.
[0071] There may be provided a method wherein the amalgamated material is
brought from annealing temperature to the room temperature at a predetermined
cooling rate.
[0072] There may be provided a method wherein the predetermined cooling rate
is between about 100 and about 400 C/hr.
[0073] There may be provided a method wherein the anodic material is selected
from the group consisting of iron, iron alloys and vanadium and the cathodic
material is selected from the group consisting of cobalt-chromium alloys,
stainless
steel, tantalum, titanium and platinum-steels.
[0074] There may be provided a method wherein the anodic material and cathodic
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material are selected from the group of couples consisting of iron/stainless
steel
and iron/tantalum.
[0075] There may be provided a method wherein the stent blank defines a
longitudinally extending stent passageway, the stent passageway being formed
in
the amalgamated material before a peripheral surface of the stent blank is
machined.
[0076] There may be provided a method wherein forming the stent passageway
includes forming a pilot hole in the amalgamated material, inserting an EDM
wire
in the pilot hole, and enlarging the pilot hole to a predetermined diameter
using
wire EDM.
[0077] There may be provided a method wherein the anodic and cathodic
particles are from about 1 pm to about 30 pm in average size.
[0078] There may be provided a method wherein the anodic and cathodic
particles include grains of about 1 pm or less in average size.
[0079] There may be provided a method wherein the anodic and cathodic
particles include grains of about 4 pm or less in average size.
[0080] There may be provided a method wherein the anodic and cathodic
particles include grains of about 10 pm or less in average size.
[0081] There may be provided a method wherein the anodic and cathodic
materials have bulk specific weights that differ by about 50% or less.
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[0082] There may be provided a method wherein the anodic and cathodic
materials have bulk specific weights that differ by about 20% or less.
[0083] There may be provided a method wherein the anodic and cathodic
materials have hardnesses that differ by about 50% or less.
[0084] There may be provided a method wherein the anodic and cathodic
materials have hardnesses that differ by about 20% or less.
[0085] There may be provided a method wherein the predetermined ratio is about
4:1 w/w or more in the anodic particles with respect to the cathodic
particles.
[0086] There may be provided a method wherein the predetermined ratio is about
8:1 w/w or more in the anodic particles with respect to the cathodic
particles.
[0087] There may be provided a method wherein the predetermined ratio is about
20:1 w/w or more in the anodic particles with respect to the cathodic
particles.
[0088] There may be provided a method wherein the mixed powder includes rate
control particles made of a rate control material, the rate control material
affecting
the galvanic corrosion to change the predetermined rate in accordance with a
predetermined rate change.
[0089] There may be provided a method wherein the bioresorption rate control
powder increases the predetermined rate.
[0090] There may be provided a method wherein the bioresorption rate control
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powder decreases the predetermined rate.
[0091] There may be provided a method wherein the rate control material is
selected from the group consisting of: salts, acids, solid electrolytes,
ceramics,
dielectrics and metal oxides.
[0092] There may be provided a method wherein the EDM is performed with the
amalgamated material immersed in an oil-based dielectric fluid. The oil-based
dielectric fluid is a fluid that will not promote corrosion of the amalgamated
material.
[0093] There may be provided a method wherein the oil-based dielectric fluid
is
actively circulated to promote heat removal from the amalgamated material
during
machining.
[0094] In yet other embodiments, bioresorbable stents are manufactured from
wires or stacked and folded sheets of material including a mix of anodic and
galvanic material building elements. For example, a wire or set of wires may
be
braided or twisted together using smaller filaments of an anodic material and
filaments of a cathodic material. Such wires can then be used to manufacture
wire
stents and other medical devices. Braiding is performed so that the cathodic
and
anodic material are in contact with each other at multiple locations there
along with
specific and predetermined alternating of the filaments. Such a wire or
individual
filaments may be used to make a bioresorbable fabric. In other embodiments,
thin
foils or cathodic and anodic materials are stacked and bonded to each other.
Folding the foils allows to the anodic and cathodic alternation to make
bioresorbable structures.
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[0095] In yet another broad aspect, the invention provides a bioresorbable
stent,
comprising: an anodic material in filament form and a cathodic material in
filament
form, the anodic and cathodic materials being metallic and forming a galvanic
couple, the anodic and cathodic materials being distributed in the stent so
that the
anodic and cathodic materials contact each other at a plurality of junctions;
wherein bioresorption of the stent is promoted by galvanic corrosion between
the
anodic and cathodic materials at the junctions.
[0096] There may also be provided a bioresorbable stent wherein at least one
anodic filament made of the anodic material and at least one cathodic filament
made of the cathodic material are braided together in a wire, the wire
including at
least some of the plurality of junctions.
[0097] There may also be provided a bioresorbable stent wherein the anodic and
cathodic filaments are also braided with a carrier filament.
[0098] There may also be provided a bioresorbable stent wherein the carrier
filament is metallic.
[0099] There may also be provided a bioresorbable stent wherein the carrier
filament is made of a material that differs from the anodic and cathodic
materials.
[00100] There may also be provided a bioresorbable stent wherein the anodic
and
cathodic filaments have different pitches relative to the wire.
[00101] There may also be provided a bioresorbable stent wherein the
bioresorbable stent is a wire stent made of one or more of the wires.
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[00102] There may also be provided a bioresorbable stent wherein a plurality
of
anodic filament segments made of the anodic material and a plurality of
cathodic
filament segments made of the cathodic material are weaved together in a
fabric,
the fabric including at least some of the plurality of junctions.
[00103] There may also be provided a bioresorbable stent wherein the anodic
filament segments are substantially parallel to each other in the fabric and
the
cathodic filament segments are substantially parallel to each other in the
fabric,
the anodic filament segment being substantially perpendicular to the cathodic
filament segments.
[00104] There may also be provided a bioresorbable stent wherein one of the
anodic and cathodic materials forms a base grid defining a plurality of grid
apertures and another one of the anodic and cathodic materials is crocheted
into
the base grid through the apertures.
[00105] There may also be provided a bioresorbable stent wherein at least one
of
the cathodic and anodic materials are in beaded filament form.
[00106] There may also be provided a bioresorbable stent wherein both the
cathodic and anodic materials are in beaded filament form.
[00107] There may also be provided a bioresorbable stent wherein the cathodic
and anodic filaments are under tension and the junctions are created due to
normal forces between the filaments at locations where the filaments
intersect.
[00108] There may also be provided a bioresorbable stent wherein the cathodic
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and anodic materials are sintered to each other.
[00109] There may also be provided a bioresorbable stent wherein the anodic
material is selected from the group consisting of iron, iron alloys, mild
steel and
vanadium and the cathodic material is selected from the group consisting of
cobalt-chromium alloys, stainless steel, mild steel, tantalum, titanium and
platinum-steels.
[00110] There may also be provided a bioresorbable stent wherein the anodic
material and cathodic material are selected from the group of couples
consisting of
iron/stainless steel, two different mild steels and iron/tantalum.
[00111] There may also be provided a bioresorbable stent wherein the cathodic
and anodic materials have different diameters.
[00112] There may also be provided a bioresorbable stent wherein a total
length
of the anodic material in the bioresorbable stent differs from a total length
of the
cathodic material in the bioresorbable stent.
[00113] In yet another broad aspect, there is provided a bioresorbable stent,
comprising a plurality of layers alternating between cathodic layers and
anodic
layers forming alternating galvanic couples promoting galvanic corrosion
between
the anodic and cathodic layers.
[00114] There may also be provided a bioresorbable stent wherein all the
cathodic
layers are made of a same cathodic material and all the anodic layers are made
of
a same anodic material, the anodic and cathodic materials forming a galvanic
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couple.
[00115] There may also be provided a bioresorbable stent wherein the anodic
material is selected from the group consisting of iron, iron alloys, mild
steel and
vanadium and the cathodic material is selected from the group consisting of
cobalt-chromium alloys, stainless steel, mild steel, tantalum, titanium and
platinum-steels.
[00116] There may also be provided a bioresorbable stent wherein the anodic
material and cathodic material are selected from the group of couples
consisting of
iron/stainless steel, two mild steels of different compositions and
iron/tantalum.
[00117] There may also be provided a bioresorbable stent wherein the anodic
layers are thinner than the cathodic layers.
[00118] There may also be provided a bioresorbable stent wherein the anodic
layers are thicker than the cathodic layers.
[00119] There may also be provided a bioresorbable stent wherein the anodic
layers and cathodic layers define concentric cylindrical layers.
[00120] There may also be provided a bioresorbable stent wherein the anodic
layers are formed by a cathodic spiralling sheet made of the cathodic material
an
the anodic layers are formed by an anodic spiralling sheet made of the anodic
material and parallel to the cathodic spiralling sheet.
[00121] There may also be provided a bioresorbable stent wherein the cathodic
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material includes a plasma deposited layer deposited the anodic material.
[00122] There may also be provided a bioresorbable stent wherein the anodic
material includes a plasma deposited layer deposited the cathodic material.
[00123] In yet another broad aspect, there is provided a method of
manufacturing
a bioresorbable wire, the method comprising braiding together at least two
metallic
filaments having different galvanic potentials. For example, the two filaments
are
different mild steels.
[00124] Other objects, advantages and features of the present invention will
become more apparent upon reading of the following non-restrictive description
of
preferred embodiments thereof, given by way of example only and in relation
with
the following Figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[00125] Figure 1, in a flow chart, illustrates a method for manufacturing a
stent in
accordance with an embodiment of the present invention;
[00126] Figures 2A to 20, in photographs, illustrate a stent manufactured
using
the method of Fig. 1;
[00127] Figure 3, in an X-Y graph, illustrates mass loss per unit area for
iron/stainless steel samples made in accordance with the method of Fig. 1 for
pure
iron (FE), pure stainless steel (316L alloy) and various mixtures of iron and
stainless steel;
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[00128] Figure 4, in an X-Y graph, illustrates corrosion rate obtained from
the data
shown in Fig. 3;
[00129] Figure 5, in an X-Y graph, illustrates polarization curves used to
determine in an alternative manner the corrosion rate for the samples used to
obtain the data presented in Figs. 3 and 4;
[00130] Figure 6, in an Electron BackScatter Diffraction (EBSD) Euler angle
map,
illustrates the microstructure of the material used to manufacture the stent
of Fig.
2;
[00131] Figure 7A, in a schematic view, illustrates a step in manufacturing a
stent
in accordance with an embodiment of the present invention;
[00132] Figure 7B, in a schematic view, illustrates another step in
manufacturing a
stent in accordance with an embodiment of the present invention;
[00133] Figure 70, in a schematic view, illustrates yet another step in
manufacturing a stent in accordance with an embodiment of the present
invention;
[00134] Figure 7D, in a schematic view, illustrates yet another step in
manufacturing a stent in accordance with an embodiment of the present
invention;
[00135] Figure 7E, in a schematic view, illustrates yet another step in
manufacturing a stent in accordance with an embodiment of the present
invention;
[00136] Figure 7F, in a schematic view, illustrates yet another step in
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manufacturing a stent in accordance with an embodiment of the present
invention;
[00137] Figure 7G, in a schematic view, illustrates yet another step in
manufacturing a stent in accordance with an embodiment of the present
invention;
[00138] Figure 7H, in a schematic view, illustrates yet another step in
manufacturing a stent in accordance with an embodiment of the present
invention;
[00139] Figure 8, in a schematic form, illustrates braiding of filaments
having
different compositions to manufacture a bioresorbable wire;
[00140] Figure 9, in a schematic view, illustrates braiding of filaments to
manufacture a bioresorbable wire;
[00141] Figure 10A, in a schematic form, illustrates a sheet usable to
manufacture
a stent blank;
[00142] Figure 10B, in a schematic form, illustrates the sheet of FIG. 10A
curved
to manufacture a stent blank;
[00143] Figure 100, in a schematic form, illustrates the sheet of FIG. 10A
forming
a cylindrical stent blank;
[00144] Figure 10D, in a schematic form, illustrates a stent blank formed from
many sheets of FIG. 10A superposed in concentric cylinders;
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[00145] Figure 10E, in a schematic form, illustrates a stent blank formed by
spiralling the sheet of FIG. 10A onto itself;
[00146] Figure 11, in a schematic view, illustrates a weaving with two
different
metallic wires;
[00147] Figure 12, in a schematic view, illustrates a beaded filament;
[00148] Figure 13, in a schematic view, illustrates crocheting of two
different
metallic materials;
[00149] Figure 14, in a schematic form, illustrates lamination of two sheets
having
different compositions to form a bioresorbable laminate;
[00150] Figure 15A, in a schematic form, illustrates a manner of flowing the
bioresorbable laminate of FIG. 14;
[00151] Figure 15B, in a schematic form, illustrates an alternative manner of
flowing the bioresorbable laminate of FIG. 14;
[00152] Figure 150, in a schematic form, illustrates another alternative
manner of
flowing the bioresorbable laminate of FIG. 14;
[00153] Figure 15D, in a schematic form, illustrates yet another alternative
manner of flowing the bioresorbable laminate of FIG. 14;
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[00154] Figure 15E, in a schematic form, illustrates yet another alternative
manner
of flowing the bioresorbable laminate of FIG. 14; and
[00155] Figure 15F, in a schematic form, illustrates yet another alternative
manner
of flowing the bioresorbable laminate of FIG. 14.
DETAILED DESCRIPTION
[00156] The present invention relates to novel materials and to bioresorbable,
or
biodegradable, medical devices including this material. Also, as detailed
hereinbelow, methods of manufacturing the materials and medical devices are
provided. While the following description mostly refers to a stent
manufactured
using the proposed material, it is within the scope of the invention to
manufacture
any suitable medical device using this material, such as, for example,
orthopedic
devices used as temporary support while tissues heal. Also, while the proposed
material is well suited to the manufacture of bioresorbable medical devices,
any
other medical devices can be manufactured using the proposed material.
Finally,
while specific methods of manufacturing the proposed medical devices is
proposed, in an alternative embodiment of the invention, the medical devices
are
manufactured using any other suitable method.
[00157] Returning to the specific case of a stent, the ideal mechanical
properties
for stent design are: high Elastic modulus E (to limit stent recoil), low
yield strength
Sy (to lower balloon pressure for stent expansion), high ultimate strength SuT
(for
stent longevity), high ductility (for stent longevity and the capacity to
withstand
deformation under heart pulsation), a high value of the equation E = t3 (for
buckling
resistance, t being the strut thickness) and the capacity of the stent to
withstand a
sufficiently large number of cycles.
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[00158] It is in order to alleviate the limitations mentioned above in the
background section that the proposed invention is put forward. One objective
was
to develop a bioresorbable stent with a new material having a small grain
size, the
highest possible ductility, high strength and a controllable degradation rate.
[00159] Small grain size is advantageous given the size of the stent struts
and to
avoid a discontinuous material and stress concentration at the interface of
grains.
It should be noted that grain size should not be confused with particle size,
as the
proposed material is particulate. The material is made of particles, and the
particles each include a plurality of grains. It is also known that for a
given
material, small grain sizes favor strength and fatigue resistance (basically
linked to
the Hall-Petch effect: strength - 1/d1/2 with d the grain size). Apart from
increasing
strength and fatigue resistance, a smaller grain size has a definite advantage
in wear
properties. Stents and other medical devices may thus benefit from a
significant
reduction in grain size. To achieve this result, a cold spray process is
proposed to
manufacture the novel material.
[00160] Indeed, conventional techniques to reduce the grain size, such as cold
work, usually make the material too brittle. We propose using the cold gas-
dynamic spraying (CGDS) process, referred herein as "cold spray", to generate
improved materials with smaller grain sizes. The cold spray process
essentially
uses the energy stored in a high pressure gas to propel ultra-fine powder
(nano-
powder) particles at supersonic velocities (300-1500 m/s). The compressed gas
is
preheated (to a temperature lower than the powder melting temperature) and
exits
through a nozzle at high velocity. The compressed gas is also fed to a powder
feeder which introduces the ultrafine powder in the gas stream jet. The nano-
structured powder impacts with a substrate and the particles deform and adhere
to
form a coating on the substrate. The particles remain relatively cold and
retain
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their submicron to micron range dimensions. No melting is observed and,
interestingly, particles flow and mix under very high strain rates generating
complex microstructures. Therefore, unwanted effects of high temperatures,
such as
oxidation, grain growth and thermal stresses, are absent.
[00161] The proposed material achieves bioresorption through the use of a
mixture of
two powders in the manufacturing process. More specifically, the bioresorbable
material is an intermixed particulate material comprising cathodic particles
and anodic
particles bound, or amalgamated, to each other. The anodic particles are made
of an
anodic material and the cathodic particles are made of a cathodic material,
the
anodic and cathodic materials forming a galvanic couple, the anodic material
being
electropositive relative to the cathodic material, which is therefore
electronegative.
The anodic and cathodic particles are present in a predetermined ratio in the
bioresorbable material. The anodic particles, cathodic particles and
predetermined
ratio are such that bioresorption of the stent is promoted by galvanic
corrosion
between the anodic and cathodic materials. Also, conventional passive
oxidation of
the cathode and anode occurs, which further enhances bioresorption.
[00162] In some embodiments, the proposed material and medical devices are
made
entirely of the cold-sprayed material, that is the bioresorbable material.
Therefore, in
opposition to some medical devices that may include a cold-sprayed coating of
cold-
sprayed particles, the proposed medical device is made entirely of the cold-
sprayed
material, or includes a bulk, structural, portion thereof that is made
entirely of the cold-
sprayed material. A structural portion is a portion of the medical device that
by itself
provides for example support to tissues when implanted in the body or that
maintains
integrity of the device. In some embodiments, the proposed medical devices are
made
entirely of metal particles.
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[00163] It should be noted that the terminology "particles" relates to
elements that are
smaller than most (or all) of the details of the structure to manufacture. In
the case of
a stent, the particles have a size that is smaller than the thickness of the
stent struts,
so that each strut includes many particles. Bioresorption is not achieved by
sudden
detachment of large elements from the stent, but by gradual disintegration of
the stent
struts.
[00164] It should be noted that this approach is to be contrasted with, for
example,
the medical devices described in US Patent Application Publication 20100249927
of
Yang et al. published on September 30, 2010, in which all the particles have a
centre
of a first material and a coating of a second material. Such devices are not
bioresorbable and the galvanic cells formed are used to generate a current to
enhance antiseptic properties of the devices. In these devices, all the
particles forming
the stent have the same composition. In contrast, the proposed bioresorbable
material stent includes two different types of particles. Also, the proposed
material
and devices manufactured therewith differ greatly from the stents described in
US
Patent 7,854,958 in the name of Kramer issued December 21, 2010 in which a
single material is cold-sprayed to obtain a porous stent. Once again, the
devices
described in this patent are not bioresorbable. In addition, due to their
porous
nature, they are relatively fragile.
[00165] Also, particulate materials, such as those manufactured using cold
spray,
are conventionally used to prevent corrosion and wear. As such, only one
material
is used, often to form a coating on the object to protect. It is contrary to
the
conventional wisdom in this field to instead promote galvanic corrosion within
the
material. Also, other techniques described herein, including folding laminates
or
braiding and weaving wires of different compositions do not require the cold
spray
process and may use any suitable conventional metal wires and films.
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[00166] The anodic and cathodic particles form a plurality of galvanic pair
cells or
structures. The proposed mechanism of bioresorption for the new biodegradable
material is similar to the concept of sacrificial anode used in the ship
industry to
protect boat hulls from corroding, but with the distinction that corrosion of
the
anode is a desired effect that will lead to loss of cohesion of the proposed
material
at a desired controlled rate. Two (or more) dissimilar powders are thoroughly
mixed prior to the cold spray. Anodic particles (less noble metal) and
cathodic
particles (more noble metal) are substantially homogeneously mixed using known
methods. When in the presence of an electrolyte, current will flow between the
anodic and cathodic particles in the cold-sprayed material, which will lead to
corrosion of the anodic material, which, in turn, will allow resorption of the
medical
devices manufactured using the proposed material. In typical embodiments, this
resorption will occur substantially homogeneously.
[00167] More generally speaking, there is proposed an intermixed particulate
material comprising cathodic particles and anodic particles bound, or
amalgamated, to each other, the anodic particles being made of an anodic
material and the cathodic particles being made of a cathodic material, the
anodic
and cathodic materials forming a galvanic couple. While bioresorption is a
useful
property of the proposed material, in alternative embodiments, the proposed
material is manufactured such that bioresorption proceeds at such a small rate
that it does not occur during the lifetime of the patient. In this case, it is
the other
properties of the proposed material, such as mechanical properties, that are
advantageously used. Typically, when the manufacturing process described
hereinbelow is used, the cathodic and anodic particles are randomly and
substantially homogeneously dispersed in the bioresorbable material. However,
it
is possible to have non-random distribution of the anodic and cathodic
particles,
for example if self-assembling materials are used.
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[00168] In the case in which a bioresorbable stent is manufactured, the stent
includes the bioresorbable material. The stent may be entirely made of the
bioresorbable material, or the stent may also include a non-bioresorbable
portion
made of a non-bioresorbable material, such as pure stainless steel, among
other
conventional possibilities. In the latter embodiments, a portion of the stent
remains
in the patient after the remainder of the stent has been resorbed. For
example, the
non-resorbed portion could include a marker usable to locate the stent
implantation site after most of the stent has been resorbed, for example for
follow
up exams. In another example, the non-resorbed portion could be a stent graft
anchoring, a valve anchoring, a clip or a suture that anchors another
structure. In
these embodiments, the other structure remains in place even after a portion
of
the stent, which was useful to support the vessel during a healing process,
has
been resorbed.
[00169] When the proposed material is used to manufacture a medical device,
the
anodic and cathodic materials or a combination of them are biocompatible,
typically during the entire life cycle of the device. Typically, the anodic
and
cathodic materials are metallic.
[00170] In some embodiments of the invention, the anodic material is selected
from the group consisting of iron, iron-alloys and vanadium, and the cathodic
material is selected from the group consisting of cobalt-chromium alloys,
stainless
steel, tantalum, titanium and platinum-steels. In more specific embodiments of
the
invention, the anodic material and cathodic material are selected from the
group of
couples consisting of iron/stainless steel and iron-tantalum. However, other
possibilities are within the scope of the invention.
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[00171] The anodic and cathodic particles are in some embodiments from about 1
m to about 30 m in average size, which is advantageous in the manufacture of
devices including sub-millimeter sized elements. Average size is defined as a
mean value in a Gaussian distribution of sizes, as assessed using microscope
imaging. For example, the anodic and cathodic particles are produced by
melting
the anodic and cathodic materials and pouring the molten materials on a
spinning
wheel, which creates a rain of small droplets of molten material. Cold water
is
sprayed afterwards on the resulting droplets, which solidifies the anodic and
cathodic particles. The resulting shape is substantially spherical and size
refers to
the diameter of the particles. In another example, the anodic and cathodic
particles
are created by grinding the anodic and cathodic materials in bulk form to make
powders. The resulting particles are irregular. These irregular particles are
then
heated, which again produces substantially spherical anodic and cathodic
particles, and size refers again to the diameter of the particles.
[00172] The anodic and cathodic particles each include grains. The grains
typically have much smaller dimensions than the particles. In some embodiments
of the invention, the grains are about 1 m or less in average size. In other
embodiments, the grains are about 4 m or less in average size. In yet other
embodiments, the grains are about 10 m or less in average size. Relatively
small
grain size promotes ductility of the devices manufactured using the proposed
devices, which is often advantageous.
[00173] When a cold spray process is used, it is useful in some embodiments to
have anodic and cathodic particles with some properties that are similar to
promote good material properties. For example, the anodic and cathodic
materials
have bulk specific weights that differ by about 50% or less, and in more
specific
examples, the anodic and cathodic materials have bulk specific weights that
differ
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by about 20% or less. This promotes good mixing of the particles to ensure
homogeneous and random distribution of the anodic and cathodic particles in
the
proposed material. The bulk specific weight refers to the specific weight of
the
material in bulk form, not to the specific weight of the material in
particulate
powder form. In the context of this document, "differing by X%" is to be
interpreted
as meaning that the largest property is X% larger than the smallest property.
For
example, a material having a specific weight of 2 g/cm3 and a material having
a
specific weight of 3 g/cm3 differ in specific weight by 50%.
[00174] In some embodiments of the invention, the anodic and cathodic
materials
have hardnesses that differ by about 50% or less, and in more specific
examples,
the anodic and cathodic materials have hardnesses that differ by about 20% or
less. This promotes good adhesion between the particles.
[00175] One could hypothesize that a ratio of 1:1 w/w between the number of
cathodic and anodic particles would be desired so that the same number of
electron receiving and releasing particles are provided. While this ratio can
provide
bioresorbable materials, it was found that, surprisingly, a predetermined
ratio of
about 4:1 w/w or more in the anodic particles with respect to the cathodic
particles
provides faster corrosion, which is advantageous in some situations. It is
believed
that in more extreme examples, a predetermined ratio of about 8:1 w/w or more
in
the anodic particles with respect to the cathodic particles, or even a
predetermined
ratio of about 20:1 w/w or more in the anodic particles with respect to the
cathodic
particles is also achievable while preserving the bioresorption properties.
[00176] In some embodiments, the proposed material is a dynamically annealed
material in which the material has been heated at a time varying temperature
to
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correct defects within the particles without promoting large grain growth.
This
preserves ductility while increasing hardness. However, other types of
annealing
are possible to achieve suitable grain size.
[00177] In addition to manipulation of the many variables involved in the
structure
of the proposed material, such as selection of anodic and cathodic materials
and
their proportions, dimensions of particles, manufacturing conditions and
annealing
conditions, in some embodiments additional particles are present in the
material to
control bioresorption rates.
[00178] More specifically, the medical device manufactured, such as a stent,
is
bioresorbable at a predetermined rate. Rate may be defined as the rate of mass
lost percentage, a corrosion rate in mm/unit of time, or in any other suitable
manner. To that effect, the anodic particles, cathodic particles and
predetermined
ratio between the two are selected such that the stent is bioresorbable at the
predetermined rate due to galvanic corrosion between the anodic and cathodic
materials. To guide the selection of particles, galvanic corrosion theories
that
relate the current density between two dissimilar materials and their
degradation
rates may be used. In those theoretical descriptions, an equation for galvanic
corrosion is derived based on the corrosion current density of uncoupled
alloys.
This allows the quantification of the corrosion rates based on potentiodynamic
current measurements and permits an estimate of the mass depletion rates based
on these current measurements. Examples of such theories are found in
"Electrochemical Theory of Galvanic Corrosion", John W. Oldfield, ASTM STP 978
H.P. Hack Ed American Society for Testing and Materials, Philadelphia, 1988,
p.
5-22 and "A Theoretical approach to galvanic corrosion, allowing for cathode
dissolution", S. Fangteng, E.A. Charles, Corrosion Science 28(7):649-655,
1988.
These two documents are hereby incorporated by reference in their entirety.
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[00179] In some embodiments of the invention, the bioresorbable material
further
includes rate control particles made of a rate control material and dispersed
in the
bioresorbable material. The rate control particles affect the galvanic
corrosion to
change the predetermined rate in accordance with a predetermined rate change.
For example, the rate control particles increase the predetermined rate by
increasing electron transport between the anodic and cathodic particles. In
another
example, the rate control particles decrease the predetermined rate by
decreasing
electron transport between the anodic and cathodic particles. Specific
examples of
rate control particles that increase the predetermined rate include salts
(such as
calcium, potassium and sodium salts), acids and solid electrolytes. Specific
examples of rate control particles that decrease the predetermined rate
include
chromium, polymer, silicon, ceramics, dielectrics and oxides.
[00180] With the cold spray materials, the corrosion rate can be adjusted
(decreased or increased) using specific thermal treatments. Indeed, with
certain
mixtures (Fe-316L), it was observed that the corrosion can be accelerated by
increasing the temperatures of the heat treatment (higher temperatures
generate
higher corrosion rates)."
[00181] Typically, the proposed material is substantially non-porous. For
example,
this is achieved by having a material that has a porosity of about 0.2% or
less.
[00182] An example of a manner of manufacturing a stent is given hereinbelow
with reference to Fig. 1. However, other devices can be similarly manufactured
using the proposed material. More specifically, Fig. 1 illustrates a method 10
for
manufacturing a bioresorbable stent. The method begins at step 12. Then, at
step
14, an anodic powder including anodic particles made of an anodic material and
a
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cathodic powder including cathodic particles made of a cathodic material are
provided. The anodic and cathodic materials form a galvanic couple, as
described
in greater detail hereinabove. Then, at step 16, the method includes mixing
the
anodic and cathodic powders together in the predetermined ratio to obtain a
mixed
powder. Afterward, at step 18, the method includes cold spraying the mixed
powder on a substrate, for example a steel substrate, to obtain a
bioresorbable
material. In some embodiments of the invention, the substrate is substantially
planar, but other shapes are possible. In some embodiments of the invention,
at
step 20, the material is annealed. In both cases, whether there is annealing
or not,
the method then proceeds to step 22 of processing the bioresorbable material
to
form the bioresorbable stent and ends at step 24. When it is desired to
manufacture the material only for future use, step 22 is omitted from the
method
10. The proposed bioresorbable materials manufactured are complex multi-scale
structures (nano-size grains, micro-size particles, and macro-size layering).
Dedicated thermal treatment, annealing, retains the multi-scale structure
while
improving the ductility for stent usage.
[00183] In some embodiments of the invention, step 14 also includes providing
a
bioresorption rate control powder including rate control particles made of the
rate
control material. In these embodiments, step 16 also includes mixing a rate
control
quantity of the bioresorption rate control powder with the anodic and cathodic
powders to obtain the mixed powder.
[00184] Step 22 may be performed in many possible manners. A non-exclusive
but advantageous manner of performing step 22 is to first take a slice of a
predetermined thickness of the bioresorbable material, removing the substrate,
and then shape the slice to form the bioresorbable stent. In some embodiments,
the slice is taken parallel to the substrate, so that the slice includes only
the
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bioresorbable material, and no part of the substrate. The slice includes
substantially opposed slice first and second side edges extending between
substantially opposed ends of the slice. The thickness of the slice is about
the
thickness of the stent after it has been manufactured. For example, taking the
slice
of the predetermined thickness of the bioresorbable material includes cutting
the
slice with an electrical discharge machine (EDM). It has been found that
slices of
less than 100 m in predetermined thickness are obtainable, which allows
manufacturing relatively small stents.
[00185] In a first example, shaping the slice includes folding the slice to
form a
cylinder so that the slice first and second side edges are substantially
adjacent to
each other and welding the slice first and second side edges to each other. In
a
second example, shaping the slice includes embossing the slice to form a half-
cylinder and welding a similar half-cylinder thereto to form a complete
cylinder.
[00186] Typically, shaping the slice to form the stent includes forming a
substantially cylindrical stent blank and cutting out portions of the stent
blank to
define stent struts. Typically, cutting out portions of the stent blank
includes laser
cutting the portions of the stent blank under conditions maintaining the stent
blank
under an annealing temperature of the anodic and cathodic materials, for
example
using a so-called "cold" laser, or femtosecond laser. However, in alternative
embodiments, the portions of the flat material are first cut out and the
resulting
flattened stent is then folded in a cylindrical shape.
[00187] In another variant, step 22 is performed using a relatively thicker
bioresorbable material and processing the bioresorbable material to form the
bioresorbable stent includes cutting a cylinder in the bioresorbable material
and
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emptying the cylinder to form the stent blank. This variant advantageously
removes the need for welding.
[00188] A specific example of this variant is illustrated in greater details
in FIGS.
7A to 7H. This example uses electrical discharge machining (EDM) to machine a
stent blank. It should be mentioned that the use of EDM in the present case is
highly unconventional. Indeed, we propose machining an amalgamated material
including particles of two different compositions with EDM. Indeed, EDM is
typically performed under a single set of parameters that would work best on a
particular metal or alloy. In the present case, the amalgamated material
includes
two different metallic phases in the same structure. It would not be expected
cutting the amalgamated material with the EDM method would work since it would
typically require two different parameters since we are dealing with two
metals at
once.
[00189] Also, in some embodiments, the EDM method is set-up to use oil-based
dielectric fluids (since aqueous-based would try to corrode the amalgamate
prematurely). These oil-based dielectric fluids are typically at high speed or
pressure to promote high convection rates since the amalgamated material is
sensitive to heat. EDM does create heat, but it quickly dissipates if we used
forced
convection from a high speed dielectric fluid flow.
[00190] Since EDM is a contactless method of cutting stent blanks, EDM will
only
minimally, if at all, mechanically affect the microstructure of the
amalgamated
material due to some mechanical deformation as it would occur with machining
or
with rolling methods. So, from this perspective EDM advantageous to preserve
as
much as possible the metallic microstructure of the different metallic phases,
or
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preserve the grain sizes after a certain heat treatment due to its contactless
nature.
[00191] More specifically, in this proposed variant, a mixed powder including
anodic particles made of a metallic anodic material and cathodic particles
made of
a metallic cathodic material are provided, the anodic and cathodic materials
forming a galvanic couple. The cathodic and anodic particles are as described
above. As seen in FIG. 7A, the variant uses a substrate 100. For example, the
substrate 100 is substantially plate-shaped and metallic.
[00192] Then, as seen in FIG. 7B, the mixed powder is cold-sprayed on the
substrate 100 to obtain an amalgamated material 102 including the anodic and
cathodic particles. The amalgamated material 102 is illustrated in the
drawings as
a sheet of substantially constant thickness thereacross. In such cases, a
plurality
of stent blanks could be manufactured in a grid-like fashion out of the
amalgamated material 102. However, in other embodiments, only a portion of the
amalgamated material is relatively thick and the stent blanks are manufactured
only in this section.
[00193] In some embodiments, as seen in FIG. 70, the amalgamated material
102 is removed from the substrate 100. This can be done in any suitable
manner,
for example using wire EDM or any of the relevant methods mentioned
hereinabove. If desired, the amalgamated material 102 may then be annealed.
However, in some embodiments, no annealing is performed, or only a resulting
stent blank is annealed.
[00194] In a specific example, the amalgamated material 102 is annealed under
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conditions resulting in grains of the anodic and cathodic materials in the
anodic
and cathodic particles to remain below about 1 pm, 4[.tm or 10 pm in average
size.
Typically, the amalgamated material is annealed at a temperature below a
sintering temperature of the amalgamated material 102. For example, the
amalgamated material 102 is annealed at a temperature between 70% and 90% of
a melting temperature of a lowest melting temperature material selected from
the
anodic and cathodic materials.
[00195] For example, if the cathodic material is stainless steel and the
anodic
material is iron, the amalgamated material 102 may be annealed at an annealing
temperature of between 800 C and 1400 C for an annealing duration of 30
minutes to 4 hours. In a more specific example, the annealing temperature is
between 1100 C and 1300 C and the annealing duration is between 1 and 3
hours. The amalgamated material may be brought from room temperature to the
annealing temperature at a predetermined heating rate. For example, the
predetermined heating rate is between about 100 C/hr and about 400 C/hr. In
a
very specific example, the predetermined heating rate is about 250 C/hr.
Also, the
amalgamated material may be brought from the annealing temperature to the
room temperature at a predetermined cooling rate, for example between about
100 and about 400 C/hr. In a very specific example, the predetermined cooling
rate is about 250 C/hr.
[00196] Afterwards, a substantially tubular stent blank 104, seen in FIG. 7G,
is
made of the amalgamated material by machining the amalgamated material using
electrical discharge machining (EDM). Then, selected portion of the stent
blank
104 are removed to form the stent 114, seen in FIG. 7H, for example by
defining
stent struts. A large variety of methods may be used to that effect, for
example
using a picosecond or femtosecond laser, among many possibilities.
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[00197] The stent blank 104 defines a longitudinally extending stent blank
passageway 106. In some embodiments, the stent blank passageway 106 is
formed in the amalgamated material before a peripheral surface 108 of the
stent
blank is machined.
[00198] As seen in the sequence of FIGS. 7D to 7F, one specific manner of
forming the stent blank passageway 106 includes forming a pilot hole 110, seen
in
FIG. 7D, in the amalgamated material 102, inserting an EDM wire 112 in the
pilot
hole 110, as seen in FIG. 7E, and enlarging the pilot hole 110 to a
predetermined
diameter using wire EDM to form the stent blank passageway 106, as seen in
FIG.
7F. The pilot hole 110 may be formed using EDM or simply drilled. Indeed, as
the
pilot hole 110 is surrounded by a large mass of the amalgamated material, and
since the material surrounding the pilot hole 110 is removed afterwards,
mechanical drilling of the pilot hole 110 will not unduly affect the portion
of the
amalgamated material that will form the stent blank 104. Once the stent blank
passageway is formed, wire EDM can be used to form the stent blank peripheral
surface 108.
[00199] After the above steps, conventional stent manufacturing steps are
performed, such as crimping the stent on a balloon for implantation. It should
be
noted that any other type of medical device that needs to be resorbed or
degraded
once implanted may also be machined using EDM from the amalgamated
material.
[00200] To use the stent in a patient, first, a desired resorption rate of the
bioresorbable stent is determined by a clinician. This determination depends
on
clinical and biological criteria. Then, the method of use includes selecting a
patient
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stent from a set of predetermined stents, the patient stent having the desired
resorption rate when implanted in the patient. Afterward, the patient stent is
implanted in the patient. The proposed stent has been found to be advantageous
for use in coronary and pulmonary blood vessels, but other uses are possible.
For
example, the proposed stent can be used in hepatic, biliary, and peripheral
vessels. Also, the proposed stent can be used in non-blood carrying vessels.
Finally, the method further comprises resorbing the stent in the patient at
the
desired resorption rate.
[00201] The ductility of the cold sprayed bioresorbable material typically
needs to
be improved with thermal treatment. Various treatments are possible to
optimize
the final desired mechanical properties. After cold spraying, the
bioresorbable
material is in a highly work-hardened state. Annealing is usually performed to
restore the structure to a re-crystalized state, which is often preferable for
various
mechanical properties. Furthermore, control of annealing parameters enables
control of the mechanical properties of the material. Annealing can be
performed
isothermally by heating the material, for example in an electric resistance
furnace
in air followed by air cooling. However, one has to ensure that the thermal
treatment preserves the micro and the nano structures of the sprayed
materials.
[00202] EXAMPLE:
[00203] Figs 2A to 20 illustrate at various scales a stent manufactured using
the
method 10. This stent is made of cold sprayed iron particles and stainless
steel
particles, both having an average size of about 5 m, in a 4:1 w/w ratio and
has an
outer diameter of 8 mm with 200 pm thick struts. No annealing was performed.
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Fig. 6 illustrates the microstructure of the material used to manufacture the
stent,
after the cold spraying step.
[00204] Fig. 3 illustrates corrosion rate of various bioresorbable materials
manufactured using the method 10, without step 22. The particles were iron and
stainless steel (316L). Curves of corrosion as a function of time per unit
area are
shown for the various proportions. Fig. 4 shows this data in a different form
where
the corrosion rate is plotted. Finally, Fig. 5 illustrates the polarization
graphs used
to investigate corrosion rate in an alternative manner. The corrosion rates
were
0.215 mm/yr for pure iron, 0.18 mm/yr for 316L/iron in a 1:4 ratio, 0.1128
mm/yr for
316L/iron in a 1:1 ratio, and 0.107 mm/yr for 316L/iron in a4:1 ratio.
[00205] In other embodiments, wires, sheets, plates, cylinders or tubular
forms of
dissimilar materials are used to manufacture other bioresorbable medical
devices,
such as stents or scaffolds. For simplicity, reference is made hereinbelow to
a
stent, which includes as mentioned hereinabove scaffolds, but other types of
medical devices may also be manufactured using similar structures and methods.
[00206] In a first variant, the stent includes an anodic material in filament
form and
a cathodic material in filament form. The stent may be made with long
filaments
that are for example braided together, of with shorter filament segments that
form
a fabric, among other possibilities. For example, the filaments have about
between
1 and 10 m in diameter, and are braided to make wires of between 50 and 200
m in diameter. In other embodiments, the filaments and/or wires may have
larger
or smaller diameters. The stent is therefore made biodegradable, or
bioresorbable,
by braiding different filaments, for example micro-wires, of dissimilar
metals. As a
result, the wire (which for example defines stent struts) exhibits a micro-
galvanic
corrosion and thus biodegrades in presence of an electrolyte (such as, non-
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limitingly, blood plasma).
[00207] The resulting braided wire (with predetermined arrangements and
predetermined ratios of anodic and cathodic wires) exhibits galvanic
degradation
at the contact areas between the two dissimilar metals. By using two metals
that
fully degrade (like mild steels, for example, but of different compositions)
this
results in a fully degradable wire. However, stents that do not fully degrade,
or in
other words that are only partially resorbed, are also within the scope of the
invention. The wire can then be shaped in any predetermined configuration (and
possibly micro-welded) to achieve a desired stent design and dimensions. It is
also
possible to perform heat treatments to improve the bioresorption properties of
the
wires and improve bonding.
[00208] The anodic and cathodic materials are typically metallic and form a
galvanic couple. The anodic and cathodic materials are distributed in the
stent so
that the anodic and cathodic materials contact each other at a plurality of
junctions. The cathodic and anodic materials usable in this variant are the
same
that are usable in the cold-sprayed material described above. Mild steel is
also
usable both in the presently described variants and in the cold-sprayed
material.
Bioresorption of the stent is promoted by galvanic corrosion between the
anodic
and cathodic materials at the junctions.
[00209] More specifically, in a specific embodiment, at least one anodic
filament
made of the anodic material and at least one cathodic filament made of the
cathodic material are braided together in a wire, the wire including at least
some of
the plurality of junctions. The wire can then be folded in a conventional
manner to
form a wire or coil stent, or a few similar wires can be used to form the
stent.
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Wire , or coil, stent are known in the art. For example, and non-limitingly,
such
stent are similar to the stent illustrates in US Design Patent 553,747 issued
October 23, 2007, to Cornova Inc., the contents of which is hereby
incorporated by
reference in its entirety.Typically, most of the junctions may be formed
within the
wire, with only a small number of them formed where the wire intersects
itself.
Micro-welding may be used an locations where the wire intersects itself if
needed.
FIG. 8 illustrates braiding of four anodic filaments 202 (in black) and four
cathodic
filaments 204 (in white) together to form a wire 200. However, any suitable
number
of anodic and cathodic filaments is usable, including less and four and more
than
four. Also, the numbers of anodic and cathodic filaments don't need to be
equal.
[00210] In some embodiments, the anodic and cathodic filaments are also
braided
with a carrier filament. The carrier filament may be metallic or not and made
of the
anodic material, cathodic material or of a material that differs from the
anodic and
cathodic materials. For example, the carrier filament is made of a
bioresorbable
polymer or of a suitable metal. The carrier filament may be of a larger
diameter
than any of the anodic and cathodic filaments. Larger filaments allow more
contact
between the filaments as more turns of the smaller filaments around the larger
filament can be made. For example ratios of the diameters of the anodic,
cathodic
and carrier filaments may vary from about 0.1 to about 10. In some
embodiments,
the anodic and cathodic filaments have different pitches relative to the wire.
This
varies the amount of contact between dissimilar materials and also allows
varying
the relative quantity of the anodic and cathodic materials, which all affect
the
bioresorption rate of the stent.
[00211] Manufacturing of a wire as described above is schematically
illustrated in
FIG. 9. The wire 300 includes one anodic filament 302, one cathodic filament
304
and one carrier filament 306, each provided from a respective bobbin 312, 314
or
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316. The anodic, cathodic and carrier filaments 302, 304 and 306 are freely
removable from the bobbins 312, 314 and 316, which are free to axially rotate.
The
bobbins 312, 314 and 316 are mounted to a carousel 308 rotable about the
longitudinal axis 310 of the wire 300. Control of the pitch of the anodic,
cathodic
and carrier filaments 302, 304 and 306 about the wire 300 is performed by
controlling the angular velocity of the carousel 308, the speed at which the
anodic,
cathodic and carrier filaments 302, 304 and 306 are drawn (by pulling on the
wire
300) and by selecting appropriate distances between the bobbins 312, 314 and
316 and the longitudinal axis 310, which varies the angle 0 between the
anodic,
cathodic and carrier filaments 302, 304 and 306 and the longitudinal axis 110.
For
example the angle 0 varies from about 0 degrees to about 89 degrees. Other
techniques known in the textile and cable manufacturing industries are also
usable
to manufacture the wire 300. Changing the angle 0 allows also to adjust the
contact areas between the threads to achieve different degrees of galvanic
corrosion.
[00212] In other variants, tubular stent blanks, similar to the stent blank
104 are
first manufactured as described below, and the stent is then crated by
removing
portions of the stent blank to create stent struts and other stent structures,
for
example using laser systems. The tubular stent blank can be manufactured from
one or more sheets of material 400, as seen in FIG. 10A. Such sheets 400 are
described below in greater details. When the sheet 400 is of sufficient
thickness,
the sheet 400 can be rolled to form a cylindrical structure and the two sheet
edges
402 and 404 that are then adjacent to each other can be secured to each other,
for
example through welding, as illustrated in the sequence of FIGS. 10B and 10C.
In
other embodiments, when the sheet 400 is too thin, multiple sheets 400 can be
rolled on top of each other, as illustrated in FIG. 10D to form a tubular
structure.
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The multiple sheets 400 can be adhered to each other in any suitable manner,
for
example through sintering. In yet other embodiments, the sheet 400 is rolled
in a
spiral to form the tubular structure, as seen in FIG. 10E, followed for
example by
sintering.
[00213] The sheet 400 may be manufactured using many different techniques. In
a first example, illustrated in FIG. 11, a plurality of anodic filament
segments 502
made of the anodic material and a plurality of cathodic filament segments 504
made of the cathodic material are weaved together in a fabric 500. The anodic
filament segments 502 may be disjoint from each other or part of longer
filaments
folded over themselves. The same applies for the cathodic filament segments
504.
The fabric 500 includes at least some of the plurality of junctions 506. For
example, the anodic filament segments 502 are substantially parallel to each
other
in the fabric 500 and the cathodic filament segments 504 are substantially
parallel
to each other in the fabric 500. In a specific example, the anodic filament
segments 502 are substantially perpendicular to the cathodic filament segments
504. In other embodiments, anodic and cathodic filament segments 502 and 504
are both present in the rows and in the columns of the fabric 504. Weaving may
be
performed using any suitable technique and any suitable weaving pattern may be
used. As with the above-described variants, the diameter of the cathodic and
anodic filament segments 502 and 504 may differ from each other, or within
each
type of segment. Multi-weaved offset layer are also usable.
[00214] In yet other embodiments, as seen for example in FIG. 13, one of the
anodic and cathodic materials, for example the anodic material, forms a base
grid
600 defining a plurality of grid apertures 602 and the other one of the anodic
and
cathodic materials, for example a cathodic filament 604 is crocheted into the
base
grid through the apertures 602 using a suitable head 606. The base 600 grid
may
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be created by weaving together the selected one of the anodic and cathodic
materials, similarly to the fabric 500, but loosely enough to create the grid
apertures 602. In other embodiments, the base grid 600 is manufactured by
removing material from a plate. Any other suitable method is also usable to
manufacture the base grid 600.
[00215] The cathodic and anodic materials may be in the form of filaments
having
a substantially constant diameter therealong, as illustrated in FIGS. 8 for
example,
or may be in a beaded filament form, as seen in FIG. 12 for the filament 700.
Beaded filament 700 may increase the contact area between the anodic and
cathodic materials. The beads of the filament 700 may extend continuously from
each other, or may be separated from each other by segments of constant
diameters.
[00216] In the sheets described hereinabove, the cathodic and anodic materials
may be sintered or otherwise thermally adhered to each other. In other
embodiments, only mechanical forces, that is tension, friction and normal
forces,
hold the sheet together so that no welding, sintering or other treatment is
required
to manufacture the sheet. In such embodiments, the cathodic and anodic
filaments
are under tension and the junctions are created due to normal forces between
the
filaments at locations where the filaments intersect. The cathodic and anodic
materials may have different or similar diameters, similarly to the braided
variant
described above. Also, a total length of the anodic material in the stent,
that is a
total sum of the length of all filament or filament segments of the anodic
material,
may be similar or may differs from a total length of the cathodic material in
the
stent.
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[00217] In yet another variant, the sheet 400 is manufactured by laminating
the
anodic and cathodic materials on top of each other. For example, as seen in
FIG.
14, one of the anodic and cathodic materials is provide in the form of a thin
sheet
800. The thin sheet has for example a thickness between 1 and 10 microns.
Then,
a suitable process, such as plasma vapor deposition (PVD), among others, is
used
to form a coating 802, also having a thickness of for example between 1 and 10
microns, on the sheet 800 with the other one from the anodic and cathodic
materials. To form the stent, the resulting coated sheet 804 is processed to
create
a thicker sheet including a plurality of layers alternating between cathodic
layers
and anodic layers, thereby forming alternating galvanic couples promoting
galvanic corrosion between the anodic and cathodic layers. In such
embodiments,
all the cathodic layers are made of a same cathodic material and all the
anodic
layers are made of a same anodic material. The anodic and cathodic layers may
have similar or different thicknesses. The coated sheet 804 can then be rolled
into
a spiral to form a cathodic spiralling sheet made of the cathodic material an
an
anodic spiralling sheet made of the anodic material and parallel to the
cathodic
spiralling sheet. In other embodiments, the coated sheet 804 is folded in any
suitable manner. Resulting in the cathodic and anodic layers to alternate in
the
folded sheet. The sheet can then be rolled to form a stent blank, as described
above.
[00218] In this approach, the micro-galvanic reaction is induced by layering
micro-
foils of dissimilar metals in alternate manners. After the lamination, the
structure is
for example heat treated to ensure proper bonding, for example at between 500
C
and 800 C. Following the heat treatment, the laminated structures is folded
to
expose the dissimilar sides to each other (in order to induce the galvanic
couple).
Different folding can be considered, some of which are illustrated in FIGS.
15A to
15F which illustrate respectively, a rri-fold, a roll fold, a gate fold, an
accordion
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fold, a double parallel fold and a flip fold. It should be noted that in some
folds, the
same metal is folded over itself, but alternating layers of different
compositions are
nevertheless created. The laminated sheet 804 can be folded repeatedly using
the
same folding method, or by mixing the folding method, to form thicker sheets.
[00219] Other suitable manners of manufacturing a layered structure as defines
above are also within the scope of the invention, such as, for example,
depositing
multiple alternating layers of anodic and cathodic materials using plasma
deposition, among others.
[00220] All the above structures allow to manufacture macro scale medical
devices that present complete bioresorption by having galvanic couples at the
micro scale (for example 1 to 10 pm order). The micro scale may be 0-
dimensional
(as in the particulate material), 1-dimensional (using wires) or 2-dimensional
(using
folded sheets). Using proper materials, dimensions and heat treatments allows
for
providing a predetermined, controlled, degradation rate.
[00221] Although the present invention has been described hereinabove by way
of preferred embodiments thereof, it can be modified, without departing from
the
spirit and nature of the subject invention as defined in the appended claims.
