U.S. patent application number 09/757396 was filed with the patent office on 2001-05-31 for medical devices comprising ionically and non-ionically crosslinked polymer hydrogels having improved mechanical properties.
Invention is credited to Ronan, John A., Thompson, Samuel A..
Application Number | 20010002411 09/757396 |
Document ID | / |
Family ID | 24727594 |
Filed Date | 2001-05-31 |
United States Patent
Application |
20010002411 |
Kind Code |
A1 |
Ronan, John A. ; et
al. |
May 31, 2001 |
Medical devices comprising ionically and non-ionically crosslinked
polymer hydrogels having improved mechanical properties
Abstract
Shaped-medical devices, e.g. stents, having improved mechanical
properties and structural integrity are disclosed. The devices
comprise shaped polymeric hydrogels which are both tonically and
non-ionically crosslinked and which exhibit improved structural
integrity after selective removal of the crosslinking ions. Process
for making such devices are also disclosed wherein an ionically
crosslinkable polymer is both ionically and non-ionically
crosslinked to form a shaped medical device. When implanted in the
body, selective in-vivo stripping of the crosslinking ions produces
a softer, more flexible implant having improved structural
integrity.
Inventors: |
Ronan, John A.; (Wilmington,
DE) ; Thompson, Samuel A.; (Wilmington, DE) |
Correspondence
Address: |
TESTA, HURWITZ & THIBEAULT, LLP
HIGH STREET TOWER
125 HIGH STREET
BOSTON
MA
02110
US
|
Family ID: |
24727594 |
Appl. No.: |
09/757396 |
Filed: |
January 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09757396 |
Jan 8, 2001 |
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09496709 |
Feb 2, 2000 |
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Current U.S.
Class: |
523/113 ;
604/8 |
Current CPC
Class: |
A61L 31/145 20130101;
A61M 27/008 20130101; A61F 2/82 20130101; C08J 3/243 20130101; A61L
31/145 20130101; Y10S 525/903 20130101; C08J 2300/14 20130101; A61L
29/145 20130101; Y10S 524/916 20130101; A61L 31/145 20130101; C08B
37/0084 20130101; Y10S 623/901 20130101; C08B 37/00 20130101 |
Class at
Publication: |
523/113 ;
604/8 |
International
Class: |
A61F 002/00; C08L
001/00; C08J 003/00; C08K 003/00; A61M 005/00 |
Claims
What is claimed is:
1. A process for improving the mechanical properties and structural
integrity of a shaped medical device comprising a crosslinked
polymeric hydrogel, said process comprising subjecting an ionically
crosslinkable polymer composition to crosslinking conditions such
that both ionic and non-ionic crosslinks are formed resulting in a
polymeric hydrogel.
2. The process of claim 1 wherein said ionic crosslinks are formed
by contacting said ionically crosslinkable polymer with a source of
ions.
3. The process of claim 2 wherein said polymer comprises one or a
mixture of polymers selected from the group consisting of
polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide,
poly (N-vinyl pyrolidone), polyethylene oxide, hydrolysed
polyacrylonitrile, polyacrylic acid, polymethacrylic acid,
polyethylene amine, alginic acid, pectinic acid, carboxy methyl
cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan,
carboxymethyl chitosan, chitin, pullulan, gellan, xanthan,
carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate,
cationic guar, cationic starch as well as salts and esters
thereof.
4. The process of claim 2 wherein said polymer comprises an anionic
polymer and said ions are cations selected from the group
consisting of calcium, magnesium, barium, strontium, boron,
beryllium, aluminum, iron, copper, lead and silver ions.
5. The process of claim 2 wherein said polymer comprises a cationic
polymer and said ions are anions selected from the group consisting
of phosphate, citrate, borate, succinate, maleate, adipate and
oxalate ions.
6. The process of claim 2 wherein said polymer comprises one or a
mixture of cationic polymers selected from the group consisting of
chitosan, cationic guar, cationic starch and polyethylene
amine.
7. The process of claim 1 wherein said non-ionic crosslinks are
formed by contacting said ionically crosslinkable polymer under
reaction conditions with a crosslinking agent having at least two
functional groups reactive with one or more functional groups
present in said hydrogel polymer to form covalent bonds.
8. The process of claim 7 wherein said crosslinking agent contains
carboxyl, hydroxy, epoxy, halogen or amino functional groups.
9. The process of claim 8 wherein said crosslinking agent is
selected from the group consisting of glutaraldehyde,
epichlorohydrin, dianhydrides and diamines.
10. The process of claim 9 wherein said crosslinking agent is
glutaraldehyde.
11. The process of claim 2 wherein said polymer comprises a polymer
selected from the group consisting of one or a mixture of alginic
acid, pectinic acid, carboxymethyl cellulose, hyaluronic acid,
chitosan, polyvinylalcohol, and salts and esters thereof.
12. The process of claim 11 wherein said polymer comprises alginic
acid.
13. The process of claim 11 wherein said polymer is an ester of
alginic acid and a C.sub.2 to C.sub.4 alkylene glycol.
14. The process of claim 13 wherein said alkylene glycol is
propylene glycol.
15. The process of claim 2 wherein said polymer comprises a mixture
of alginic or pectinic acid and polyvinylalcohol.
16. The process of claim 1 wherein said shaped medical device is in
the form of a cylindrical hollow tube.
17. The process of claim 1 wherein said shaped medical device is
selected from the group consisting of stents, catheters or
cannulas, plugs, constrictors and tissue or biological
encapsulants.
18. A process for improving the mechanical properties and
structural integrity of a shaped medical device comprising a
polymeric hydrogel, said process comprising: a) providing a
crosslinked polymeric hydrogel composition containing a non-ionic
crosslink structure, said hydrogel polymer characterized as being
ionically crosslinkable and having a primary shape; b) imparting a
secondary shape to said hydrogel polymer composition; and c)
subjecting said hydrogel polymer to ionic crosslinking conditions
to ionically crosslink said hydrogel polymer while retaining said
secondary shape.
19. The process of claim 18 wherein said crosslinked polymeric
hydrogel contains both an ionic and non-ionic crosslink structure,
and wherein at least a portion of the crosslinking ions are
selectively stripped away either prior to or subsequent to step (b)
but prior to step (c).
20. The process of claim 19 wherein said crosslinking ions are
selectively stripped away subsequent to step (b).
21. The process of claim 19 wherein said crosslinking ions are
selectively stripped away by contacting said crosslinked hydrogel
polymer with an aqueous electrolytic solution containing monovalent
cations.
22. The process of claim 21 wherein said monovalent cations are
selected from the group consisting of potassium, sodium and
lithium.
23. The process of claim 18 wherein said non-ionic crosslink
structure present in said crosslinked polymeric hydrogel is formed
by contact of said polymer under reaction conditions with a
crosslinking agent having at least two functional groups reactive
with one or more functional groups present in said polymer to form
covalent bonds.
24. The process of claim 23 wherein said crosslinking agent
contains carboxyl, hydroxy, epoxy, halogen or amino functional
groups.
25. The process of claim 24 wherein said crosslinking agent is
selected from the group consisting of glutaraldehyde,
epichlorohydrin, dianhydrides and diamines.
26. The process of claim 25 wherein said crosslinking agent is
glutaraldehyde.
27. The process of claim 18 wherein said step (c) is carried out by
contacting said hydrogel polymer with an aqueous solution
containing ions.
28. The process of claim 27 wherein said hydrogel polymer comprises
an anionic polymer and said ions are cations selected from the
group consisting of calcium, magnesium, barium, strontium, boron,
beryllium, aluminum, iron, copper, lead and silver.
29. The process of claim 27 wherein said hydrogel polymer comprises
a cationic polymer and said ions are anions selected from the group
consisting of phosphate, citrate, borate, succinate, maleate,
adipate and oxalate ions.
30. The process of claim 18 wherein said shaped medical device is
selected from the group consisting of stents, catheters or
cannulas, plugs, constrictors and tissue or biological
encapsulants.
31. A shaped medical device having improved mechanical properties
comprising a crosslinked polymeric hydrogel, said hydrogel
containing both an ionic and a non-ionic crosslink structure.
32. The device of claim 31 wherein said non-ionic crosslink
structure is a covalent crosslink structure.
33. The device of claim 31 wherein, upon selective removal of the
ionic crosslinks, said device reconfigures substantially to the
non-ionically crosslinked shape.
34. The device of claim 31 wherein said hydrogel comprises one or a
mixture of polymers selected from the group consisting of
polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide,
poly (N-vinyl pyrolidone), polyethylene oxide, hydrolysed
polyacrylonitrile, polyacrylic acid, polymethacrylic acid,
polyethylene amine, alginic acid, pectinic acid, carboxy methyl
cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan,
carboxymethyl chitosan, chitin, pullulan, gellan, xanthan,
carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate,
cationic guar, cationic starch as well as salts and esters
thereof.
35. The device of claim 31 wherein said hydrogel comprises an
anionic polymer and said ions are cations selected from the group
consisting of calcium, magnesium, barium, strontium, boron,
beryllium, aluminum, iron, copper, lead and silver ions.
36. The device of claim 31 wherein said hyrdrogel comprises a
cationic polymer and said ions are anions selected from the group
consisting of phosphate, citrate, borate, succinate, maleate,
adipate and oxalate ions.
37. The device of claim 31 wherein said hydrogel comprises one or a
mixture of cationic polymers selected from the group consisting of
chitosan, cationic guar, cationic starch and polyethylene
amine.
38. The device of claim 31 wherein said non-ionic crosslink
structure is formed by contacting said tonically crosslinkable
polymer under reaction conditions with a crosslinking agent having
at least two functional groups reactive with one or more functional
groups present in said hydrogel polymer to form covalent bonds.
39. The device of claim 38 wherein said crosslinking agent contains
carboxyl, hydroxy, epoxy, halogen or amino functional groups.
40. The device of claim 39 wherein said crosslinking agent is
selected from the group consisting of glutaraldehyde,
epichlorohydrin, dianhydrides and diamines.
41. The device of claim 40 wherein said crosslinking agent is
glutaraldehyde.
42. The device of claim 31 wherein said hydrogel comprises a
polymer selected from the group consisting of one or a mixture of
alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic
acid, chitosan, polyvinylalcohol, and salts and esters thereof.
43. The device of claim 42 wherein said hydrogel comprises alginic
acid.
44. The device of claim 42 wherein said hydrogel is an ester of
alginic acid and a C.sub.2 to C.sub.4 alkylene glycol.
45. The device of claim 44 wherein said alkylene glycol is
propylene glycol.
46. The device of claim 42 wherein said hydrogel comprises a
mixture of alginic or pectinic acid and polyvinylalcohol.
47. The device of claim 31 in the shape of a cylindrical, hollow
tube.
48. The device of claim 31 wherein said shaped medical device is
selected from the group consisting of stents, catheters or
cannulas, plugs, constrictors and tissue or biological
encapsulants.
49. A medical procedure comprising: a. inserting the medical device
of claim 31 into a human or animal body to form an implant; and b.
selectively removing at least a portion of said crosslinking ions
from said implant in-vivo to soften said implant.
50. The procedure of claim 49 further including the step: c.
subjecting said implant to ionic crosslinking conditions to
ionically re-crosslink said implant prior to removal thereof from
said body.
51. The procedure of claim 49 wherein said implant is a cylindrical
hollow tube.
52. The procedure of claim 49 wherein said hydrogel comprises one
or a mixture of polymers selected from the group consisting of
polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide,
poly (N-vinyl pyrolidone), polyethylene oxide, hydrolysed
polyacrylonitrile, polyacrylic acid, polymethacrylic acid,
polyethylene amine, alginic acid, pectinic acid, carboxy methyl
cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan,
carboxymethyl chitosan, chitin, pullulan, gellan, xanthan,
carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate,
cationic guar, cationic starch as well as salts and esters
thereof.
53. The procedure of claim 49 wherein said hydrogel comprises an
anionic polymer and said ions are cations selected from the group
consisting of calcium, magnesium, barium, strontium, boron,
beryllium, aluminum, iron, copper, lead and silver ions.
54. The procedure of claim 49 wherein said hydrogel comprises a
cationic polymer and said ions are anions selected from the group
consisting of phosphate, citrate, borate, succinate, maleate,
adipate and oxalate ions.
55. The procedure of claim 49 wherein said hydrogel comprises one
or a mixture of cationic polymers selected from the group
consisting of chitosan, cationic guar, cationic starch and
polyethylene amine.
56. The procedure of claim 49 wherein said non-ionic crosslink
structure is formed by contacting said ionically crosslinkable
polymer under reaction conditions with a crosslinking agent having
at least two functional groups reactive with one or more functional
groups present in said hydrogel polymer to form covalent bonds.
57. The procedure of claim 56 wherein said crosslinking agent
contains carboxyl, hydroxy, epoxy, halogen or amino functional
groups.
58. The procedure of claim 57 wherein said crosslinking agent is
selected from the group consisting of glutaraldehyde,
epichlorohydrin, dianhydrides and diamines.
59. The procedure of claim 58 wherein said crosslinking agent is
glutaraldehyde.
60. The procedure of claim 49 wherein said hydrogel comprises a
polymer selected from the group consisting of one or a mixture of
alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic
acid, chitosan, polyvinylalcohol, and salts and esters thereof.
61. The procedure of claim 60 wherein said hydrogel comprises
alginic acid.
62. The procedure of claim 60 wherein said hydrogel is an ester of
alginic acid and a C.sub.2 to C.sub.4 alkylene glycol.
63. The procedure of claim 62 wherein said alkylene glycol is
propylene glycol.
64. The procedure of claim 60 wherein said hydrogel comprises a
mixture of alginic or pectinic acid and polyvinylalcohol.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to medical devices comprising polymer
hydrogels having improved mechanical properties.
[0003] 2. Description of Related Art
[0004] Medical devices adapted for implant into the body to
facilitate the flow of bodily fluids, to serve as vascular grafts
or for other purposes have been developed. Typically, these devices
include stents, catheters or cannulas, plugs, constrictors, tissue
or biological encapsulants and the like.
[0005] Typically, many of these devices used as implants are made
of durable, non-degradable plastic materials such as polyurethanes,
polyacrylates, silicone polymers and the like, or more preferably
from biodegradable polymers which remain stable in-vivo for a
period of time but eventually biodegrade in-vivo into small
molecules which are removed by the body by normal elimination in
the urine or feces.
[0006] Typical of such biodegradable polymers are polyesters,
polyanhydrides and polyorthoesters which undergo hydrolytic chain
cleavage, as disclosed in U.S. Pat. No. 5,085,629; crosslinked
polysaccharide hydrogel polymers as disclosed in EPA 0507604 A-2
and U.S. Pat. No. 5,057,606 and other tonically crosslinked
hydrogels as disclosed in U.S. Pat. Nos. 4,941,870, 4,286,341 and
4,878,907.
[0007] EPA 0645150 A-1 describes hydrogel medical devices prepared
from ionically crosslinked anionic polymers, e.g. polysaccharides
such as calcium alginate or ionically crosslinked cationic polymers
such as chitosan, cationic guar, cationic starch and polyethylene
amine. These devices are adapted for more rapid in-vivo
disintegration upon the administration of a chemical trigger
material which displaces crosslinking ions.
[0008] Hydrogels offer excellent biocompatibility and have been
shown to have reduced tendency for inducing thrombosis,
encrustation, and inflammation. Unfortunately, the use of hydrogels
in biomedical device applications has often been hindered by poor
mechanical performance. Although many medical device applications
exist where minimal stresses are encountered by the device in-vivo,
most applications require that the device survive high stresses
during implantation. Hydrogels suffer from low modulus, low yield
stress and low strength when compared to non-swollen polymer
systems. Lower mechanical properties result from the swollen nature
of hydrogels and the non-stress bearing nature of the swelling
agent, e.g., aqueous fluids.
[0009] Accordingly, there is a need in the art to provide shaped
medical devices which not only offer the advantages of polymer
hydrogels in terms of biological compatibility, but which also have
improved mechanical properties, e.g. improved strength and modulus
properties, such that they retain their shape and stiffness during
insertion into the body, such as by delivery through an endoscope,
and which also can swell and soften inside the body to enhance
patient comfort.
SUMMARY OF THE INVENTION
[0010] This invention provides a means of boosting the mechanical
performance of shaped medical devices comprising polymer hydrogels,
such as stents, so that they may be more easily inserted into the
body, and at the same time provides a means to soften such devices
in-vivo while retaining the structural integrity of the device.
[0011] The invention provides a process for improving the
mechanical properties and structural integrity of a shaped medical
device comprising a crosslinked polymeric hydrogel, said process
comprising subjecting an ionically crosslinkable polymer
composition to crosslinking conditions such that both ionic and
non-ionic crosslinks are formed resulting in a polymeric hydrogel,
wherein a medical device of improved structural integrity is
obtained upon selective removal of said crosslinking ions from said
polymeric hydrogel.
[0012] In addition, the invention also provides a process for
improving the mechanical properties and structural integrity of a
shaped medical device comprising a polymeric hydrogel, said process
comprising:
[0013] a) providing a crosslinked polymeric hydrogel composition
containing a non-ionic crosslink structure, said hydrogel polymer
characterized as being ionically crosslinkable and having a primary
shape;
[0014] b) imparting a secondary shape to said hydrogel polymer
composition; and
[0015] c) subjecting said hydrogel polymer to ionic crosslinking
conditions to tonically crosslink said hydrogel polymer while
retaining said secondary shape.
[0016] A medical device substantially conforming to the primary
shape of said hydrogel is obtained upon selective removal of the
crosslinking ions from said crosslinked polymeric hydrogel, such as
by removal of said ions after the device is implanted into the
body.
[0017] The invention also provides a shaped medical device having
improved mechanical properties comprising a cross-linked polymeric
hydrogel, said hydrogel containing both an ionic and a non-ionic
crosslink structure. The device is characterized by improved
structural integrity after selective removal of said ionic
crosslinking ions as compared with an otherwise identical device
containing only an ionic structure.
[0018] The invention further provides a medical procedure
comprising insertion of the above-described medical device into a
human or animal body to form an implant, followed by the selective
removal of at least a portion of the crosslinking ions from the
implant in-vivo to soften the implant. Where the implant is later
surgically removed, it may be once again subjected to ionic
crosslinking conditions to ionically re-crosslink the implant prior
to removal from the body.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The ionically crosslinkable polymers from which the medical
devices of this invention may be fabricated may be anionic or
cationic in nature and include but are not limited to carboxylic,
sulfate, hydroxy and amine functionalized polymers, normally
referred to as hydrogels after being crosslinked. The term
"hydrogel" indicates a crosslinked, water insoluble, water
containing material.
[0020] Suitable crosslinkable polymers which may be used in the
present invention include but are not limited to one or a mixture
of polymers selected from the group consisting of polyhydroxy ethyl
methacrylate, polyvinyl alcohol, polyacrylamide, poly (N-vinyl
pyrolidone), polyethylene oxide, hydrolysed polyacrylonitrile,
polyacrylic acid, polymethacrylic acid, polyethylene amine, alginic
acid, pectinic acid, carboxy methyl cellulose, hyaluronic acid,
heparin, heparin sulfate, chitosan, carboxymethyl chitosan, chitin,
pullulan, gellan, xanthan, carboxymethyl starch, carboxymethyl
dextran, chondroitin sulfate, cationic guar, cationic starch as
well as salts and esters thereof. Polymers listed above which are
not ionically crosslinkable are used in blends with polymers which
are ionically crosslinkable.
[0021] The most preferred polymers include one or a mixture of
alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic
acid, chitosan, polyvinyl alcohol and salts and esters thereof.
Preferred anionic polymers are alginic or pectinic acid; preferred
cationic polymers include chitosan, cationic guar, cationic starch
and polyethylene amine.
[0022] Other preferred polymers include esters of alginic, pectinic
or hyaluronic acid and C.sub.2 to C.sub.4 polyalkylene glycols,
e.g. propylene glycol, as well as blends containing 1 to 99 wt % of
alginic,-pectinic or hyaluronic acid with 99 to 1 wt % polyacrylic
acid, polymethacrylic acid or polyvinylalcohol. Preferred blends
comprise alginic acid and polyvinylalcohol.
[0023] The crosslinking ions used to crosslink the polymers may be
anions or cations depending on whether the polymer is anionically
or cationically crosslinkable. Appropriate crosslinking ions
include but are not limited to cations selected from the group
consisting of calcium, magnesium, barium, strontium, boron,
beryllium, aluminum, iron, copper, cobalt, lead and silver ions.
Anions may be selected from but are not limited to the group
consisting of phosphate, citrate, borate, succinate, maleate,
adipate and oxalate ions. More broadly, the anions are derived from
polybasic organic or inorganic acids. Preferred crosslinking
cations are calcium, iron, and barium ions. The most preferred
crosslinking cations are calcium and barium ions. The most
preferred crosslinking anion is phosphate. Crosslinking may be
carried out by contacting the polymers with an aqueous solution
containing dissolved ions.
[0024] As indicated above, the polymer hydrogels forming the shaped
medical device of this invention are also crosslinked by non-ionic
crosslinking mechanisms to produce a device having a higher
crosslink density and one which has improved mechanical properties,
i.e., improved stiffness, modulus, yield stress and strength. This
may be accomplished by additionally subjecting the tonically
crosslinkable polymer to non-ionic crosslinking mechanisms such as
high energy radiation (gamma rays) or treatment with a chemical
crosslinking agent reactive with groups present in the polymer such
that covalent bonds are formed connecting the polymer network.
Another non-ionic crosslinking mechanism useful with respect to
some classes of hydrogel polymers is physical crosslinking which is
typically accomplished by crystal formation or similar association
of polymer blocks such that the polymer molecules are physically
tied together and prevented from complete dissolution. Non-ionic
crosslinking may be carried out prior to, subsequent to or
concurrently with ionic crosslinking.
[0025] The most preferred method for non-ionic crosslinking is
contact of the tonically crosslinkable polymer with a chemical
crosslinking agent, because the degree of crosslinking can be more
readily controlled, mainly as a function of the concentration of
the crosslinking agent in the reaction medium. Suitable
crosslinking agents are polyfunctional compounds preferably having
at least two functional groups reactive with one or more functional
groups present in the polymer. Preferably the crosslinking agent
contains one or more of carboxyl, hydroxy, epoxy, halogen or amino
functional groups which are capable of undergoing facile
nucleophilic or condensation reactions at temperatures up to about
100.degree. C. with groups present along the polymer backbone or in
the polymer structure. Suitable crosslinking reagents include
polycarboxylic acids or anhydrides; polyamines; epihalohydrins;
diepoxides; dialdehydes; diols; carboxylic acid halides, ketenes
and like compounds. A particularly preferred crosslinking agent is
glutaraldehyde.
[0026] One of the unique properties of the polymer hydrogels of
this invention is that the ionic crosslinks can be easily and
selectively displaced in-vivo after implantation of the device in
the body, resulting in a swelling and softening of the device in
the body which enhances patient comfort. Since the non-ionic
crosslinks are not significantly displaced, the device will retain
its original non-ionically crosslinked shape configuration to a
large degree and will not disintegrate.
[0027] For example, a biliary or urethral stent can be fabricated
which has improved modulus (stiffness) properties due to the dual
crosslinking treatment of this invention. Such a stent will be
robust enough and be sufficiently resistant to buckling such that
it can be readily inserted into the appropriate part of the body
with an endoscope. Once inserted, the ionic crosslinks present in
the device can be selectively at least partially stripped either
directly by the physician, by dietary means or by means of natural
body fluids such as bile or urine. As the ionic crosslinks are
removed, the modulus of the device will be lowered and the device
will soften and swell in body fluids, resulting in a more
comfortable and conformable element and a larger lumen through
which body fluids-may flow. An enlarged lumen is typically
preferred in tubular shaped devices to allow higher flow rates, to
provide anchoring force to the body and to decrease the likelihood
of occlusion during service.
[0028] Displacement of the crosslinking ions can be accomplished by
flowing a solution containing a stripping agent around and/or
through the medical device in-vivo. The stripping agent serves to
displace, sequester or bind the crosslinking ions present in the
ionically crosslinked polymer, thereby removing the ionic
crosslinks. The choice of any particular stripping agent will
depend on whether the ion to be displaced is an anion or a cation.
Suitable stripping agents include but are not limited to organic
acids and their salts or esters, phosphoric acid and salts or
esters thereof, sulfate salts and alkali metal or ammonium
salts.
[0029] Examples of stripping agents include, but are not limited
to, ethylene diamine tetraacetic acid, ethylene diamine
tetraacetate, citric acid and its salts, organic phosphates such as
cellulose phosphate, inorganic phosphates, as for example,
pentasodium tripolyphosphate, mono and dibasic potassium phosphate,
sodium pyrophosphate, phosphoric acid, trisodium
carboxymethyloxysuccinate, nitrilotriacetic acid, maleic acid,
oxalate, polyacrylic acid, as well as sodium, potassium, lithium,
calcium and magnesium ions. Preferred agents are citrate, inorganic
phosphates and sodium, potassium and magnesium ions. The most
preferred agents are inorganic phosphates and magnesium ions.
[0030] Specific methods for introduction of the stripping agent
include introduction through the diet of the patient or through
parenteral feeding, introduction of a solution directly onto the
device such as by insertion of a catheter-which injects the. agent
within the device, or through an enema.
[0031] For example, one dietary technique for stripping urinary
device such as an implanted calcium alginate ureteral stent
strippable by phosphate anions would be to include in the patient's
diet materials which bind phosphate e.g., calcium salts, to lower
the content of PO.sub.4.sup. -3 present in the urine which can be
normally up to about 0.1%. When it is desired to strip the medical
device, phosphate binders can be eliminated from the diet and also
replaced by foods or substances which generate phosphate ions in
the urine. Achievement of levels of phosphate in the urine of from
0.2 to 0.3% will result in the in-vivo stripping of the calcium
ions from the calcium alginate stent. Lower levels of phosphate in
the urine will also result in a more gradual stripping of the
calcium ions, but higher levels are preferred for rapid stripping
of the calcium.
[0032] Another advantage of the invention is that the stripping
process may be reversed to re-stiffen the medical device which
facilitates surgical removal of the device from the body. This may
be accomplished by flowing a source of crosslinking ions through
and/or around the implant to ionically re-crosslink the implant,
essentially the reverse of the stripping process described above.
Dietary modifications can also be used to re-crosslink the medical
device in-vivo.
[0033] In another embodiment of the invention, a secondary shape
can be imparted to the medical device prior to implant in the body.
This is accomplished by deforming the primary shape of a device
which is crosslinked at least non-ionically, setting the device in
the deformed shape by ionic crosslinking and implanting the device
in the body in the deformed shape. Stripping the ions in-vivo as
described above will cause the device to revert in-vivo to its
primary non-ionically crosslinked shape. In accordance with one
aspect of this embodiment, an tonically crosslinkable polymer is
formed into a primary shape and subjected to non-ionic crosslinking
conditions to form a non-ionically crosslinked hydrogel having said
primary shape. Non-ionic crosslinking can be carried out by the
methods described above, and is preferably carried out by extruding
the polymer into a bath containing a sufficient amount of one or
more of the non-ionic crosslinking agents to-form a shape-retaining
hydrogel. Next, a secondary shape is imparted to the non-ionically
crosslinked hydrogel and the hydrogel is then subjected to ionic
crosslinking conditions to ionically crosslink the hydrogel while
retaining this secondary shape.
[0034] In another aspect of this embodiment, an ionically
crosslinkable polymer is formed into a primary shape and subjected
to both non-ionic and ionic crosslinking conditions to form a
hydrogel having said primary shape and containing both an ionic and
non-ionic crosslink structure. In accordance with this second
aspect, an ionically and non-ionically crosslinked shaped hydrogel
is prepared as above. Then, the shaped hydrogel is selectively
stripped ex-vivo of at least a portion or essentially all of the
crosslinking ions; the shaped hydrogel is conformed to a secondary
shape, e.g., bent around a wire, stretched, compressed or the like;
and the shaped hydrogel is ionically re-crosslinked while retained
in the secondary shape. Release of the crosslinking ions in-vivo
will cause the implanted device to revert substantially to the
original primary, non-ionically crosslinked shape. The stripping
step described above can occur immediately prior to or subsequent
to the secondary shaping step, but preferably subsequent such step
but prior to the ionic recrosslink step.
[0035] This embodiment is particularly useful where the medical
device is of hollow, tubular configuration, such as a stent. Where
the stent is both ionically and non-ionically crosslinked, it is
selectively stripped of the crosslinking ions. The stent is
stretched to form a narrower stent which facilitates insertion into
the body, ionically crosslinked or re-crosslinked in the stretched
state to fix the stent in the stretched state, implanted in the
body and then re-stripped in-vivo of the ionic crosslinks to
produce a softer implant having a wider lumen. Other stent shapes
such as pigtail ends, flaps, curves and the like can be developed
in-vivo by subjecting devices having these primary initial shapes
to the process described above, i.e., deforming the primary shape
ex-vivo and reforming the primary shape in-vivo.
[0036] The stripping step described above is preferably
accomplished by dipping or spraying the crosslinked device with an
aqueous electrolyte solution for an appropriate time to selectively
strip the crosslinking ions from the device. Preferred electrolytes
for ex-vivo stripping are chlorides of monovalent cations such as
sodium, potassium or lithium chloride, as well as other stripping
salts described above. The concentration of the electrolyte salt in
the solution may range from about 1 wt % up to the solubility
limit. The solution may also contain plasticizing ingredients such
as glycerol or sorbitol to facilitate inter and intra polymer chain
motion during and after secondary shaping.
[0037] Secondary shaping of the medical device may be done by hand,
i.e., using pinning boards or jig pins, or by using shaped presses
or molds.
[0038] The device may be ionically crosslinked or re-crosslinked in
the secondary shape by contacting the device, while retaining the
secondary shape, with an aqueous solution containing the
crosslinking ions described above. After crosslinking, the device
will essentially retain the secondary shape.
[0039] Medical devices which may be fabricated in accordance with
this invention include stents, catheters or cannulas, plugs and
constrictors, for both human and animal use. The invention is
particularly applicable to medical stents of tubular configuration
which come in contact with one or more body fluids such as blood,
urine, gastrointestinal fluids and bile. The devices are
particularly applicable for use in gastrointestinal, urogenital,
cardiovascular, lymphatic, otorhinolaryngological, optical,
neurological, integument and muscular body systems.
[0040] The devices may optionally include fillers, disintegration
agents, additives for medical treatment such as antiseptics,
antibiotics, anticoagulants, or medicines, and additives for
mechanical property adjustment of the device.
[0041] Linear device or pre-device -configurations -such as fibers,
rods, tubes or ribbons can be manufactured in accordance with the
present invention by using a spinning device in which an aqueous
solution of an ionically crosslinkable matrix polymer is forced
through a shaping die into a crosslinking bath containing the
crosslinking ions. The product after crosslinking is typically
described as a hydrogel. The hydrogel may be used as made, or
further given a three dimensional shape through treatment in a
crosslinking solution after being forced into the desired shape.
After equilibration, the hydrogel will retain the new three
dimension shape. The device may be used in its hydrogel form or in
a dehydrated form. During dehydration, the three dimensional shape
is retained.
[0042] Another process for manufacturing the articles of the
present invention comprises introducing a solution comprising
ionically crosslinkable polymer through a die to form a tube,
simultaneously pumping a solution comprising crosslinking ion
through the formed tube, and extruding the formed tube from said
die into a solution comprising crosslinking ion. In this process,
the crosslinking step may involve shaping of the device as in wet
spinning of a tubular device. Alternatively, the device may be
prepared by molding a latent crosslinking composition using a one
or two part reaction injection molding system. The term "tubular"
as used herein, includes not only cylindrical shaped devices having
circular cross sections, but also devices having different cross
sections as long as such articles have a hollow passageway, which
distinguishes a tube from a rod.
[0043] The ionically crosslinked, shaped polymer prepared as above
is then subjected to non-ionic crosslinking, e.g. high energy
radiation or by contact under appropriate acidic or basic
conditions with the appropriate chemical crosslinking agent.
Crosslinking is preferably carried out by soaking the polymer in an
aqueous solution containing a water soluble crosslinking agent such
as glutaraldehyde, ethylene diamine or a lower alkylene glycol.
Generally, the concentration of crosslinking agent in solution may
range from about 0.25 to about 10 wt %, more preferably from about
0.5 to 5.0 wt %. The degree of non-ionic crosslinking is controlled
as a function of the concentration of the crosslinking agent in
solution. The level should be selected such that a stiffer, higher
modulus device is produced which will revert to a soft, stretchy,
shape retaining device after removal of the ionic crosslinks. Some
trial and error may be required to determine optimum levels
depending on the particular polymer and the identity of the
crosslinking agent.
[0044] The crosslinking process may also be conducted by first
crosslinking the polymer non-ionically, followed by ionic
crosslinking, essentially the reverse of the process described
above.
[0045] Where the ionically crosslinkable polymer composition
includes polymers which are partially water soluble, it is
preferred to include in the aqueous spinning solution and treatment
solutions described above one or more additives which retard the
tendency of the solution to dissolve the polymer, i.e., provide
non-solvent conditions. Example of such conditions include high
salt concentrations, or inclusion in the solution of additives such
as borax, boric acid, alkali metal salts and/or a lower alcohol
such as methanol.
[0046] The various steps may be performed at any suitable
temperature, e.g., at room temperature or at temperatures up to
about 100.degree. C. Preferably, soaking steps are conducted at
room temperature. Moreover, the steps may be performed one
immediately after another, or a drying step (e.g., air-drying) may
be interposed between one or more steps. Additionally, the shaped
medical device may be sterilized after the sequence of
secondary-shaping steps.
[0047] The medical device may be stored wet or dry. For example,
the medical device may be stored in a suitable aqueous solution or
may be dried prior to storage. For example, the medical device
could be stored in deionized water, or in water containing water
soluble agents such as glycerol, sorbitol, sucrose and the
like.
[0048] Exemplary hydrogel systems which may be prepared in
accordance with this invention can be prepared by the following
procedures:
[0049] a) Alginate which has been covalently and ionically
crosslinked.
[0050] A solution of sodium alginate is extruded through a tube die
into a calcium chloride bath while calcium chloride solution is
simultaneously introduced through the lumen of the tube. This
ionically crosslinked tube is then covalently crosslinked by
treatment with an aqueous solution containing glutaraldehyde. The
now covalently and tonically crosslinked gel has a higher crosslink
density and therefore higher modulus than a similar tube having
only the covalent or only the ionic crosslinks. The tube therefore
has higher stiffness and improved resistance to buckling than a
tube having the covalent or ionic crosslinks alone. After insertion
into the body, exposure of the tube to ions in body fluids will
remove the calcium crosslinks, lower the modulus of the gel and
therefore reduce the stiffness of the tube, allowing for maximum
patient comfort and biocompatibility. Suitable ions which will
displace the calcium crosslinking ions include phosphate, sulfate,
carbonate, potassium, sodium and ammonium. The implanted device may
be stiffened and strengthened during removal from the body via
exposure of the device to an infusion fluid which contains a
solution of the crosslinking ions (calcium).
[0051] b) Polyvinyl alcohol and alginate.
[0052] A blend of polyvinyl alcohol (PVA) and sodium alginate may
be dispersed or dissolved in water, extruded into a bath containing
calcium ions, said bath also containing non-solvent conditions for
the polyvinyl alcohol. The polyvinyl alcohol component of the
formed article may then be covalently crosslinked with an aqueous
solution containing glutaraldehyde. The article is now ready for
insertion or implantation. After implantation, the article may be
softened and swollen by removal of the ionic crosslinks as above.
Removal of the ionic crosslinks may also optionally allow the
alginate to fully or partially dissolve in the body fluids, leaving
behind a less dense, more porous hydrogel. The morphology of the
final hydrogel device may be controlled through judicious selection
of polyvinyl alcohol molecular weight, degree of crosslinking,
solvent composition, alginate molecular weight, alginate salt used,
state of the alginate salt (dissolved, particulated, gel), alginate
monomer makeup, temperature, pressure, mix time, solution age, and
rheological factors during manufacture.
[0053] c) Polyvinyl alcohol and alginate--shape memory.
[0054] The blend of PVA and sodium alginate described in (b) above
may be used to make a stent having a shape memory feature to gain
increased lumen size after deployment in-vivo. A tube is made by
extruding the mixture through a tube die into a concentrated
calcium chloride bath, optionally containing other salts and boric
acid. The tube is then transferred into a bath which contains
calcium chloride and a chemical crosslinker (glutaraldehyde). After
allowing for reaction, the tube will become a covalently
crosslinked PVA/calcium alginate system. The tube is immersed in
concentrated potassium chloride solution to remove the calcium
crosslinks from the alginate while preventing the alginate from
dissolving. The tube is then stretched to form a longer length tube
having a more narrow lumen. While in this stretched configuration,
the tube is immersed into concentrated calcium chloride solution to
re-crosslink the alginate. The tube is frozen into the longer
length, narrow lumen configuration. Upon insertion into the body,
the tube will return to it's original shorter length, large lumen
configuration as the calcium is stripped from the alginate. The
alginate may eventually dissolve, leaving behind a more porous
glutaraldehyde crosslinked PVA tube. Other imposed shapes may be
used to accommodate body insertion in a compact form, followed by
shape change upon displacement of the ionic crosslinks.
[0055] d) Propyleneglycol alginate.
[0056] Propyleneglycol alginate may be covalently crosslinked with
ethylene diamine under basic conditions and ionically crosslinked
with calcium ions. This covalently and tonically crosslinked
material will exhibit higher stiffness than the material
crosslinked with covalent linkages only. Removal of the ionic
crosslinks will occur in-vivo after deployment in body fluid. A
stent, catheter or cannula can be manufactured from this material,
implanted while both ionically and covalently crosslinked, then
in-vivo the device will soften as the ionic crosslinks are
displaced. A device of this construction would provide stiffness
for implantation and softness for patient comfort.
EXAMPLE 1
[0057] This example illustrates the preparation of tubing from a
mixture of sodium alginate (Protanol LF 10/60 from Pronova
Bipolymers A. S., Drammen, Norway) and polyvinylalcohol (PVA). A
series of four different formulations were prepared as shown in
Table 1.
1TABLE 1 PVA/alginate (wt. rat.) 15/5 20/5 15/7.5 20/5 Deionized
water 72 g 67.5 g 69.7 g 74.25 g PVA 13.5 g 18.0 g 13.5 g 19.8 g
Sodium alginate 4.5 g 4.5 g 6.75 g 4.95 g Bismuth subcarbonate 9.68
g 9.77 g 9.69 g 9.9 g
[0058] The deionized water was weighed into a 4 oz. jar, while
stirring the water, the PVA and sodium alginate were added and
mixed until uniform. The jar was capped and heated to 100.degree.
C. to dissolve the ingredients. The jar was cooled to 37.degree.
C., then the bismuth. subcarbonate (radiopaque filler) which had
been sifted through a 325 mesh screen was added and the composition
was mixed with a jiffy mixer until uniform. The samples were loaded
into 30 cc syringes, centrifuged to remove air, then extruded
through a tubing die into a coagulant solution. The coagulant
solution was made from 100 grams of calcium chloride dihydrate, 30
grams of sodium chloride, 50 grams of boric acid and 820 grams of
deionized water. The spun tubing was left in the coagulant solution
overnight. Lengths of tubing were then soaked in a
glutaraldehyde/coagulant solution mixture to covalently crosslink
the sample. Glutaraldehyde levels were tested from 0.5% by weight
to 12.5% by weight. pH was adjusted to 1.5 using 20% HCL solution.
After reacting overnight at room temperature, the tubes were
examined and then immersed in 0.4% sodium phosphate solution to
strip the ionic crosslinks. Results are recorded in Table 2.
2TABLE 2 Glutaraldehyde (wt %) 0.5% 1.0% 5.0% 12.5% 15/5
(PVA/Alginate soft, slightly stiffer, stiff, wt. ratio) stretchy
stiffer but still brittle soft 15/7.5 (PVA/Alginate soft, slightly
much stiff, wt. ratio) stretchy stiffer stiffer brittle 20/5
(PVA/Alginate soft, slightly stiff, stiff, wt. ratio) stretchy
stiffer brittle brittle
[0059] Control samples which were not treated with glutaraldehyde
were swollen and broken apart in the phosphate solution.
* * * * *