U.S. patent application number 15/033227 was filed with the patent office on 2016-09-29 for absorbable iron alloy stent.
This patent application is currently assigned to Lifetech Scientific (Shenzhen) Co., Ltd.. The applicant listed for this patent is LIFETECH SCIENTIFIC (SHENZHEN) CO., LTD.. Invention is credited to Liping Chen, Hongtao Sun, Deyuan Zhang.
Application Number | 20160279303 15/033227 |
Document ID | / |
Family ID | 53003389 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160279303 |
Kind Code |
A1 |
Zhang; Deyuan ; et
al. |
September 29, 2016 |
Absorbable Iron Alloy Stent
Abstract
The invention discloses an absorbable iron alloy stent,
comprising an iron alloy substrate and a degradable polymer in
contact with the surface of the substrate, in which the degradable
polymer has a weight average molecular weight of more than or equal
to 20,000 and less than or equal to 1,000,000 and a polydispersity
index of more than 1.0 and less than or equal to 50. After the iron
alloy stent is implanted into the body, the degradable polymer
degrades to produce a carboxyl group. After the degradable stent is
implanted into the human body, the effects of oxygen-consuming
corrosion enable the stent both to mainly function as a mechanical
support and then to degrade gradually, and the amount of hydrogen
produced in the degradation process does not reach the level that
can lead to a risk of air embolism.
Inventors: |
Zhang; Deyuan; (Shenzhen,
CN) ; Sun; Hongtao; (Shenzhen, CN) ; Chen;
Liping; (Shenzhen, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LIFETECH SCIENTIFIC (SHENZHEN) CO., LTD. |
Shenzhen |
|
CN |
|
|
Assignee: |
Lifetech Scientific (Shenzhen) Co.,
Ltd.
Shenzhen
CN
|
Family ID: |
53003389 |
Appl. No.: |
15/033227 |
Filed: |
October 31, 2014 |
PCT Filed: |
October 31, 2014 |
PCT NO: |
PCT/CN2014/090107 |
371 Date: |
April 29, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 31/042 20130101;
A61L 31/06 20130101; A61L 31/022 20130101; A61L 31/148 20130101;
A61F 2210/0004 20130101; A61F 2002/91575 20130101; A61L 2300/416
20130101; A61L 2300/434 20130101; A61F 2250/0067 20130101; A61F
2/915 20130101; A61L 2300/236 20130101; A61L 31/10 20130101; A61L
2300/606 20130101; A61L 31/041 20130101; A61L 2400/18 20130101;
A61L 31/16 20130101; A61F 2210/0076 20130101; A61L 31/08 20130101;
A61L 31/146 20130101; A61L 31/10 20130101; A61L 2300/604 20130101;
A61L 2420/06 20130101; A61L 2300/42 20130101; A61L 2430/20
20130101; C08L 67/04 20130101 |
International
Class: |
A61L 31/10 20060101
A61L031/10; A61L 31/16 20060101 A61L031/16; A61F 2/915 20060101
A61F002/915; A61L 31/04 20060101 A61L031/04; A61L 31/02 20060101
A61L031/02; A61L 31/08 20060101 A61L031/08; A61L 31/14 20060101
A61L031/14; A61L 31/06 20060101 A61L031/06 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 31, 2013 |
CN |
201310533326.6 |
Claims
1-43. (canceled)
44. An absorbable iron-based alloy stent, comprising an iron-based
alloy substrate and a degradable polyester in contact with the
surface of the substrate, characterized in that the degradable
polyester has a weight average molecular weight in the range of
20,000 to 1,000,000 and a polydispersity index more than or equal
to 1.2 and less than or equal to 30, or more than 1.0 and less than
1.2, or more than 30 and less than or equal to 50.
45. The absorbable iron-based alloy stent as set forth in claim 44,
characterized in that the weight average molecular weight of the
degradable polyester is more than or equal to 20,000 and less than
100,000, or more than or equal to 100,000 and less than 250,000, or
more than or equal to 250,000 and less than 400,000, or more than
or equal to 400,000 and less than 600,000, or more than or equal to
600,000 and less than or equal to 1,000,000.
46. The absorbable iron-based alloy stent as set forth in claim 44,
characterized in that the polydispersity index is more than or
equal to 1.2 and less than 2, or more than or equal to 2 and less
than 3, or more than or equal to 3 and less than 5, or more than or
equal to 5 and less than 10, or more than or equal to 10 and less
than 20, or more than or equal to 20 and less than or equal to
30.
47. The absorbable iron-based alloy stent as set forth in claim 44,
characterized in that the mass ratio of the iron-based alloy
substrate to the degradable polyester is more than or equal to 1
and less than or equal to 200.
48. The absorbable iron-based alloy stent as set forth in claim 47,
characterized in that the mass ratio of the iron-based alloy
substrate to the degradable polyester is more than or equal to 5
and less than or equal to 50.
49. The absorbable iron-based alloy stent as set forth in claim 44,
characterized in that the surface of the iron-based alloy substrate
is coated with the degradable polyester in the form of a coating
layer; or/and the iron-based alloy substrate is provided with gaps
or grooves, and the degradable polyester is arranged in the gaps or
grooves; or/and the iron-based alloy substrate is provided with an
inner cavity, and the degradable polyester is filled in the inner
cavity.
50. The absorbable iron-based alloy stent as set forth in claim 49,
characterized in that when the surface of the iron-based alloy
substrate is coated with the degradable polyester in the form of
the coating layer, a wall thickness of the iron-based alloy
substrate is more than or equal to 30 .mu.m and less than 50 .mu.m,
and a thickness of the degradable polyester coating layer is more
than or equal to 3 .mu.m and less than 5 .mu.m, or more than or
equal to 5 .mu.m and less than 10 .mu.m, or more than or equal to
10 .mu.m and less than 15 .mu.m, or more than or equal to 15 .mu.m
and less than or equal to 20 .mu.m; or the wall thickness of the
iron-based alloy substrate is more than or equal to 50 .mu.m and
less than 100 .mu.m, and the thickness of the degradable polyester
coating layer is more than or equal to 5 .mu.m and less than 10
.mu.m, or more than or equal to 10 .mu.m and less than 15 .mu.m, or
more than or equal to 15 .mu.m and less than 20 .mu.m, or more than
or equal to 20 .mu.m and less than or equal to 25 .mu.m; or the
wall thickness of the iron-based alloy substrate is more than or
equal to 100 .mu.m and less than 200 .mu.m, and the thickness of
the degradable polyester coating layer is more than or equal to 10
.mu.m and less than 15 .mu.m, or more than or equal to 15 .mu.m and
less than 20 .mu.m, or more than or equal to 20 .mu.m and less than
25 .mu.m, or more than or equal to 25 .mu.m and less than or equal
to 35 .mu.m; or the wall thickness of the iron-based alloy
substrate is more than or equal to 200 .mu.m and less than or equal
to 300 .mu.m, and the thickness of the degradable polyester coating
layer is more than or equal to 10 .mu.m and less than 15 .mu.m, or
more than or equal to 15 .mu.m and less than 20 .mu.m, or more than
or equal to 20 .mu.m and less than 25 .mu.m, or more than or equal
to 25 .mu.m or less than 35 .mu.m, or more than or equal to 35
.mu.m and less than or equal to 45 .mu.m.
51. The absorbable iron-based alloy stent as set forth in claim 44,
characterized in that the degradable polyester is any one of the
followings: polylactic acid, polyglycolic acid, poly(butylene
succinate), poly (beta-hydroxybutyrate), polycaprolactone,
poly(ethyleneglycol adipate), poly(lactic-co-glycolic acid), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate); or the degradable
polyester comprises at least two kinds of degradable polyester
polymers with high molecular weights, wherein each of the two kinds
of degradable polyester polymers with high molecular weight has a
weight average molecular weight of more than or equal to 100,000
and less than 200,000, or more than or equal to 200,000 and less
than 400,000, or more than or equal to 400,000 and less than
600,000, or more than or equal to 600,000 and less than or equal to
1000,000; or the degradable polyester is a mixture of at least two
of polylactic acid, polyglycolic acid, poly(butylene succinate),
poly (beta-hydroxybutyrate), polycaprolactone, poly(ethyleneglycol
adipate), poly(lactic-co-glycolic acid), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), or a copolymer formed
by copolymerizing at least two of monomers forming polylactic acid,
polyglycolic acid, poly(butylene succinate), poly
(beta-hydroxybutyrate), polycaprolactone, poly(ethyleneglycol
adipate), poly(lactic-co-glycolic acid), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate); or the degradable
polyester is a mixture of at least two kinds of degradable
polyester polymers with different crystallinity, wherein the
content of degradable polyester polymer with crystallinity more
than or equal to 5% and less than or equal to 50% is more than or
equal to 10% and less than or equal to 90% in percentage by mass,
and the degradable polyester polymer is selected from the group
consisting of polylactic acid, polyglycolic acid, poly (butylene
succinate), poly (beta-hydroxybutyrate), polycaprolactone, poly
(ethyleneglycol adipate), poly (lactic-co-glycolic acid), and poly
(3-hydroxybutyrate-co-3-hydroxyvalerate).
52. The absorbable iron-based alloy stent as set forth in claim 44,
characterized in that the degradable polyester comprises at least
two kinds of the same type of degradable polyester polymers,
wherein the first kind of degradable polyester polymer has a weight
average molecular weight of more than or equal to 20,000 and less
than 100,000, the second kind of degradable polyester polymer has a
weight average molecular weight more than or equal to 100,000 and
less than or equal to 1,000,000, the mass ratio of the first kind
of degradable polyester polymer to the second kind of degradable
polyester polymer is more than or equal to 1:9 and less than or
equal to 9:1, and the same type of degradable polyester polymer is
any one of the followings: polylactic acid, polyglycolic acid,
poly(butylene succinate), poly (beta-hydroxybutyrate),
polycaprolactone, poly(ethyleneglycol adipate),
poly(lactic-co-glycolic acid), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate).
53. The absorbable iron-based alloy stent as set forth in claim 52,
characterized in that the mass ratio of the first kind of
degradable polyester polymer to the second kind of degradable
polyester polymer is more than or equal to 1:5 and less than or
equal to 5:1.
54. The absorbable iron-based alloy stent as set forth in claim 44,
characterized in that the degradable polyester is mixed with an
active drug, and the mass ratio of the degradable polyester to the
drug is more than or equal to 0.1 and less than or equal to 20.
55. The absorbable iron-based alloy stent as set forth in claim 54,
characterized in that the mass ratio of the degradable polyester to
the drug is more than or equal to 0.5 and less than or equal to
10.
56. The absorbable iron-based alloy stent as set forth in claim 44,
characterized in that the iron-based alloy substrate is selected
from pure iron or an iron-based alloy formed by doping at least one
of C, N, O, S, P, Mn, Pd, Si, W, Ti, Co, Cr, Cu, and Re into pure
iron.
57. An absorbable iron-based alloy stent, comprising an iron-based
alloy substrate and a degradable polymer in contact with the
surface of the substrate, characterized in that the degradable
polymer has a weight average molecular weight more than or equal to
20,000 and less than or equal to 1,000,000 and a polydispersity
index of more than 1.0 and less than or equal to 50, and the
degradable polymer is capable of producing a carboxyl group after
degrading.
58. The absorbable iron-based alloy stent as set forth in claim 57,
characterized in that the degradable polymer is a degradable
polyester; or the degradable polymer is a blend of the degradable
polyester and a degradable polyanhydride; or the degradable polymer
is a degradable copolymer formed by copolymerizing monomers forming
the degradable polyester and the degradable polyanhydride, and the
degradable polyester and the degradable polyanhydride have a weight
average molecular weight more than or equal to 20,000 and less than
or equal to 1,000,000, and polydispersity indexes of more than 1.0
and less than or equal to 50.
59. The absorbable iron-based alloy stent as set forth in claim 58,
characterized in that the polydispersity indexes of the degradable
polyester and the degradable polyanhydride are more than or equal
to 1.2 and less than 2, or more than or equal to 2 and less than 3,
or more than or equal to 3 and less than 5, or more than or equal
to 5 and less than 10, or more than or equal to 10 and less than
20, or more than or equal to 20 and less than 30, or more than or
equal to 30 and less than or equal to 50.
60. The absorbable iron-based alloy stent as set forth in claim 58,
characterized in that the mass ratio of the iron-based alloy
substrate to the degradable polymer is more than or equal to 1 and
less than or equal to 200.
61. The absorbable iron-based alloy stent as set forth in claim 60,
characterized in that the mass ratio of the iron-based alloy
substrate to the degradable polymer is more than or equal to 5 and
less than or equal to 50.
62. The absorbable iron-based alloy stent as set forth in claim 58,
characterized in that the weight average molecular weight of the
degradable polyester is more than or equal to 20,000 and less than
100,000, or more than or equal to 100,000 and less than 250,000, or
more than or equal to 250,000 and less than 400,000, or more than
or equal to 400,000 and less than 600,000, or more than or equal to
600,000 and less than 1,000,000.
63. The absorbable iron-based alloy stent as set forth in claim 57,
characterized in that the surface of the iron-based alloy substrate
is coated with the degradable polymer in the form of a coating
layer; or/and the iron-based alloy substrate is provided with gaps
or grooves, and the degradable polymer is arranged in the gaps or
grooves; or/and the iron-based alloy substrate is provided with an
inner cavity, and the degradable polymer is filled in the inner
cavity.
64. The absorbable iron-based alloy stent as set forth in claim 63,
characterized in that when the surface of the iron-based alloy
substrate is coated with the degradable polymer in the form of a
coating layer, a wall thickness of the iron-based alloy substrate
is more than or equal to 30 .mu.m and less than 50 .mu.m, and a
thickness of the degradable polymer coating layer is more than or
equal to 3 .mu.m and less than 5 .mu.m, or more than or equal to 5
.mu.m and less than 10 .mu.m, or more than or equal to 10 .mu.m and
less than 15 .mu.m, or more than or equal to 15 .mu.m and less than
or equal to 20 .mu.m; or the wall thickness of the iron-based alloy
substrate is more than or equal to 50 .mu.m and less than 100
.mu.m, and the thickness of the degradable polymer coating layer is
more than or equal to 5 .mu.m and less than 10 .mu.m, or more than
or equal to 10 .mu.m and less than 15 .mu.m, or more than or equal
to 15 .mu.m and less than 20 .mu.m, or more than or equal to 20
.mu.m and less than or equal to 25 .mu.m; or the wall thickness of
the iron-based alloy substrate is more than or equal to 100 .mu.m
and less than 200 .mu.m, and the thickness of the degradable
polymer coating layer is more than or equal to 10 .mu.m and less
than 15 .mu.m, or more than or equal to 15 .mu.m and less than 20
.mu.m, or more than or equal to 20 .mu.m and less than 25 .mu.m, or
more than or equal to 25 .mu.m and less than or equal to 35 .mu.m;
or the wall thickness of the iron-based alloy substrate is more
than or equal to 200 .mu.m and less than or equal to 300 .mu.m, and
the thickness of the degradable polymer coating layer is more than
or equal to 10 .mu.m and less than 15 .mu.m, or more than or equal
to 15 .mu.m and less than 20 .mu.m, or more than or equal to 20
.mu.m and less than 25 .mu.m, or more than or equal to 25 .mu.m and
less than 35 .mu.m, or more than or equal to 35 .mu.m and less than
or equal to 45 .mu.m.
65. The absorbable iron-based alloy stent as set forth in claim 58,
characterized in that the degradable polyester is any one of the
followings: polylactic acid, polyglycolic acid, poly(butylene
succinate), poly (beta-hydroxybutyrate), polycaprolactone,
poly(ethyleneglycol adipate), poly(lactic-co-glycolic acid), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate); or the degradable
polyester comprises at least two kinds of the same type of
degradable polyester polymers, wherein the first kind of degradable
polyester polymer has a weight average molecular weight of more
than or equal to 20,000 and less than 100,000, the second kind of
degradable polyester polymer has a weight average molecular weight
more than or equal to 100,000 and less than or equal to 1,000,000,
the mass ratio of the first kind of degradable polyester polymer to
the second kind of degradable polyester polymer is more than or
equal to 1:9 and less than or equal to 9:1, and the same type of
degradable polyester polymer is any one of the followings:
polylactic acid, polyglycolic acid, poly(butylene succinate), poly
(beta-hydroxybutyrate), polycaprolactone, poly(ethyleneglycol
adipate), poly(lactic-co-glycolic acid) and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate); or the degradable
polyester comprises at least two kinds of degradable polyester
polymers with high molecular weights, and each of the at least two
kinds of degradable polyester polymers with high molecular weights
has a weight average molecular weight of more than or equal to
100,000 and less than 200,000, or more than or equal to 200,000 and
less than 400,000, or more than or equal to 400,000 and less than
600,000, or more than or equal to 600,000 and less than or equal to
1,000,000; or the degradable polyester is a blend of at least two
of polylactic acid, polyglycolic acid, poly(butylene succinate),
poly (beta-hydroxybutyrate), polycaprolactone, poly(ethyleneglycol
adipate), poly(lactic-co-glycolic acid), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), or a copolymer formed
by copolymerizing at least two of monomers forming polylactic acid,
polyglycolic acid, poly(butylene succinate), poly
(beta-hydroxybutyrate), polycaprolactone, poly(ethyleneglycol
adipate), poly(lactic-co-glycolic acid), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate); or the degradable
polyester is a mixture of at least two kinds of degradable
polyester polymers with different crystallinity, wherein the
content of degradable polyester polymer with crystallinity more
than or equal to 5% and less than or equal to 50% is more than or
equal to 10% and less than or equal to 90% in percentage by mass,
and the degradable polyester polymer is selected from the group
consisting of polylactic acid, polyglycolic acid, poly (butylene
succinate), poly (beta-hydroxybutyrate), polycaprolactone, poly
(ethyleneglycol adipate), poly (lactic-co-glycolic acid), and poly
(3-hydroxybutyrate-co-3-hydroxyvalerate).
66. The absorbable iron-based alloy stent as set forth in claim 65,
characterized in that when the degradable polyester comprises at
least two kinds of the same type of degradable polyester polymers,
the mass ratio of the first kind of degradable polyester polymer to
the second kind of degradable polyester polymer is more than or
equal to 1:5 and less than or equal to 5:1.
67. The absorbable iron-based alloy stent as set forth in claim 58,
characterized in that the polyanhydride is any one of the
followings: poly(1, 3-bis(p-carboxyphenoxy) propane-sebacic acid)
and poly(erucic acid dimer-sebacic acid) or poly(fumaric-sebacic
acid), the degradable polyester is any one of the followings:
polylactic acid, polyglycolic acid, poly(butylene succinate), poly
(beta-hydroxybutyrate), polycaprolactone, poly(ethyleneglycol
adipate), poly(lactic-co-glycolic acid), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), and the mass ratio of
the degradable polyester to the polyanhydride is more than or equal
to 1:9 and less than or equal to 9:1.
68. The absorbable iron-based alloy stent as set forth in claim 58,
characterized in that in the blend of the degradable polyester and
the degradable polyanhydride, the content of degradable polyester
or degradable polyanhydride with crystallinity more than or equal
to 5% and less than or equal to 50% is more than or equal to 10%
and less than or equal to 90% in percentage by mass, the degradable
polyester polymer is selected from the group consisting of
polylactic acid, polyglycolic acid, poly (butylene succinate), poly
(beta-hydroxybutyrate), polycaprolactone, poly (ethyleneglycol
adipate), poly (lactic-co-glycolic acid), and poly
(3-hydroxybutyrate-co-3-hydroxyvalerate), and the polyanhydride is
selected from the group consisting of poly(1,
3-bis(p-carboxyphenoxy) propane-sebacic acid) and poly(erucic acid
dimer-sebacic acid) or poly(fumaric-sebacic acid).
69. The absorbable iron-based alloy stent as set forth in claim 57,
characterized in that the degradable polymer is mixed with an
active drug, and the mass ratio of the degradable polymer to the
drug is more than or equal to 0.1 and less than or equal to 20.
70. The absorbable iron-based alloy stent as set forth in claim 69,
characterized in that the mass ratio of the degradable polymer to
the drug is more than or equal to 0.5 and less than or equal to
10.
71. The absorbable iron-based alloy stent as set forth in claim 57,
characterized in that the iron-based alloy substrate is selected
from pure iron or an iron-based alloy formed by doping at least one
of C, N, O, S, P, Mn, Pd, Si, W, Ti, Co, Cr, Cu, and Re into pure
iron.
Description
TECHNICAL FIELD
[0001] The present invention relates to a degradable implantable
medical device, and particularly relates to an absorbable
iron-based alloy device capable of degrading rapidly and
controllably within a predetermined period.
BACKGROUND ART
[0002] At present, the implantable medical devices are usually made
from metals and their alloys, ceramics, polymers and the related
composite materials, wherein the metal-based implantable medical
devices are particularly popular because of their superior
mechanical properties, such as high strength, and high
toughness.
[0003] Iron as an important element in the human body, is involved
in many biochemical processes, such as in the delivery of oxygen.
Easily corrosive pure iron stents each of the shape similar to that
of a clinically used metal stent, made by Peuster M et al. through
a laser engraving method, were respectively implanted to the
descending aortas of 16 New Zealand rabbits. The animal
experimental results showed that there was no thrombosis
complication within 6 to 18 months, and also no adverse events
occurred. The pathological examination confirmed that there were no
inflammation in local blood vessel walls and no obvious
proliferation on smooth muscle cells, preliminarily indicating that
the degradable iron stent is safe and reliable and has good
application prospects. But the study also found that the corrosion
rate of pure iron was relatively slow in vivo, which cannot meet
the clinical degradation time requirement for the degradable stent,
thus the corrosion rate of iron needed to be accelerated.
[0004] Various techniques for improving the corrosion rate of iron
have been continuously developed, including alloying, changing the
iron metallurgical structure, or coating of a degradable polyester
coating layer on the surface of the iron-based alloy stent. For the
method for increasing the corrosion rate of the iron-based material
by the polyester, the literature disclosed that the degradable
polyester coating would produce a product with a carboxyl group in
the degradation process in the human body, so that the pH value of
the local microenvironment near the stent implantation position
dropped to form a local subacid environment, thereby the
overpotential of hydrogen evolution reaction on the surface of the
iron-based alloy substrate was reduced, and the hydrogen evolution
corrosion was produced in the iron-based alloy substrate, thus
producing an iron salt as a degradation product. The literature
also indicated that the degradation process of iron-based alloy was
accompanied by the oxygen-consuming corrosion process and the
hydrogen evolution corrosion process, and because the highest
oxygen-consuming corrosion rate of a solution in the local subacid
environment is a constant value, it is difficult to improve the
corrosion rate of the iron-based alloy by speeding up the
oxygen-consuming corrosion rate. Namely, the literature believed
that the corrosion rate of the iron-based alloy was improved only
by the hydrogen evolution corrosion in the degradation of
iron-based alloy. In addition, the literature only provided
experimental data to indicate that the corrosion rate of iron-based
alloy was increased under the action of polyester, and did not
disclose the molecular weight and molecular weight distribution of
the polymer, namely, did not disclose the match between the
degradable polymer degradation and the iron-based alloy substrate
corrosion. The literature also did not provide any experimental
data to prove that the iron-based alloy stent can meet the clinical
early mechanical property requirement after being implanted into
the human body, and also did not disclose the corrosion period of
the stent, so that whether the stent meets the clinical property
requirement for the stent cannot be known by those skilled in the
art.
[0005] In fact, a large amount of hydrogen produced by hydrogen
evolution corrosion will cause the tissue tolerance risk such as
formation of air embolism, so that the stent cannot be used
clinically. Our early experiments showed that after nitrogen was
introduced and oxygen was removed in the corrosion environment, the
corrosion rate of iron-based alloy was greatly reduced. i.e., the
hydrogen evolution corrosion indicated by the above-mentioned
literature was not produced in the iron-based alloy in the body. If
the corrosion rate of iron is too rapid, it is possible that the
iron-based alloy stent at early stage (such as 3 months) after the
implanting would not have sufficient structural integrity, and it
is difficult to reach the radial support force required by the
blood vessel clinically, so that the stent loses its clinical
application value. Otherwise, if an increase in the corrosion rate
of iron caused by the polymer is limited, the corrosion period of
the iron-based alloy is longer, and it is difficult to meet the
clinical degradation time requirement for the degradable stent.
Therefore, it is necessary to adopt a specific degradable polymer
that is matched with the iron-based alloy substrate, realizing the
rapid and controllable corrosion of the iron-based alloy, thus
obtaining an absorbable iron-based alloy stent capable of meeting
the clinical requirements.
SUMMARY OF THE INVENTION
[0006] The technical problem to be solved by the present invention
is to provide an absorbable iron-based alloy stent capable of
degrading rapidly and controllably within a predetermined period
after being implanted into the body in order to overcome the
shortcomings of the prior art.
[0007] As the first technical solution adopted by the present
invention, the absorbable iron-based alloy stent comprises an
iron-based alloy substrate and a degradable polyester in contact
with the surface of the substrate, in which the degradable
polyester has a weight average molecular weight in range of 20,000
and 1,000,000 and a polydispersity index of between 1.2 and 30.
[0008] As the second technical solution adopted by the present
invention, the absorbable iron-based alloy stent comprises an
iron-based alloy substrate and a degradable polyester in contact
with the surface of the substrate, in which the degradable
polyester has a weight average molecular weight in range of 20,000
and 1,000,000 and a polydispersity index of more than 1.0 and less
than 1.2, or more than 30 and less than or equal to 50.
[0009] As the third technical solution adopted by the present
invention, the absorbable iron-based alloy stent comprises an
iron-based alloy substrate and a degradable polymer in contact with
the surface of the substrate, in which the degradable polymer has a
weight average molecular weight in range of 20,000 and 1,000,000
and a polydispersity index of more than 1.0 and more than or equal
to 50. After the iron-based alloy stent is implanted into the body,
the degradable polymer degrades to produce a carboxyl group. In the
third technical solution, the degradable polymer may be a
degradable polyester, a blend of the degradable polyester and a
degradable polyanhydride, or a copolymer formed by copolymerizing
monomers forming the degradable polyester and the degradable
polyanhydride.
[0010] The iron-based alloy substrate described in the present
invention refers to a bare iron-based alloy stent, and the
iron-based alloy substrate is selected from pure iron or a medical
iron-based alloy. At least one of nutrient elements and harmless
elements in the human body, or less toxic elements, such as C, N,
O, S, P, Mn, Pd, Si, W, Ti, Co, Cr, Cu, and Re may be doped into
the pure iron to form the medical iron-based alloy.
[0011] The numerical interval is in accordance with the
mathematical knowledge, namely. [a, b] means more than or equal to
a and less than or equal to b; (a, b] means more than a and less
than or equal to b; [a, b) means more than or equal to a and less
than b. The same symbols shall apply hereinafter without need of
repetition.
[0012] The term "rapid" means that the degradable polyester can
accelerate the corrosion of the iron-based alloy substrate, so that
the iron-based alloy substrate can completely corrode within 5
years after being implanted into the body.
[0013] The term "controllable" means that the corrosion of the
iron-based alloy substrate caused by the degradable polyester
ensures that the iron-based alloy stent has good mechanical
properties at early stage after being implanted into the human
body, and also enables the stent to produce a small amount of
hydrogen or no hydrogen. A small amount of hydrogen refers to an
amount that is not sufficient to form a risk of air embolism
clinically.
[0014] The term "complete corrosion" means that the mass loss rate
W of the iron-based alloy stent is more than or equal to 90
percent.
[0015] The complete corrosion is characterized by a mass loss test
of an animal experiment. The mass loss test is carried out by
implanting an iron-based alloy stent with an iron-based alloy
substrate (i.e., a bare stent excluding a degradable polymer) of
which the mass is M.sub.0 into the abdominal aorta of a rabbit,
cutting out the iron-based alloy stent implanted into an animal
body and the tissue in which the iron-based alloy stent is placed
at a predetermined observation point in time, soaking the tissue
together with the stent in a solution of certain concentration
(such as 1 mol/L of a sodium hydroxide solution) so that the tissue
is digested, and then taking a stent strut out of the solution,
putting the stent strut into a solution of a certain concentration
(such as 3% of a tartaric acid solution, and/or an organic
solution) to be ultrasonically cleaned so that corrosion products
on the surface of the stent are all stripped off or dissolved in
the solution, taking the residual stent strut out of the solution,
drying and weighing the stent strut to obtain the mass M.sub.t. The
mass loss rate W is expressed by a percentage of the weight loss
difference value of the stent strut after corrosion and cleaning in
weight of the iron-based alloy substrate, as shown in Formula
1-1:
W = ( M 0 - M t ) M 0 .times. 100 % ( Formula 1 - 1
##EQU00001##
[0016] W--Mass loss rate
[0017] M.sub.t--Mass of the residual stent strut after
corrosion
[0018] M.sub.0--Mass of the iron-based alloy substrate
[0019] When the mass loss rate W of the stent is more than or equal
to 90 percent, the iron-based alloy stent is deemed to be
completely corroded.
[0020] The good mechanical properties obtained at early stage of
implantation into the body are determined by specific clinical
requirements. Generally. "early stage" refers to within 1 month, or
3 months, or 6 months after implantation into the body. The
mechanical properties can be tested and verified by an animal
experiment, and expressed by early OCT follow-up or a radial
support force test. When the OCT follow-up is carried out, there is
no obvious difference between the surrounding area of the stent and
the surrounding area of the stent at the beginning of implanting,
or when the radial support force test is carried out, the radial
support force is more than 23.3 kPa (175 mm mercury column),
indicating that the stent has good mechanical properties at early
stage of implantation into the body.
[0021] Compared with the prior art, the iron-based alloy stent
provided by the present invention does not produce hydrogen at all
or only produces a small amount of hydrogen in the whole corrosion
process, which is specifically tested and verified by means of an
animal experiment. For example, the iron-based alloy stent is
implanted into the abdominal aorta of a rabbit, and the periphery
of the support strut is observed by a microscope at the same
amplification factor at the predetermined observation point in
time, such as 1 month, 3 months, 6 months, 2 years, 3 years or 5
years after the stent is implanted into the body; if few stent
strut coating slightly bulges, the stent is deemed to produce a
small amount of hydrogen during corrosion; if the stent strut
uniformly corrodes, and there are no bubbles around the stent
strut, the stent is deemed to not produce hydrogen at all in the
corrosion process.
[0022] In the above-mentioned first to third technical solutions,
the weight average molecular weight of the degradable polyester is
more than or equal to 20,000 and less than 100,000, or more than or
equal to 100,000 and less than 250,000, or more than or equal to
250,000 and less than 400,000, or more than or equal to 400,000 and
less than 600,000, or more than or equal to 600,000 and less than
or equal to 1,000,000.
[0023] In the above-mentioned first technical solution, the
polydispersity index of the degradable polyester is more than or
equal to 1.2 and less than 2, or more than or equal to 2 and less
than 3, or more than or equal to 3 and less than 5, or more than or
equal to 5 and less than 10, or more than or equal to 10 and less
than 20, or more than or equal to 20 and less than or equal to
30.
[0024] In the above-mentioned third technical solution, the
polydispersity index of the degradable polyester is more than or
equal to 1.2 and less than 2, or more than or equal to 2 and less
than 3, or more than or equal to 3 and less than 5, or more than or
equal to 5 and less than 10, or more than or equal to 10 and less
than 20, or more than or equal to 20 and less than 30, or more than
or equal to 30 and less than or equal to 50.
[0025] In the above-mentioned first and second technical solutions,
the mass ratio of the iron-based alloy substrate to the degradable
polyester is more than or equal to 1 and less than or equal to 200.
Furthermore, in the above-mentioned first and second technical
solutions, the mass ratio of the iron-based alloy substrate to the
degradable polyester is more than or equal to 5 and less than or
equal to 50.
[0026] In the above-mentioned third scheme, the mass ratio of the
iron-based alloy substrate to the degradable polymer is more than
or equal to 1 and less than or equal to 200.
[0027] Furthermore, in the above-mentioned third scheme, the mass
ratio of the iron-based alloy substrate to the degradable polymer
is more than or equal to 5 and less than or equal to 50.
[0028] In the above-mentioned first and second technical solutions,
the surface of the iron-based alloy substrate is coated with the
degradable polyester in the form of a coating layer. In the
above-mentioned third technical solution, the surface of the
iron-based alloy substrate is coated with the degradable polymer in
the form of a coating layer.
[0029] In the above-mentioned first to third technical solutions,
the wall thickness of the iron-based alloy substrate is more than
or equal to 30 .mu.m and less than 50 .mu.m, and the thickness of
the degradable polyester coating or degradable polymer coating is
more than or equal to 3 .mu.m and less than 5 .mu.m, or more than
or equal to 5 .mu.m and less than 10 .mu.m, or more than or equal
to 10 .mu.m and less than 15 .mu.m, or more than or equal to 15
.mu.m and less than or equal to 20 .mu.m.
[0030] In the above-mentioned first to third technical solutions,
the wall thickness of the iron-based alloy substrate is more than
or equal to 50 .mu.m and less than 100 .mu.m, and the thickness of
the degradable polyester coating or degradable polymer coating is
more than or equal to 5 .mu.m and less than 10 .mu.m, or more than
or equal to 10 .mu.m and less than 15 .mu.m, or more than or equal
to 15 .mu.m and less than 20 .mu.m, or more than or equal to 20
.mu.m and less than or equal to 25 .mu.m.
[0031] In the above-mentioned first to third technical solutions,
the wall thickness of the iron-based alloy substrate is more than
or equal to 100 .mu.m and less than 200 .mu.m, and the thickness of
the degradable polyester coating or degradable polymer coating is
more than or equal to 10 .mu.m and less than 15 .mu.m, or more than
or equal to 15 .mu.m and less than 20 .mu.m, or more than or equal
to 20 .mu.m and less than 25 .mu.m, or more than or equal to 25
.mu.m and less than or equal to 35 .mu.m.
[0032] In the above-mentioned first to third technical solutions,
the wall thickness of the iron-based alloy substrate is more than
or equal to 200 .mu.m and less than or equal to 300 .mu.m, and the
thickness of the degradable polyester coating or degradable polymer
coating is more than or equal to 10 .mu.m and less than 15 .mu.m,
or more than or equal to 15 .mu.m and less than 20 .mu.m, or more
than or equal to 20 .mu.m and less than 25 .mu.m, or more than or
equal to 25 .mu.m or less than 35 .mu.m, or more than or equal to
35 .mu.m and less than or equal to 45 .mu.m.
[0033] In the above-mentioned first to second technical solutions
and the third technical solution, when the degradable polymer is a
degradable polyester, the degradable polyester is any one of the
following: polylactic acid (PLA), polyglycolic acid (PGA), poly
(butylene succinate) (PBS), poly (beta-hydroxybutyrate) (PHB),
polycaprolactone (PCL), poly (ethyleneglycol adipate) (PEA), poly
(lactic-co-glycolic acid) (PLGA), and poly
(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV).
[0034] In the above-mentioned first to second technical solutions
and the third technical solution, when the degradable polymer is a
degradable polyester, the degradable polyester comprises at least
two kinds of the same type of degradable polyester polymers. The
"same type" refers to a general term of polymers with the same
structural unit (i.e., the monomers are the same) and different
weight average molecular weights. The first kind of degradable
polyester polymer has a weight average molecular weight of more
than or equal to 20,000 and less than 100,000 and the second kind
of degradable polyester polymer has a weight average molecular
weight that is greater than or equal to 100,000 and less than or
equal to 1,000,000. The mass ratio of the first kind of degradable
polyester polymer to the second kind of degradable polyester
polymer is in the range of 1:9 to 9:1. The same type of degradable
polyester polymer is selected from the group consisting of
polylactic acid (PLA), polyglycolic acid (PGA), poly(butylene
succinate)(PBS), poly (beta-hydroxybutyrate) (PHB),
polycaprolactone (PCL), poly(ethyleneglycol adipate) (PEA),
poly(lactic-co-glycolic acid) (PLGA), or
poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). The surface of
the stent can be respectively coated with at least two kinds of the
same type of degradable polyester polymers with different weight
average molecular weights respectively, and can also be coated with
the uniformly mixed degradable polyester polymers with different
weight average molecular weights.
[0035] Furthermore, in the above-mentioned first to second
technical solutions and the third technical solution, when the
degradable polymer is a degradable polyester, the mass ratio of the
first kind of degradable polyester polymer to the second kind of
degradable polyester polymer is in the range of 1:5 to 5:1.
[0036] In the above-mentioned first to second technical solutions
and the third technical solution, when the degradable polymer is a
degradable polyester, the degradable polyester comprises at least
two kinds of degradable polyester polymers with high molecular
weights, wherein the weight average molecular weights of at least
two kinds of degradable polyester polymers with high molecular
weights are more than or equal to 100,000 and less than 200,000, or
more than or equal to 200,000 and less than 400,000, or more than
or equal to 400,000 and less than 600,000, or more than or equal to
600,000 and less than or equal to 1000,000.
[0037] In the above-mentioned first to second technical solutions
and the third technical solution, when the degradable polymer is a
degradable polyester, the degradable polyester is a mixture of at
least two of polylactic acid (PLA), polyglycolic acid (PGA), poly
(butylene succinate) (PBS), poly (beta-hydroxybutyrate) (PHB),
polycaprolactone (PCL), poly(ethyleneglycol adipate) (PEA),
poly(lactic-co-glycolic acid) (PLGA), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), or a copolymer
formed by copolymerizing at least two of monomers forming
polylactic acid (PLA), polyglycolic acid (PGA), poly (butylene
succinate)(PBS), poly (beta-hydroxybutyrate) (PHB),
polycaprolactone (PCL), poly(ethyleneglycol adipate) (PEA),
poly(lactic-co-glycolic acid) (PLGA), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). As an example,
the degradable polyester may comprise polylactic acid (PLA) and
poly (lactic-co-glycolic acid)(PLGA), wherein the weight average
molecular weight of PLGA is more than or equal to 20,000 and less
than 300,000, the weight average molecular weight of PLA is more
than or equal to 20,000 and less than or equal to 1,000,000, and
the content ratio of the two is in the range of 1:9 to 9:1.
[0038] In the above-mentioned first to second technical solutions
and the third technical solution, when the degradable polymer is a
degradable polyester, the degradable polyester is a mixture of at
least two kinds of degradable polyester polymers with different
crystallinity, wherein the content of degradable polyester polymer
with crystallinity in the range of 5% to 50% is in the range of 10%
to 90% in percentage by mass. The degradable polyester polymer is
selected from the group consisting of polylactic acid (PLA),
polyglycolic acid (PGA), poly (butylene succinate)(PBS), poly
(beta-hydroxybutyrate) (PHB), polycaprolactone (PCL), poly
(ethyleneglycol adipate) (PEA), poly (lactic-co-glycolic acid)
(PLGA), and poly (3-hydroxybutyrate-co-3-hydroxyvalerate)
(PHBV).
[0039] At least two kinds of degradable polyester polymers with
different crystallinity include the following: the degradable
polyester may be a mixture of crystalline and non-crystalline
degradable polyester polymers, or a blend of degradable polyester
polymers with low crystallinity and high crystallinity. For
example, the degradable polyester comprises polylactic acid (PLA)
with crystallinity in the range of 5% to 50%, and the content of
the polylactic acid (PLA) is in the range of 10% to 900% in
percentage by mass. Preferably, the polylactic acid (PLA) may be
poly (DL-lactic acid) or poly (L-lactic acid).
[0040] In the above-mentioned third technical solution, when the
degradable polymer is a mixture of a degradable polyester and a
degradable polyanhydride, or a degradable copolymer formed by
copolymerizing monomers forming the degradable polyester and the
degradable polyanhydride, the degradable polyester and the
degradable polyanhydride have weight average molecular weights more
than or equal to 20,000 and less than or equal to 1,000,000, and
polydispersity indexes of more than 1.0 and less than or equal to
50, the polyanhydride is selected from the group consisting of poly
(1, 3-bis(p-carboxyphenoxy) propane-sebacic acid) and poly (erucic
acid dimer-sebacic acid) or poly (fumaric-sebacic acid), and the
degradable polyester is any one of the following: polylactic acid
(PLA), polyglycolic acid (PGA), poly (butylene succinate)(PBS),
poly (beta-hydroxybutyrate) (PHB), polycaprolactone (PCL),
poly(ethyleneglycol adipate) (PEA), poly(lactic-co-glycolic acid)
(PLGA), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV).
The mass ratio of the degradable polyester to the polyanhydride is
in the range of 1:9 to 9:1.
[0041] In the above-mentioned third technical solution, in the
mixture of the degradable polyester and the degradable
polyanhydride, the content of degradable polyester or degradable
polyanhydride with crystallinity in the range of 5% to 50% is in
the range of 10% to 90% in percentage by mass, the degradable
polyester polymer is selected from the group consisting of
polylactic acid (PLA), polyglycolic acid (PGA), poly (butylene
succinate) (PBS) and poly (beta-hydroxybutyrate) (PHB),
polycaprolactone (PCL), poly (ethyleneglycol adipate) (PEA), poly
(lactic-co-glycolic acid) (PLGA), and poly
(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), and the
polyanhydride is selected from the group consisting of poly (1,
3-bis(p-carboxyphenoxy) propane-sebacic acid) and poly(erucic acid
dimer-sebacic acid) or poly(fumaric-sebacic acid).
[0042] In the above-mentioned first to third technical solution,
the degradable polyester or degradable polymer may also be in
contact with the surface of the iron-based alloy substrate in the
form of a non-coating layer, for example, the iron-based alloy
substrate is provided with gaps or grooves, and the degradable
polyester or the degradable polymer is arranged in the gaps or
grooves; or the iron-based alloy substrate is provided with an
inner cavity, and the degradable polyester or the degradable
polymer is filled in the inner cavity. At least one of the
non-coating contact form and the coating form in the
above-mentioned example is selected. Namely, in the above-mentioned
first to third technical solutions, the "surface" of "in contact
with the surface of the substrate" not only refers to the outer
surface, but also refers to all circumstances in which the
degradable polyester or the degradable polymer has a contact point
or contact surface with the iron-based alloy substrate.
[0043] In the above-mentioned first to third technical solutions,
the degradable polyester or the degradable polymer may also be
mixed with an active drug, and the mass ratio of the degradable
polyester or the degradable polymer to the drug is in the range of
0.1 to 20. The active drug may be a vascular proliferation
inhibiting drug such as paclitaxel, rapamycin and their
derivatives, or an antiplatelet drug selected from cilostazol, or
an antithrombotic drug such as heparin, or an anti-inflammatory
drug such as dexamethasone, or a mixture of the above-mentioned
drugs. Furthermore, the mass ratio of the degradable polyester or
the degradable polymer to the drug is in the range of 0.5 to
10.
[0044] Compared with the prior art, the specific degradable polymer
used by the absorbable iron-based alloy stent provided by the
present invention can allow the iron-based alloy substrate to
undergo oxygen-consuming corrosion under the action of the
degradable polymer, with minimal or no hydrogen produced, thus
avoiding the clinical air embolism risk caused by a large amount of
hydrogen being produced by hydrogen evolution corrosion in the
prior art, and also meeting the clinical early mechanical property
requirements for the stent.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0045] FIG. 1 is a sectional schematic diagram of a stent strut
after an iron-based alloy stent provided by Example 5 of the
present invention is coated with a degradable polyester coating
layer;
[0046] FIG. 2 is a microphotograph illustrating that a small amount
of hydrogen is produced in a stent strut in Example 7 of the
present invention;
[0047] FIG. 3 is a microphotograph illustrating that a small amount
of hydrogen is produced in a stent strut in Example 9 of the
present invention;
[0048] FIG. 4 is a microphotograph illustrating that a small amount
of hydrogen is produced in a stent strut in Example 12 of the
present invention;
[0049] FIG. 5 is a microphotograph illustrating that a small amount
of hydrogen is produced in a stent strut in Example 13 of the
present invention;
[0050] FIG. 6 is a microphotograph illustrating that a small amount
of hydrogen is produced in a stent strut in Example 14 of the
present invention;
[0051] FIG. 7 is a microphotograph illustrating that a large amount
of hydrogen is produced in a stent strut in the corrosion process
in Control Example 2.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0052] According to the absorbable iron-based alloy stent provided
by the present invention, animal experiments are adopted to test
and verify whether the iron-based alloy stent can rapidly and
controllably corrode under the action of a degradable polymer or
not, whether the iron-based alloy stent controllably corrodes or
not is mainly determined by early mechanical properties and whether
a large amount of hydrogen is produced at predetermined observation
points in time or not, and whether the iron-based stent rapidly
corrodes or not is determined by a mass loss test.
[0053] Specifically after the iron-based alloy stent containing the
degradable polymer was implanted into an animal body, the test was
carried out at each of the predetermined observation points in
time. For example, at 3 months from the date of implantation, an
OCT follow-up test was carried out, it was found that there was no
obvious difference between the surrounding area of the stent strut
at this observation point and that of the original stent strut at
the beginning of implanting, or animals were killed humanely, the
stent and the tissue in which the stent is placed were taken out of
the body, and the stent together with the blood vessel in which the
stent is placed were subject to a radial support force test to
determine if the stent meets the early mechanical properties; a
stent was taken out at 2 years to measure the mass loss of the
stent so as to observe the corrosion situation of the stent. The
stent taken out of the body was axially split at each observation
point in time, and the periphery of the support strut of each
observed stent was observed by a microscope at the same
amplification factor so as to determine whether a large amount of
hydrogen is produced in the corrosion process of the stent.
[0054] The radial support force can be tested by means of a radial
support force tester RX550-100 produced by the MSI Company; namely,
the radial support force can be obtained by taking out the stent
implanted into the animal body at a predetermined observation point
in time together with the blood vessel and then directly
testing.
[0055] The complete corrosion is characterized by a mass loss test
of an animal experiment. The mass loss test is carried out by
implanting an iron-based alloy stent with an iron-based alloy
substrate (i.e., a bare stent excluding a degradable polymer) of
which the mass is M.sub.0 into the abdominal aorta of a rabbit,
cutting out the iron-based alloy stent implanted into an animal
body and the tissue in which the iron-based alloy stent is placed
at a predetermined observation point in time, soaking the tissue
together with the stent in a solution of certain concentration
(such as 1 mol/L of a sodium hydroxide solution) so that the tissue
is digested, and then taking a stent strutout of the solution,
putting the stent strut into a solution of certain concentration
(such as 3% of a tartaric acid solution, and/or an organic
solution) to be ultrasonically cleaned so that corrosion products
on the surface of the stent are all stripped off or dissolved in
the solution, taking the residual stent strut out of the solution,
drying and weighing the stent strut to obtain the mass M.sub.t. The
mass loss rate W is expressed by a percentage of the weight loss
difference value of the stent strut after corrosion and cleaning in
weight of the iron-based alloy substrate, as shown in Formula
1-1:
W = ( M 0 - M t ) M 0 .times. 100 % ( Formula 1 - 1
##EQU00002##
[0056] W--Mass loss rate
[0057] M.sub.t--Mass of the residual stent strut after
corrosion
[0058] M.sub.0--Mass of the iron-based alloy substrate
[0059] When the mass loss rate W of the stent is more than or equal
to 90 percent, the iron-based alloy stent is deemed to completely
corroded. The weight average molecular weight and the
polydispersity index of the degradable polymer were tested by using
an eight-angle laser light scattering instrument produced by the
Wyatt Technology Corporation.
[0060] The absorbable iron-based alloy stent provided by the
present invention is further illustrated in conjunction with the
following accompanying drawings and examples. It should be
understood that the following examples are only preferred examples
of the present invention described herein, but not to limit the
present invention. Any modifications, equivalent replacements,
improvements. etc. made within the spirit and principles of the
present invention should fall in the scope of the present invention
described herein.
Example 1
[0061] A pure iron stent comprises a pure iron substrate and a
degradable polymer coating with which the surface of the pure iron
substrate is coated, wherein the mass ratio of the pure iron
substrate to the degradable polymer is 5:1. The degradable polymer
is polyglycolic acid (PLA) with a weight average molecular weight
of 200,000 and a polydispersity index of 1.8, and the wall
thickness of the iron substrate is between 80 .mu.m and 90 .mu.m,
and the thickness of the degradable polymer coating is between 15
.mu.m and 20 .mu.m. The stent was implanted into the abdominal
aorta of a rabbit. The stent and the tissue in which the stent was
placed were taken out at 3 months after the date of implantation, a
radial support force test was carried out, and the test result that
the radial support force was 70 kPa was obtained, indicating that
the degradable polymer was well matched with the iron-based alloy
substrate, and the early mechanical properties of the stent could
be ensured; the periphery of the stent strut was observed with a
microscope, no hydrogen bubbles were found. After 2 years from the
date of implantation, a mass loss test was carried out by sampling
again, and the mass loss rate of the stent was 95 percent,
indicating that the stent completely corroded; no hydrogen bubbles
were found by observing the periphery of the stent strut with a
microscope.
Example 2
[0062] The surface of a bare nitrided pure iron stent (i.e., a
nitrided pure iron substrate) of which the wall thickness is
between 65 .mu.m and 75 .mu.m was uniformly coated with a 10 to 12
.mu.m thick degradable polymer coating, wherein the mass ratio of
the nitrided pure iron substrate to the degradable polymer is 25,
and the degradable polymer coating is a poly(DL-lactic acid)
coating with a weight average molecular weight of 100,000 and a
polydispersity index of 3. The absorbable iron-based alloy stent
was obtained after drying. The iron-based alloy stent was implanted
into the coronary artery of a pig. At 3 months from the date of
implantation, it was found that there was no difference between the
surrounding area of the stent strut and the surrounding area of the
stent strut at the beginning of implanting by OCT follow-up. The
stent was taken out at 1 year after the implanting, the mass loss
rate of the stent was 92 percent by a mass loss test, indicating
that the stent completely corroded. At 3 months and 1 year after
the date of implantation, the stent was taken out, and then no
hydrogen bubbles were produced by observing the periphery of the
stent strut with a microscope respectively.
Example 3
[0063] The surface of a bare electrodeposited pure iron
(550.degree. C. annealing) stent (i.e., an electrodeposited pure
iron substrate) of which the wall thickness is between 40 .mu.m and
50 .mu.m was uniformly coated with a 3 to 5 .mu.m thick mixture
coating of polycaprolactone (PCL) and paclitaxel, wherein the mass
ratio of the electrodeposited pure iron substrate to the degradable
polymer was 35:1, the polycaprolactone (PCL) was formed by mixing
two kinds of polycaprolactones (PCL) with weight average molecular
weights of 30,000 and 80,000 according to a ratio of 1 to 2, the
polydispersity index of the mixed polycaprolactones (PCL) was 25,
and the mass ratio of polycaprolactones (PCL) to paclitaxel was 2
to 1. An absorbable iron-based alloy stent was obtained after
drying. The iron-based alloy stent was implanted into the abdominal
aorta of a rabbit. The stent was taken out at a corresponding
observation point in time, the surface of the stent was observed
with a microscope, and the radial support force and the mass loss
percentage of the stent were tested. The test results showed that
the radial support force was 60 kPa at 3 months after the date of
implantation; after 1 year from the date of implantation, the mass
loss rate of the stent was 98 percent, indicating that the stent
completely corroded, and there were no hydrogen bubbles around the
stent strut by observing with a microscope at the two observation
points in time.
Example 4
[0064] The outer wall surface of a bare carburized iron stent
(i.e., a carburized iron substrate) obtained after heat treatment
was coated with a poly (L-lactic acid) coating, wherein the wall
thickness of the carburized iron substrate is between 140 .mu.m and
160 .mu.m, the thickness of the poly (L-lactic acid) coating is
between 30 .mu.m and 35 .mu.m, and the mass ratio of the carburized
iron substrate to the poly (L-lactic acid) is 120. The coating
comprises two layers. i.e., a PLLA coating with crystallinity of 50
percent as a bottom layer and a PLLA coating with crystallinity of
5 percent as a top layer, the weight average molecular weights of
the two layers are 600,000, and the polydispersity indexes of the
two layers of poly (L-lactic acid) are 1.2. The mass ratio of the
degradable polymer coating with crystallinity of 50 percent to the
degradable polymer coating with crystallinity of 5 percent is 1:1.
An absorbable iron-based alloy stent was obtained after drying. The
stent was implanted into the abdominal aorta of a rabbit. The stent
was taken out at a corresponding observation point in time, the
surface of the stent was observed with a microscope, and the radial
support force and the weight loss percentage of the stent were
tested. The test results showed that the radial support force was
45 kPa at 6 months after the implanting; after 3 years from the
date of implantation, the mass loss rate of the stent was 92
percent, and there were no hydrogen bubbles around the stent strut
at the above-mentioned two observation points in time.
Example 5
[0065] A bare iron-manganese alloy stent (i.e., an iron-manganese
alloy substrate) was polished so that grooves were distributed in
the surface of the stent. As shown in FIG. 1, a stent strut of the
stent has a thickness of between 100 .mu.m and 120 .mu.m, and
grooves 2 are arranged in the surface of the stent strut 1. A
degradable polyester polymer mixture coating 3 was uniformly coated
on the surface of the stent strut 1 and in the grooves 2. The
degradable polyester polymer coating was formed by mixing poly
(L-lactic acid) with a weight average molecular weight of 1,000,000
and poly (lactic-glycolic acid) with a weight average molecular
weight of 20,000 (the molar ratio of lactic acid to glycolic acid
is 50:50) according to a mass ratio of 5 to 1, wherein the
polydispersity index of the polyglycolic acid is 10 after mixing,
the thickness of the mixture coating is between 20 .mu.m and 25
.mu.m, and the mass ratio of the iron-based alloy substrate to the
degradable polymer is 40:1. An absorbable iron-based alloy stent
was obtained after drying. The stent was implanted into the
abdominal aorta of a pig. A stent was taken out at a corresponding
observation point in time, and then the mass loss rate and the
radial support force of the stent were tested. The test results
showed that the radial support force was 60 kPa at 3 months after
the implanting; after 2 years from the date of implantation, the
mass loss rate of the stent was 95% by a mass loss test, and there
were no hydrogen bubbles around the stent strut by observing at the
above-mentioned two observation points in time.
Example 6
[0066] The outer surface of a bare iron-carbon alloy stent (i.e.,
an iron-carbon alloy substrate) with a thickness of between 30
.mu.m and 40 .mu.m, excluding the inner wall of a tubular cavity of
the stent, was uniformly coated with a 5 to 8 .mu.m thick
poly(butylene succinate) (PBS) coating, wherein the mass ratio of
the iron-carbon alloy substrate to poly(butylene succinate) (PBS)
is 12:1, and the poly(butylene succinate) (PBS) has a weight
average molecular weight of 60,000 and a polydispersity index of 2.
An absorbable iron-based alloy stent was obtained after drying. The
stent was implanted into the abdominal aorta of a rabbit. The stent
was taken out at a corresponding observation point in time, and a
mass loss test and a radial support force test of the stent were
carried out. The results showed that the radial support force of
the stent was 50 kPa at 1 month after the implanting; after 1.5
years from the date of implantation, the mass loss rate of the
stent was 99 percent, and no hydrogen bubbles were found by
observing the periphery of the stent strut with a microscope at the
above-mentioned observation points in time.
Example 7
[0067] The surface of a bare sulfurized iron stent (i.e., a
sulfurized iron-based alloy substrate) with a wall thickness of
between 250 .mu.m and 270 .mu.m was uniformly coated with a 35 to
45 .mu.m thick degradable polymer coating. The mass ratio of the
sulfurized iron-based alloy substrate to the degradable polymer is
50:1, and the degradable polymer is formed by mixing polylactic
acid (PLA) and PLGA, wherein the polylactic acid has a weight
average molecular weight of 30,000, crystallinity of 40 percent,
the content of 90 percent, and a polydispersity index of 1.8, and
the PLGA has a weight average molecular weight of 30,000, a
polydispersity index of 4, crystallinity of 5 percent and the
content of 10 percent. An absorbable iron-based alloy stent was
obtained after drying. The stent was implanted into the abdominal
aorta of a pig. The stent was taken out at a corresponding
observation point in time, and a mass loss test of the iron-based
alloy stent was carried out. The test results showed that the
radial support force of the stent was 50 kPa at 6 months after the
date of implantation, and it was found that the periphery of few
stent strut slightly bulges. i.e., a small amount of hydrogen was
produced by observing the periphery of the iron-based alloy stent
strut with a microscope as shown in FIG. 2; after 4.5 years from
the date of implantation, the mass loss rate of the stent was 90
percent, and no hydrogen bubbles were found.
Example 8
[0068] The surface of a bare iron-manganese alloy stent (i.e., an
iron-manganese alloy substrate) with a wall thickness of between
120 .mu.m and 150 .mu.m was coated with a 15 to 20 .mu.m thick
coating. The coating was formed by mixing poly
(beta-hydroxybutyrate) (PHB), poly (fumaric-sebacic acid) and
heparin according to a mass ratio of 8 to 1 to 1, wherein the mass
ratio of the iron-based alloy substrate to a degradable polymer.
i.e., the mass sum of poly (beta-hydroxybutyrate) (PHB) and poly
(fumaric-sebacic acid) is 80. PLLA has a weight average molecular
weight of 300,000, crystallinity of 30%, and a polydispersity index
of 2, and the PLGA has a weight average molecular weight of 100,000
and a polydispersity index of 45. An absorbable iron-based alloy
stent was obtained after drying. The stent was implanted into the
abdominal aorta of a rabbit. The stent was taken out at a
corresponding observation point in time, and then the radial
support force test and the mass loss test of the iron-based alloy
stent were carried out. The results showed that that the radial
support force of the iron-based alloy stent was 60 kPa at 3 months
after the date of implantation; after 3 years from the date of
implantation, the mass loss rate of the stent was 95 percent, and
no hydrogen bubbles were found by observing the periphery of the
stent strut with a microscope at the above-mentioned observation
points in time.
Example 9
[0069] The surface of a bare carburized iron stent (i.e., a
carburized iron substrate) with a wall thickness of between 50
.mu.m and 70 .mu.m was coated with a degradable polymer coating
with an average thickness of between 12 .mu.m and 15 .mu.m. The
degradable polymer coating was formed by mixing poly (DL-lactic
acid) (PDLLA) and rapamycin according to a mass ratio of 2 to 1,
wherein the PDLLA has a weight average molecular weight of 200,000
and a polydispersity index of 1.6, and the mass ratio of the
carburized iron substrate to the degradable polymer coating is 30.
An absorbable iron-based alloy stent was obtained after drying. The
iron-based alloy stent was implanted into the coronary artery of a
pig. The iron-based alloy stent was taken out at a corresponding
observation point in time to undergo a mass loss test and a radial
support force test. The results showed that at 3 months after the
date of implantation, the radial support force was 60 kPa, and it
was found that a small amount of hydrogen was produced in the local
stent strut, and few iron-based alloy stent coating slightly bulges
by observing the periphery of the iron-based alloy stent strut with
a microscope as shown in FIG. 3. At 2 years after the date of
implantation, the mass loss rate of the stent was 98 percent, and
no hydrogen bubbles were found.
Example 10
[0070] The surface of a bare pure iron stent (i.e., a pure iron
substrate) of which the wall thickness is between 50 .mu.m and 60
.mu.m was uniformly coated with a 8 to 12 .mu.m thick degradable
polymer coating, wherein the mass ratio of the pure iron substrate
to the degradable polymer coating is 20:1, the degradable polymer
as a bottom layer in the degradable polymer coating is PLLA with a
weight average molecular weight of 300,000 and a thickness of about
6 to 8 .mu.m, the top layer is PDLLA with a weight average
molecular weight of 300,000, and the polydispersity index of the
degradable polymer coating is 15. An iron-based alloy stent was
obtained after drying. The iron-based alloy stent was implanted
into the coronary artery of a pig. OCT follow-up was carried out at
3 months after the date of implantation, the OCT testing results
showed that there was no difference between the surrounding area of
the iron-based alloy stent and the surrounding area of the
iron-based alloy stent at the beginning of implanting. After 2.5
years from the date of implantation, a mass loss test of the stent
was carried out by sampling, the mass loss rate of the stent was 98
percent, and it was found that no hydrogen bubbles were produced by
observing the periphery of a stent strut by sampling at the
above-mentioned two observation points in time.
Example 11
[0071] The surface of a bare nitrided iron stent (i.e., a nitrided
iron substrate) of which the wall thickness is between 60 .mu.m and
90 .mu.m was coated with a 10 to 15 .mu.m thick
poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) coating with a
weight average molecular weight of 400,000 and a polydispersity
index of 3, and then coated with a mixed coating comprising
polylactic acid (PLA), poly (erucic acid dimer-sebacic acid) and
cilostazol by praying again. The mixed coating with a thickness of
about 10 .mu.m was mainly sprayed on the outer wall and the side
walls of the nitrided iron substrate, wherein the polylactic acid
(PLA) has a weight average molecular weight of 50,000 and a
polydispersity index of 1.6, the poly (erucic acid dimer-sebacic
acid) has a weight average molecular weight of 20,000 and a
polydispersity index of 10, the mass ratio of the polylactic acid
(PLA), the poly (erucic acid dimer-sebacic acid) to the cilostazol
is 1:1:1, and the ratio of the mass of the nitrided iron substrate
to the mass sum of the two degradable polymer coatings is 35:1. An
iron-based alloy stent was obtained after drying. The iron-based
alloy stent was implanted into the coronary artery of a pig. OCT
follow-up was carried out at 3 months after the date of
implantation, and the OCT testing results showed that there was no
difference between the tubular cavity area of the iron-based alloy
stent and the tubular cavity area of the iron-based alloy stent at
the beginning of implanting. After 1.5 years from the date of
implantation, the mass loss rate of the stent was 95 percent, and
it was found that no hydrogen bubbles were produced around the
stent strut by sampling at the two points in time.
Example 12
[0072] A stent strut of a bare nitrided iron stent (i.e., a
nitrided iron substrate) of which the wall thickness is between 220
.mu.m and 240 .mu.m was treated so that micropores and grooves are
arranged in the stent strut, and poly (butylene succinate) (PBS) is
uniformly filled in the micropores and the grooves, wherein the
poly (butylene succinate)(PBS) has a weight average molecular
weight of 150,000 and a polydispersity index of 5, and the mass
ratio of the nitrided iron substrate to the poly (butylene
succinate)(PBS) is 5:1. An iron-based alloy stent was obtained
after drying. The stent was implanted into a rabbit body. The
iron-based alloy stent was taken out at a corresponding observation
point in time, and a mass loss test and a radial support force test
were carried out. At 2 months after the date of implantation, the
radial support force of the stent was 75 kPa, and it was found that
a small amount of bubbles was produced by observing the periphery
of the stent strut with a microscope shown in FIG. 4. The mass loss
rate of the iron-based alloy stent was 90 percent and no hydrogen
bubbles were found around the stent strut at 3 years after the date
of implantation.
Example 13
[0073] An iron-cobalt alloy stent comprises an iron-cobalt alloy
substrate and a degradable polymer coating covering the surface of
the substrate, wherein the wall thickness of the iron-cobalt alloy
substrate is in the range of 280 .mu.m to 300 .mu.m, the degradable
polymer coating is a copolymer coating formed by copolymerizing
monomers forming PLLA and PGA, the mass ratio of the monomers
forming the two kinds of degradable polymers is 9:1, the copolymer
has a weight average molecular weight of 50,000, a polydispersity
index of 1.1 and crystallinity of 50 percent, and the thickness of
the copolymer coating is in the range of 35 .mu.m to 45 .mu.m. The
copolymer coating also comprises rapamycin, the ratio of the mass
sum of the two kinds of polymers to the mass of the drug is 0.1:1,
and the mass ratio of the iron-cobalt alloy substrate to the
polymer coating is 25:1. The iron-cobalt alloy stent was implanted
into the abdominal aorta of a pig. The radial support force was
tested by sampling, and the periphery of the stent strut was
observed with a microscope at 3 months and 4.5 years after the date
of implantation. The test results showed that at 3 months after the
date of implantation, the radial support force of the iron-based
alloy stent was 45 kPa and a small amount of hydrogen bubbles was
produced around the stent strut as shown in FIG. 5; the mass loss
rate of the stent strut was 90 percent, and no hydrogen bubbles
were produced around the stent strut at 5 years after the date of
implantation.
Example 14
[0074] The surface of a bare iron-carbon alloy stent (i.e., an
iron-carbon alloy substrate) was coated with a degradable polyester
coating, wherein the wall thickness of the iron-carbon alloy
substrate is in the range of 180 .mu.m to 200 .mu.m, the thickness
of the degradable polyester coating is in the range of 20 .mu.m to
25 .mu.m. The degradable polyester coating is formed by mixing poly
(butylene succinate) (PBS) and polyglycolic acid (PGA) according to
a mass ratio of 9:1, and the blend has a weight average molecular
weight of 250,000 and a polydispersity index of 2. The degradable
polyester coating may also be mixed with heparin, wherein the mass
ratio of the degradable polyester to the heparin is 20:1, and the
mass ratio of the iron-carbon alloy substrate to the degradable
polyester is 40:1. An iron-based alloy stent was obtained after
drying. The iron-based alloy stent was implanted into the abdominal
aorta of a pig. The radial support force was tested by sampling,
and the periphery of a stent strut was observed with a microscope
at 3 months and 3 years after the date of implantation. The test
results showed that the radial support force was 75 kPa at 3 months
after the date of implantation, and a small amount of hydrogen
bubbles was produced around the stent strut as shown in FIG. 6; the
mass loss rate of the stent strut was 95 percent, and no hydrogen
bubbles were produced around the stent strut at 3 years after the
date of implantation.
Example 15
[0075] An iron-nitrogen alloy stent comprises an iron-nitrogen
alloy substrate and a degradable polymer coating covering the
surface of the substrate, wherein the wall thickness of the
iron-nitrogen alloy substrate is in the range of 90 .mu.m to 100
.mu.m, and the thickness of the degradable polymer coating is in
the range of 15 .mu.m to 20 .mu.m. The coating is formed by mixing
polylactic acid (PLA) and poly(ethyleneglycol adipate) (PEA)
according to a mass ratio of 1 to 5, wherein the weight average
molecular weights of the polylactic acid (PLA) and the
poly(ethyleneglycol adipate) (PEA) are 500.000 and 300,000
respectively, the polydispersity index of the degradable polyester
coating is 3, and the mass ratio of the iron-nitrogen alloy
substrate to the degradable polyester coating is 10:1. The
iron-based alloy stent was implanted into the abdominal aorta of a
rabbit. The radial support force was tested by sampling, and the
periphery of a stent strut was observed by a microscope at 3 months
and 3 years after the date of implantation. The test results showed
that the radial support force of the iron-based alloy stent was 50
kPa, and no hydrogen bubbles were produced around the stent strut
at 3 months after the date of implantation; the mass loss rate of
the stent strut was 95 percent, and no hydrogen bubbles were
produced around the stent strut at 3 years after the date of
implantation.
Example 16
[0076] An iron-palladium alloy stent comprises an iron-palladium
alloy substrate and a degradable polymer coating covering the
surface of the substrate, wherein the wall thickness of the
iron-palladium alloy substrate is in the range of 70 .mu.m to 90
.mu.m, and the thickness of the degradable polyester coating is in
the range of 10 .mu.m to 15 .mu.m. The degradable polyester coating
is formed by mixing polylactic acid (PLA) and polyglycolic acid
(PGA) according to a mass ratio of 5 to 1, wherein the weight
average molecular weights of the polylactic acid (PLA) and the
polyglycolic acid (PGA) are 800,000 and 20,000 respectively, the
polydispersity index of the mixture is 50, and the mass ratio of
the iron-palladium alloy substrate to the degradable polyester
coating is 15:1. The iron-based alloy stent was implanted into the
abdominal aorta of a rabbit. The radial support force was tested by
sampling, and the periphery of a stent strut was observed with a
microscope at 2 months and 2 years after the date of implantation.
The test results showed that the radial support force of the stent
was 80 kPa, and no hydrogen bubbles were produced around the stent
strut at 2 months after the date of implantation; the mass loss
rate of the stent was 98 percent, and no hydrogen bubbles were
produced around the stent strut at 2 years after the date of
implantation.
[0077] There were thickness differences between every part of each
absorbable iron-based alloy stent in the preparation process,
therefore, the coating thickness and the wall thickness of the
iron-based alloy substrate were interval values in the Examples 1
to 16, and whether hydrogen bubbles were produced around the stent
or not at predetermined observation points in time was observed
with a microscope at the same magnification factor in each
Example.
Control Example 1
[0078] A bare pure iron stent (a pure iron substrate, uncoated with
any coating on the surface) of which the wall thickness is between
60 .mu.m and 70 .mu.m was implanted into the abdominal aorta of a
rabbit. After 3 months from the date of implantation, the stent was
taken out, and the radial support force was 120 kPa by testing; at
3 years after the date of implantation, the stent was taken out to
undergo a mass loss test, and the mass loss rate of the stent was
25 percent at the moment, indicating that the bare pure iron stent
corroded slowly.
Control Example 2
[0079] The surface of a bare pure iron stent (i.e., a pure iron
substrate) of which the wall thickness is in the range of 60 .mu.m
to 70 .mu.m was coated with a 25 .mu.m to 35 .mu.m thick polylactic
acid (PLA) coating, wherein the mass ratio of the pure iron
substrate to the polylactic acid (PLA) is 10:1, and the polylactic
acid (PLA) has a weight average molecular weight of 15,000 and a
polydispersity index of 1.8. An iron-based stent was obtained after
drying. The iron-based stent was implanted into the abdominal aorta
of a rabbit. After 1 month from the date of implantation, the stent
was taken out and axially split, and the periphery of the support
strut was observed with a microscope at the same amplification
factor as those of the above-mentioned Examples; it was found that
a large amount of hydrogen was produced around the stent strut in
the corrosion process, and larger hydrogen bulges were formed as
shown in FIG. 7, indicating that there was a relatively large risk
of air embolism formation. The radial support force was 20 kPa by
testing at 3 months after the date of implantation, and the mass
loss test of the stent showed that the mass loss rate of the stent
was 100 percent at 6 months after the date of implantation,
indicating that the stent completely corroded, the corrosion was
too rapid, and the clinical mechanical property requirement could
not be met at predetermined points in time.
[0080] It can be seen from the test results of the above-mentioned
Examples 1 to 16 and Control examples 1 to 2 that the absorbable
iron-based alloy stent provided by the present invention uses the
degradable polymer with a weight average molecular weight in the
range of 20,000 to 1000,000 and a polydispersity index of more than
1.0 and less than or equal to 50 to achieve a result that no
hydrogen is produced or only a small amount of hydrogen is produced
in 5 years after the iron-based alloy substrate is implanted into
the body. i.e., the oxygen-consuming corrosion mainly occurs, and
the internal corrosion rate is improved by means of
oxygen-consuming corrosion, thereby overcoming the technical biases
that the corrosion rate of an iron-based alloy can only be improved
by hydrogen evolution corrosion in the degradation of the
iron-based alloy and that the degradation speed of the iron-based
alloy is not easily improved by increasing the oxygen-consuming
corrosion rate in the prior art, and further avoiding the clinical
air embolism risk brought by a large amount of hydrogen produced
from the iron-based alloy substrate due to hydrogen evolution
corrosion in the prior art. In addition, the mass loss rate of the
absorbable iron-based alloy stent provided by the invention is not
less than 90 percent in 5 years after the implantation into the
body, thus meeting the clinical corrosion period requirements for
the degradable stent; when the OCT follow-up was carried out, there
was no obvious difference between the surrounding area of the stent
and the surrounding area of the stent at the beginning of
implanting, or the early radial support forces were all more than
23.3 kPa (175 mm mercury column), thus meeting the clinical early
mechanical property requirements for the stent after the
implantation into the body
* * * * *