U.S. patent application number 10/751706 was filed with the patent office on 2004-07-22 for polysaccharide biomaterials and methods of use thereof.
This patent application is currently assigned to Biointeractions, Ltd., University of Reading. Invention is credited to Hudson, John O., Luthra, Ajay K., Sandhu, Shivpal S..
Application Number | 20040142016 10/751706 |
Document ID | / |
Family ID | 23162274 |
Filed Date | 2004-07-22 |
United States Patent
Application |
20040142016 |
Kind Code |
A1 |
Luthra, Ajay K. ; et
al. |
July 22, 2004 |
Polysaccharide biomaterials and methods of use thereof
Abstract
Materials and methods for reacting polysaccharides are set
forth. Examples include reacting polysaccharides with a surface,
and reacting polysaccharides with other polysaccharides or polymers
to form a polysaccharide polymer. Layers of polysaccharides and/or
polysaccharide polymers may be formed on surfaces, for example,
medical device surfaces that contact bodily fluids.
Inventors: |
Luthra, Ajay K.; (Middlesex,
GB) ; Sandhu, Shivpal S.; (Slough, GB) ;
Hudson, John O.; (Leicester, GB) |
Correspondence
Address: |
Patterson, Thuente, Skaar & Christensen, P.A.
4800 IDS Center
80 South 8th Street
Minneapolis
MN
55402-2100
US
|
Assignee: |
Biointeractions, Ltd., University
of Reading
|
Family ID: |
23162274 |
Appl. No.: |
10/751706 |
Filed: |
January 5, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10751706 |
Jan 5, 2004 |
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10179453 |
Jun 25, 2002 |
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60301176 |
Jun 26, 2001 |
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Current U.S.
Class: |
424/423 ;
514/54 |
Current CPC
Class: |
A61L 33/0064 20130101;
D10B 2403/0122 20130101; C08B 37/0063 20130101; A61L 33/0011
20130101; C08B 37/0069 20130101; C08B 37/0075 20130101; Y10S
514/822 20130101; A61L 27/34 20130101; A61L 27/507 20130101; D10B
2509/06 20130101; Y10S 514/944 20130101; A61L 27/20 20130101; A61L
27/52 20130101; Y10S 514/953 20130101; D04B 21/205 20130101; A61L
27/34 20130101; C08L 39/06 20130101 |
Class at
Publication: |
424/423 ;
514/054 |
International
Class: |
A61K 031/715 |
Claims
1. A method for forming a layer on at least a portion of a surface
of a biocompatible medical device, the method comprising: reacting
a first functional group on a polysaccharide in a polysaccharide
complex with a second functional group on the at least a portion of
the surface of the medical device to covalently bond the
polysaccharide to the surface in the presence of an organic
solvent, wherein the polysaccharide complex comprises quaternary
ammonium cations associated with the polysaccharide.
2. The method of claim 1 wherein the polysaccharide is a
derivitized, natural polysaccharide.
3. The method of claim 1 wherein the polysaccharide, before being
complexed with the quaternary cations, comprises the first
functional group.
4. The method of claim 3 wherein the polysaccharide, before being
complexed with the quaternary cations, is decorated with the first
functional group in a chemical reaction that takes place in a
non-organic solvent.
5. The method of claim 1 wherein the polysaccharide, after being
complexed with the quaternary cations, is chemically decorated with
the first functional group.
6. The method of claim 1 wherein the polysaccharide is a
W-MPSAC.
7. The method of claim 1 wherein the polysaccharide is an
O-MPSAC.
8. The method of claim 1 wherein the first functional group is a
photoactivatable group.
9. The method of claim 1 wherein the second functional group is a
photoactivatable group.
10. The method of claim 1 wherein the first functional group or the
second functional group is an azide.
11. The method of claim 1 wherein the first functional group and
the second functional groups are reactive functional groups that
can undergo a reaction to bond to each other.
12. The method of claim 7 wherein the polymerizable groups are
photoinitiatable free radical polymerization groups.
13. The method of claim 1 wherein the first functional group is an
electrophile and the second functional group is a nucleophile.
14. The method of claim 1 wherein the first functional group or the
second functional group comprises a member of the group consisting
of primary amines, sulfhydryls, carboxyls, and hydroxyls.
15. The method of claim 1 wherein the first functional group or the
second functional group comprises a member of the group consisting
of methacrylates, acrylates, isocyanates, epoxides, carbodiimides,
diimidazoles, and acid anhydrides.
16. The method of claim 1 wherein the organic solvent has a boiling
point at atmospheric pressure of less than approximately 115
degrees Centigrade.
17. The method of claim 1 wherein the organic solvent has a boiling
point at atmospheric pressure of less than approximately 70 degrees
Centigrade.
18. The method of claim 16 wherein the organic solvent has a
dielectric constant that is less than that of DMSO.
19. The method of claim 1 wherein the organic solvent has a
dielectric constant that is less than that of DMSO.
20. The method of claim 1 further comprising removing the organic
solvent by a process that uses a vacuum.
21. The method of claim 1 wherein polysaccharide is chosen from the
group consisting of glycosaminoglycans, chondroitin sulfate,
dermatan sulfate, heparan sulfate, keratan sulfate, proteoglycans
and combinations thereof and mixtures thereof.
22. The method of claim 1 wherein polysaccharide comprises
heparin.
23. The method of claim 1 further comprising reacting the first
functional group with the second functional group in the presence
of a member of a set consisting of monomers, polymers, and
combinations thereof.
24. The method of claim 23 wherein the polymers comprise
polyethylene glycol or a derivative of polyethylene glycol.
25. The method of claim 1 further comprising reacting the first
functional group with the second functional group in the presence
of polymer having a molecular weight of at least about 100,000.
26. The method of claim 1 further comprising reacting the first
functional group with the second functional group in the presence
of a third functional group, wherein the third functional group
forms a covalent bond with at least one of the first functional
group and the second functional group.
27. The method of claim 26 wherein the third functional group
comprises a polymerizable or photoactivatable group.
28. The method of claim 26 wherein the third functional group
comprises an acrylate or a methacrylate.
29. The method of claim 26 wherein the polysaccharide comprises the
third functional group.
30. The method of claim 26 wherein, before the reaction of the
third functional group, a monomer or polymer distinct from the
polysaccharide and the surface comprises the third functional
group.
31. The method of claim 1 further comprising exposing the
covalently bonded polysaccharide complex to a salt solution to
decomplex the quaternary ammonium cations from the polysaccharide
bound to the surface.
32. The method of claim 1 wherein the quaternary ammonium cation is
chosen from the group consisting of cetyltrimethylammonium
chloride, dodecyldimethylbenzylammonium chloride, benzalkonium
chloride, didecyldimethylammonium chloride, benzethonium chloride,
hexyl trimethyl ammonium, decyl trimethyl ammonium, lauryl
trimethyl ammonium, myristyl trimethyl ammonium, cetyl trimethyl
ammonium, stearyl trimethyl ammonium, didecyl dimethyl ammonium,
dilauryl dimethyl ammonium, and distearyl dimethyl ammonium.
33. The method of claim 1 wherein the organic solvent comprises at
least one member of the group consisting of dimethylformamide,
dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric
triamide, formic acid, acetonitrile, methanol, ethanol, acetone,
acetic acid, dichloromethane, pyridine, and formamide.
34. A method for forming a layer on at least a portion of a surface
of a biocompatible medical device, the method comprising:
contacting the surface of the medical device with a plurality of
synthetic polysaccharide polymers, with the polysaccharide polymers
having an average length of at least two polysaccharides covalently
bonded per polymer, to form the layer, wherein the polysaccharide
polymers are formed by chemically reacting polysaccharide complexes
in an organic solvent, the polysaccharide complexes comprising
quaternary ammonium cations associated with polysaccharides and at
least one functional group capable of forming a covalent bond.
35. The method of claim 34 wherein the polysaccharide is a
derivitized, natural polysaccharide.
36. The method of claim 34 wherein the polysaccharide, before being
complexed with the quaternary cations, comprises the functional
group.
37. The method of claim 34 wherein the polysaccharide, before being
complexed with the quaternary cations, is decorated with the
functional group in a chemical reaction that takes place in a
non-organic solvent.
38. The method of claim 34 wherein the polysaccharide is a
W-MPSAC
39. The method of claim 34 wherein the polysaccharide is an
O-MPSAC.
40. The method of claim 34 wherein the functional group is a
photoactivatable group.
41. The method of claim 34 wherein the polysaccharide polymers
further comprise a second functional group for forming a covalent
bond after the layer is formed.
42. The method of claim 41 wherein the second functional group is a
photoactivatable group.
43. The method of claim 42 wherein the second functional group is
an azide.
44. The method of claim 34 wherein the functional group comprises a
polymerizable group.
45. The method of claim 44 wherein the polymerizable groups
comprises a photoinitiatable free radical polymerization group.
46. The method of claim 34 wherein the second functional group is a
nucleophile.
47. The method of claim 34 wherein the functional group comprises a
member of the group consisting of primary amines, sulfhydryls,
carboxyls, and hydroxyls.
48. The method of claim 34 wherein the functional group comprises a
member of the group consisting of methacrylates, acrylates,
isocyanates, epoxides, carbodiimides, diimidazoles, and acid
anhydrides.
49. The method of claim 34 wherein the organic solvent has a
boiling point at atmospheric pressure of less than approximately
115 degrees Centigrade.
50. The method of claim 34 wherein the organic solvent has a
boiling point at atmospheric pressure of less than approximately 70
degrees Centigrade.
51. The method of claim 50 wherein the organic solvent has a
dielectric constant that is less than that of DMSO.
52. The method of claim 34 wherein the organic solvent has a
dielectric constant that is less than that of DMSO.
53. The method of claim 34 further comprising removing the organic
solvent by a process that uses a vacuum.
54. The method of claim 34 wherein polysaccharide is chosen from
the group consisting of macromers of glycosaminoglycans,
chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan
sulfate, and proteoglycans.
55. The method of claim 34 wherein polysaccharide comprises
heparin.
56. The method of claim 34 further comprising polymerizing monomers
into the polysaccharide polymers.
57. The method of claim 34 wherein the polysaccharide polymers are
formed in the presence of a solubilized a non-polysaccharide
polymer.
58. The method of claim 57 wherein the non-polysaccharide polymer
comprises polyethylene glycol or a derivative of polyethylene
glycol.
59. The method of claim 34 wherein the polysaccharide polymers
further comprise non-polysaccharide polymers.
60. The method of claim 59 wherein the non-polysaccharide polymers
comprise an acrylate or a methacrylate that participates in the
formation of a covalent bond between the non-polysaccharide
polymers and the polysaccharide-polymers.
61. The method of claim 34 wherein the polysaccharide polymer
comprises a cross-linked structure.
62. The method of claim 34 wherein the polysaccharide polymer
comprises a branched structure.
63. The method of claim 34 wherein the polysaccharide polymer has
an average molecular weight in the range of about 50,000 and about
5,000,000.
64. The method of claim 34 wherein the polysaccharide polymer is
covalently bonded to the surface.
65. The method of claim 34 wherein the polysaccharide polymer is
bound to the surface through electrostatic interactions.
66. The method of claim 34 wherein the polysaccharide complex is
covalently bonded to the surface and further comprising exposing
the covalently bonded polysaccharide complex to a salt solution to
decomplex the quarterary ammonium cations from the polysaccharide
bound to the surface.
67. The method of claim 34 wherein the quaternary ammonium cation
is chosen from the group consisting of cetyltrimethylammonium
chloride, dodecyldimethylbenzylammonium chloride, benzalkonium
chloride, didecyldimethylammonium chloride, benzethonium chloride,
hexyl trimethyl ammonium, decyl trimethyl ammonium, lauryl
trimethyl ammonium, myristyl trimethyl ammonium, cetyl trimethyl
ammonium, stearyl trimethyl ammonium, didecyl dimethyl ammonium,
dilauryl dimethyl ammonium, and distearyl dimethyl ammonium.
68. The method of claim 34 wherein the organic solvent comprises at
least one member of the group consisting of dimethylformamide,
dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric
triamide, formic acid, acetonitrile, methanol, ethanol, acetone,
acetic acid, dichloromethane, pyridine, and formamide.
69. A preparation of a synthetic modified polysaccharide polymer
soluble in a solvent comprising: at least two polysaccharides
joined with at least one covalent bond to the modified polymer,
wherein the modified polysaccharide polymer has a branched
structure and has a molecular weight of at least 50,000.
70. The preparation of claim 69 wherein the polysaccharides are
polymerized to the polymer by the reaction of chemical moieties
chosen from the group from the group consisting of
polyhydroxyethylmethylacrylat- es, methyl methacrylates,
methacrylates, acrylates, photopolymerizable monomers, monomers
with hydroxyl groups, monomers with glycerol groups, monomers with
polyoxyalkylene ether groups, monomers with polypropylene oxide
groups, monomers with vinyl groups, monomers with zwitterionic
groups, monomers with silicone groups, monomers having sulphate
groups, monomers having sulphonate groups, and heparin monomer, and
wherein the polymer is in an isolatable form.
71. The preparation of claim 69 wherein the polysaccharides
comprise heparin.
72. The preparation of claim 69 wherein the polysaccharides are
chosen from the group consisting of glycosaminoglycans, chondroitin
sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and
proteoglycans.
73. The preparation of claim 69 wherein the polysaccharides are
polymerized in a solvent chosen from the group consisting of
aqueous solvents, organic solvents, and mixtures thereof.
74. The preparation of claim 69 wherein the polysaccharides are
complexed with cations.
75. The preparation of claim 69 further comprising an organic
solvent, and wherein the modified polysaccharide polymer is soluble
in the organic solvent.
76. The preparation of claim 69 wherein the modified polysaccharide
polymer further comprises a chemical group for forming a covalent
bond with a functional group.
77. The preparation of claim 76 wherein the chemical group is a
photoactivatable functional group.
78. The preparation of claim 77 wherein the photoactivatable
functional group is an azide.
79. The preparation of claim 77 wherein the polysaccharide polymer
comprises polysaccharides covalently bonded to each other to form
the polysaccharide polymer.
80. The preparation of claim 77 wherein the polysaccharide polymer
comprises polysaccharide and non-polysaccharide polymers.
81. A medical device surface having a layer on at least a portion
if its surface, the layer comprising: polysaccharide polymers
comprising at least two polysaccharides synthetically covalently
bonded per polymer wherein the polysaccharide polymers are
covalently linked to the surface with at least one covalent bond
per polysaccharide polymer.
82. The medical device of claim 80 wherein the polysaccharide is a
derivitized, natural polysaccharide.
83. The medical device of claim 80 wherein the polysaccharide is an
O-MPSAC.
84. The medical device of claim 80 wherein the covalent bond is
formed from a photoactivatable group.
85. The medical device of claim 83 wherein the photoactivatable
group is an azide.
86. The medical device of claim 80 wherein the covalent bond is
formed from a polymerizable group.
87. The medical device of claim 80 wherein the covalent bond is
formed from a member of the group consisting of methacrylates,
acrylates, isocyanates, epoxides, carbodiimides, diimidazoles, and
acid anhydrides.
88. The medical device of claim 80 wherein polysaccharide is chosen
from the group consisting of macromers of glycosaminoglycans,
chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan
sulfate, and proteoglycans.
89. The medical device of claim 80 wherein polysaccharide comprises
heparin.
90. The medical device of claim 88 wherein the polysaccharide
polymers further comprise non-polysaccharide polymers.
91. The medical device of claim 88 wherein the polysaccharide
polymer comprises a cross-linked structure.
92. The medical device of claim 88 wherein the polysaccharide
polymer comprises a branched structure.
93. The medical device of claim 88 wherein the polysaccharide
polymer has an average molecular weight in the range from about
50,000 to about 5,000,000.
94. The medical device of claim 88 wherein the polysaccharide is
associated with a plurality of quaternary ammonium cations.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of U.S.
application Ser. No. 10/179,453, filed Jun. 25, 2002, which claims
priority to U.S. provisional patent application serial No.
60/301,176, entitled "Polysaccharide Biomaterials and Methods of
Use Thereof", filed Jun. 26, 2001, all of which applications are
claimed as priority documents and which are hereby incorporated
herein by reference.
[0002] Further, certain other commonly owned and assigned patent
applications are hereby incorporated by reference herein: U.S.
patent Ser. No. 10/179,453, filed Jun. 26, 2002; Ser. No.
10/467,950, filed Aug. 15, 2003; and No. 60/451,333, filed Feb. 28,
2003.
FIELD OF INVENTION
[0003] Some aspects of the invention relate to the field of making
and using polysaccharides and polymers of polysaccharides as layers
on medical devices.
BACKGROUND OF THE INVENTION
[0004] Many synthetic materials have been medically used in the
body, including polyester (e.g., DACRON.TM.), polyethylene (e.g.,
milk jugs), and fluorocarbons (e.g., TEFLON.TM.), and metals. A
patient's body responds by treating a synthetic material as an
invader, although it responds only mildly in some medical
applications; for example, a metal hip implant is generally well
tolerated. One common response to an implant is called a foreign
body response in which the body forms a capsule of cells around the
material; the body's response to a splinter is a foreign body
response. When synthetic material is used as an artificial blood
vessel, for example, the blood that flows through the artificial
blood vessel reacts with the synthetic material. The reaction can
cause clots to form that flow downstream that may eventually become
stuck in a smaller vessel; if this happens in the brain, it is
called a stroke. The blood clot can also grow on the inside of the
vessel and block or severely restrict the blood flow. Blood's
clotting mechanism is highly reactive and, despite years of medical
research, no implantable blood-contacting synthetic material has
yet been found that does not cause blood to react. Synthetic, as
used herein, means not naturally found in nature and does not refer
to the process whereby an object is made.
[0005] Tubes made of polyester or fluorocarbons are currently used
as large diameter blood vessels. The blood clots onto the interior
walls and reduces the inside diameter of the vessel but the blood
flow is not unduly reduced. The blood clot on the tubular wall
serves as a protective layer that elicits very little reaction from
blood flowing through the vessel. This approach, however, does not
work for small diameter blood vessels because the small diameter
tubes are blocked when the blood clots onto the walls.
[0006] There are no currently known materials and techniques for
manufacturing small diameter vascular grafts made of synthetic
materials. Unfortunately, there is a great need for such grafts.
One example is the condition called deep vein thrombosis wherein a
patient's veins become blocked. The blood drains poorly from the
leg and amputation can result. Unlike heart bypass surgeries where
the patient often has some blood vessels that can be harvested from
elsewhere in the body and sewn into place, there are few choices
for replacing the long veins of the leg.
[0007] One area of synthetic biomaterials research has focused on
hydrogels, materials that have a high water content and are soft
and slippery. Soft contact lenses are examples of hydrogels. The
materials used to make a pure hydrogel might all dissolve in water
but the hydrogel itself does not dissolve in water because the
materials are cross-linked; in other words, the individual
molecular chains are linked together like the strands in a net or a
spider's web. Hydrogels tend to elicit a milder foreign body
response than other synthetic materials. Some hydrogel biomaterials
that are currently considered to be commercially useful are made
from polyethylene glycol (PEG), hyaluronic acid, and alginates.
Although hydrogels tend to elicit less blood clotting than other
synthetic materials, hydrogels have not previously been
successfully used to make a small diameter vascular graft.
[0008] Scientists have also tried to use heparin to coat the inside
of vascular grafts made of synthetic materials. Heparin is a
molecule that belongs to a group of molecules called
polysaccharides that are polymers made from combinations of sugar
monomers. There are many sugars; glucose and sucrose (table sugar)
are two examples. Polysaccharides are naturally-occurring polymers.
The terms polysaccharide and mucopolysaccharide are used
interchangeably herein. Polymers are molecules built up by the
repetition of smaller units that are sometimes called monomers.
Polymers are typically made by special chemical schemes that make
the monomers chemically react with each other to form molecular
chains that can range in length from short to very long molecules.
Polymers can be assembled into larger materials; for example, many
polymers may be linked together to form a hydrogel.
[0009] Heparin is a polysaccharide polymer with an important
property: it interferes with key molecules in the blood clotting
mechanism such that the blood will not clot. Coating the inside of
a synthetic material tube with heparin tends to increase the amount
of time that the tube remains open to blood flow but, to date,
small diameter vascular grafts coated with heparin have failed to
resist blockage by blood clots for a medically useful length of
time.
[0010] Heparin has been applied to materials in many ways. General
strategies include letting it naturally stick to a surface (termed
adsorption), making a charge-charge bond with the surface (e.g., an
ionic bond), and attaching it via an even stronger, more permanent
chemical linkage such as a covalent bond. Heparin has been applied
as a thin coating of polymers adsorbed to a surface by dipping the
surface into a solution of heparin or drying the heparin onto the
surface. Heparin has a negative charge and has been exposed to
surfaces that have a positive charge so that it remains there via a
charge-charge interaction. Photoactivated chemical groups have been
put onto heparin so that the heparin is put close to the surface,
the surface is bathed in light, and the photoactive groups make
permanent covalent chemical bonds between the heparin polymer and
the surface. Similarly, heparin has been chemically attached to
monomers that have then been reacted with the surface.
[0011] Patent families and patent applications that describe the
use of heparin include U.S. Pat. No. 6,127,348, which include
descriptions of cross-linked alginate and certain other
polysaccharides as compositions useful for inhibiting fibrosis.
U.S. Pat. No. 6,121,027 includes descriptions of decorating heparin
with a photoactive cross linking chemical group. Application PCT
GB9701173 and U.S. Pat. No. 6,096,798 include descriptions of
heparins with monomers used to make polymers. U.S. Pat. Nos.
5,763,504 and 5,462,976 include descriptions of glycosaminoglycans
derivatized with photoactive groups and cross-linked thereby. U.S.
Pat. No. 6,060,582 includes descriptions of macromers with a water
soluble region, a biodegradable region, and at least two
free-radical polymerizable regions. Other patents include
descriptions of a polysaccharide reacted with other polymers,
decorated with a polymerizable group, and/or reacted to form a
coating on a surface; including U.S. Pat. Nos. 5,993,890;
5,945,457; 5,877,263; 5,855,618; 5,846,530; 5,837,747; 5,783,570;
5,776,184; 5,763,504; 5,741,881; 5,741,551; 5,728,751; 5,583,213;
5,512,329; 5,462,976; 5,344,455; 5,183,872; 4,987,181; 4,331,697;
4,239,664; 4,082,727; and European patents 049,828 A1 & B1.
[0012] Despite many years of research in the areas of
polysaccharides, hydrogels, and blood-contacting materials, the
need for better implantable synthetic materials that cause little
or no unfavorable reaction from a patient's body remains acute. In
particular, there is a great need for a medically useful small
diameter vascular graft made of synthetic materials.
SUMMARY OF THE INVENTION
[0013] Materials and methods disclosed herein are provided to meet
all of these needs by providing synthetic materials that
successfully combine the advantages of polysaccharides and
hydrogels in a medically useful manner so that they may be used for
devices, including small diameter vascular grafts. Other
embodiments include hydrogels made of polysaccharides and materials
and methods for making such hydrogels, as well as products that
incorporate such hydrogels. Another embodiment is a hydrogel made
of a polysaccharide, for example heparin. Another embodiment is a
hydrogel made by polymerizing heparin macromers. Another embodiment
is a small diameter vascular graft made by polymerizing heparin
macromers around a tube, for example a polyester tube.
[0014] Another embodiment is a medical apparatus having
polysaccharide macromers polymerized into a three-dimensional
crosslinked hydrogel that makes a hollow cylinder; with the
cylinder being formed during polymerization of the polysaccharide
macromers. A hollow cylinder is essentially equivalent to a tubular
structure and may be made out of any material, e.g., metals,
plastics, ceramics, having a variety of properties, including e.g.,
rigid, compliant, and elastic.
[0015] Another embodiment is a biocompatible encapsulation for an
inert medical device. The encapsulation has polysaccharide
macromers polymerized into a three-dimensional crosslinked hydrogel
that encapsulates the medical device.
[0016] Another embodiment is a medical apparatus made of a material
that has a heparin macromers polymerized into a three-dimensional
crosslinked hydrogel that forms a hollow cylinder that is not
covalently bonded to another material.
[0017] Another embodiment is a pollyvinylpyrrolidone macromer.
Another embodiment is a biocompatible coating system that has
polyvinylpyrrolidone macromers polymerized into a three-dimensional
crosslinked material that contacts a medical device and thereby
forms the coating.
[0018] Another embodiment is a polysaccharide polymer of at least
two polysaccharide macromers polymerized together. The polymer is
preferably in an isolatable form. The macromers may have
polymerizable moieties such as polyhydroxyethylmethylacrylates,
methyl methacrylates, methacrylates, acrylates, photopolymerizable
monomers, monomers with hydroxyl groups, monomers with glycerol
groups, monomers with polyoxyalkylene ether groups, monomers with
polypropylene oxide groups, monomers with vinyl groups, monomers
with zwitterionic groups, monomers with silicone groups, monomers
having sulphate groups, monomers having sulphonate groups, and
heparin monomer.
[0019] Another embodiment is a method of making a medical apparatus
from a material that includes a plurality of polysaccharide
macromers by polymerizing the macromers into a three-dimensional
crosslinked hydrogel that defines a hollow cylinder, wherein the
cylinder is formed during polymerization of the polysaccharide
macromers.
[0020] Another embodiment is a method of encapsulating an inert
medical device by polymerizing a plurality of polysaccharide
macromers into a three-dimensional crosslinked hydrogel that
encapsulates the medical device.
[0021] Another embodiment is a method of making a medical apparatus
by polymerizing heparin macromers into a three-dimensional
crosslinked hydrogel and thereby making a hollow cylinder having an
exterior, wherein the cylinder is formed during polymerization of
the heparin macromers and the exterior is not covalently bonded to
another material.
[0022] Another embodiment is a method of making
polyvinylpyrrolidone polymers from polyvinylpyrrolidone macromers.
Another embodiment is coating a medical device with
polyvinylpyrrolidone macromers by polymerizing the macromers into a
three-dimensional crosslinked polyvinylpyrrolidone material, and
applying a coating that includes the crosslinked
polyvinylpyrrolidone material onto the medical device.
[0023] Another embodiment is a method of making a polysaccharide
polymer by obtaining or making polymerizable polysaccharide
macromers, synthetically polymerizing the macromers with each other
to form a group of polymers having an average length of at least
two macromers per polymer, and isolating the polymers.
[0024] Another embodiment is a method of making a coating on a
medical device by providing a group of polysaccharide polymers
having an average length of at least two macromers per polymer,
putting the polymers in a solvent to make a mixture, and contacting
the medical device with the mixture.
[0025] Certain embodiments include a material made of a hydrogel
that preferably has at least 5% polymerized polysaccharide
macromers by dry weight. The hydrogel is preferably covalently
cross-linked such that the hydrogel remains intact in water and
preferably contains at least 30% water by total weight when
hydrated. The polysaccharide macromers are polymerizable while in a
solution or in a suspension. Normal polymerization techniques,
including free-radical, addition, and condensation polymerization,
may be used to polymerize the polysaccharide macromers.
[0026] One product is a tubular member with its inner wall and
outer wall covered with a hydrogel as described herein, i.e., the
tubular member is "encapsulated" by the hydrogel. A preferred
macromer formulation is made from heparin, the term heparin
including all molecular weights of heparin, heparan sulfate,
heparan sulfate proteoglycans, fragments thereof, and/or
derivatives thereof. The preferred embodiment of the heparin
hydrogel is at least 80% heparin by dry weight. The tubular member
preferably has a diameter of less than approximately 6.0 mm when
the hydrogel is hydrated and blood is flowing though the tubular
member. The tubular member may be a simple plastic extrusion or a
stent, but the preferred embodiment is a knitted or woven fabric
substrate. The fabric substrate is preferably pre-coated to enhance
the integrity and adhesion of the encapsulant and/or improve the
non-thrombogenic or anti-thrombogenic properties or both of the
encapsulant.
[0027] In an embodiment of the tubular member, the tubular member
is pre-coated with a very thin layer of the hydrogel containing
non-thrombogenic or anti-thrombogenic properties or both, the layer
being applied to cover the components of the tubular member. In the
case of the knitted or woven tube, these are the individual strands
from which the fabric is made. The tubular member preferably has a
low porosity such that blood leakage is not a paramount
concern.
[0028] In another embodiment, a porous tubular member, such as one
made from a fabric, is used as the tubular member. The fabric
tubular member is pre-coated with a polymeric material in order to
prevent blood leakage. The coated fabric tubular member is then
further coated with the hydrogel containing non-thrombogenic or
anti-thrombogenic properties or both. This structure imparts an
extremely thin, flexible, and compliant wall that can serve as a
vascular prosthesis, especially in the context of a small diameter
vascular graft.
[0029] Another embodiment is a tissue engineering matrix made from
a polysaccharide hydrogel. A tissue engineering matrix is, for
example, a three-dimensional material that serves as a scaffold for
cellular invasion or a nerve growth matrix. Examples of tissue
engineering matrices include matrices for making cartilaginous body
parts such as ears or joint cartilage; ligaments; scaffolds for
breast tissue invasion; liver matrices; and tissue engineered blood
vessels.
[0030] The present inventors have also recognized that there is a
need to use better organic solvents to dissolve polysaccharides,
including heparin. The use of better organic solvents allows
scientists to use chemistries and chemical techniques that are more
powerful than those that are conventionally used. These techniques
improve the cost, quality, and efficiency of conventional
techniques for making materials from polysaccharides and enable
better materials to be made.
[0031] Embodiments include the use of low dielectric organic
solvents and/or low boiling-point solvents for polysaccharide
chemistries to make derivatives of polysaccharides, including
attaching monomers to polysaccharides to make polysaccharide
macromers and the use of these improved solvents for making
polysaccharide hydrogels from polysaccharide macromers or
polysaccharide polymers. Further, some embodiments include steps
for using salts to decomplex the quaternary ammonium-heparin
complex.
[0032] Another embodiment is a method of making a polysaccharide
macromer, for example from heparin. The polysaccharide is reacted
with a quaternary ammonium salt to form a polysaccharide-quaternary
ammonium salt complex and then dissolved in an organic solvent with
a dielectric constant less than the dielectric constant of DMSO
and/or in an organic solvent with a boiling point less than DMSO.
The polysaccharide-quaternary ammonium salt complex may be reacted
with a chemical such as a monomer to form useful derivatives. The
polysaccharide-quaternary ammonium salt complex may then be treated
with another salt to remove the quaternary ammonium salt.
[0033] Certain embodiments optionally include steps of using a
vacuum to remove organic solvent from the polysaccharide,
derivatized polysaccharide, or complexes of the polysaccharide. The
vacuum removal is preferably performed at room temperature without
adding heat. Alternatively, heat may be applied to evaporate the
solvent, preferably enough heat to raise the temperature of the
solvent to its boiling point without denaturing the heparin such
that its biological activity is substantially reduced, a
temperature that may vary according to the solvent used but
typically being a temperature of less than approximately 100
degrees Centigrade and preferably less than 70 degree Centigrade.
Alternatively, a mix of vacuum and heat may be used.
[0034] A preferred embodiment uses an organic solvent that has a
boiling point at atmospheric pressure and a dielectric constant
that are less than conventionally used organic solvents. A more
preferred embodiment has a boiling point of less than approximately
115 degrees Centigrade and a dielectric constant that is less than
that of DMSO. A more preferred embodiment uses an organic solvent
that has a boiling point of less than approximately 70.degree. C.
at atmospheric pressure and a dielectric constant that is less than
that of DMSO.
[0035] Certain embodiments include polymerizing the polysaccharide
macromer in an organic solvent to make a polymer of at least two
macromers. The macromers may be the same or different, to thereby
make a homopolymer or a copolymer. Some embodiments include making
a hydrogel from the polysaccharide macromer and/or polysaccharide
macromer, preferably in an organic solvent.
DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 is a longitudinal sectional view of an embodiment of
the invention having a fabric graft encapsulated within a
hydrogel;
[0037] FIG. 2 is a side elevational view of the structure depicted
in FIG. 1;
[0038] FIG. 3 depicts a longitudinal sectional view of an
alternative embodiment of the invention having a fabric graft
coated with a hydrogel;
[0039] FIG. 4 depicts a longitudinal sectional view of another
alternative embodiment of the invention having a double-coated
fabric graft; and
[0040] FIG. 5 depicts a longitudinal sectional view of another
alternative embodiment of the invention like the embodiment of FIG.
4 except that the fabric graft tube has been inverted.
[0041] FIG. 6 depicts a partial view of an alternate embodiment of
the invention having a plastic surface coated with a hydrogel.
[0042] FIG. 7 depicts a cross-sectional view of a hydrogel being
formed on a mandrel.
[0043] FIG. 8 is a sectional view of FIG. 7.
[0044] FIG. 9 depicts a reaction scheme for making and using
polysaccharide macromers.
[0045] FIG. 10 depicts an alternative reaction scheme for making
and using polysaccharide macromers.
DETAILED DESCRIPTION
[0046] Synthetic materials implanted into the soft tissue of a
patient elicit a range of undesirable reactions that are typically
categorized as acute inflammation, chronic inflammation, the
formation of granulation tissue, foreign body reaction, and
fibrosis (Ratner et al., 165-173, Biomaterials Science, 1996
Academic Press). Other reactions are possible, such as an immune
system response or systemic toxicity and hypersensitivity. At a
materials-blood interface, the blood coagulation mechanism can be
activated to cause local clotting and downstream events such as
complement activation or generation of blood clots (Ratner et al.,
193-199). These reactions impact how synthetic articles, including
vascular grafts, are designed and manufactured.
[0047] Current medical practices for the use of synthetic articles
as vascular grafts are essentially restricted to the use of
polyester and polytetrafluoroethylene tubes as replacements for
large-diameter blood vessels to treat patients with certain types
of vascular disease.
[0048] Vascular disease takes many forms, but one of the most
common is stenosis, where an artery becomes narrowed by build up of
plaque. Atheroscherotic Stenosis is a condition where the artery
becomes hardened and less flexible by the process of calcification.
The condition is often accompanied by a build up of tissue or
plaque on the inside wall of the lumen of the artery. This build up
causes the lumen of the artery to narrow and restrict the passage
of blood.
[0049] Total occlusion of an artery may occur when a clot of blood
(a thrombus) lodges inside an artery, at a narrowing. Such
occlusions can prove fatal if the artery is in a critical position;
for example, coronary thrombosis causing a heart attack, or
cerebral thrombosis causing a stroke.
[0050] Even if there is not total occlusion, a restriction of the
flow of blood can cause severe problems in limbs and organs
downstream from the stenosis, due to starvation of the oxygen and
nutrients supplied by the blood. A very common example is the
reduction of flow in the lower leg, which may lead to claudication
and eventually to gangrene and loss of a limb.
[0051] A higher profile example of stenosis is observed when the
disease affects the coronary arteries, which supply blood to the
muscle of the heart. Stenosis, or occlusion due to thrombosis, can
lead to an infarction due to parts of the muscle tissue of the
heart dying (necrosis). That is, a myocardial infarction or heart
attack.
[0052] Another common form of vascular pathology is an aneurysm. An
aneurysm is a condition where the wall of the artery weakens and
dilates to form a balloon-like swelling. An aneurysm is a weakening
of the artery wall leading to dilation. This dilation can develop
so that the arterial wall is too thin and weak to withstand the
pressure of the blood. A burst aneurysm causes severe hemorrhage,
and can be fatal. One example is the so-called AAA (triple A) or
abdominal aortic aneurysm; rupture of an artery having this defect
is almost always fatal.
[0053] Conventional vascular surgery techniques have made the
surgical replacement of diseased arteries commonplace. The use of
autologous grafts where a non-essential vein from a person's own
blood vessels is used as a replacement artery is the oldest form of
vascular grafting, and is still used today especially for coronary
bypass procedures. A patient, however, may not have enough
autologous donor vessels to fill the needs of the replacement
surgery. Further, it is desirable that there be an alternative to
the loss of a functioning blood vessel. It was the development in
the 1960s of synthetic fabric prostheses, which led to the range of
products available to the vascular surgeon today.
[0054] Conventional synthetic vascular grafts are woven or fabric
seamless fabric tubes, which are used as a direct replacement for a
section of diseased artery. Various materials have been tried, but
the most successful is polyester, which is the only material now
used by clinicians for fabric grafts. Polyester is a very
bio-stable material and, although slightly thrombogenic, is
reasonably well tolerated in use for larger diameter arteries
(approximately 6-mm diameter and above).
[0055] When implanted, a vascular graft causes the body to react
and generate a blood clot layer around its inner perimeter. This
blood clot may be accompanied by tissue growth. If such tissue
growth is not securely anchored in place, there is a danger of a
loose blood/tissue clot or embolus being formed. The flow of blood
may carry the embolus downstream until it reaches a narrower part
of the artery where it may cause a blockage or occlusion.
[0056] In order to ensure that tissue growth remains anchored to
the graft, fabric grafts are made slightly porous so that the
tissue grows into the pores of the fabric and is firmly attached.
This has an added advantage that the tissue encapsulates the fabric
graft and covers it, using the graft as scaffolding for new growth.
In general, grafts with higher porosities, and especially flexible
and elastic fabric grafts, heal better and generally perform better
than low porosity woven grafts. It is because of this effect that
the so-called "velour" grafts have been developed. Velour grafts
have textile filaments raised up on the surface of the fabric.
[0057] The need for porosity creates an initial problem for the
surgeon since a high porosity graft will leak if simply implanted
with no special preparation. After implantation, tissue growth
fills in the pores in the fabric and therefore renders the graft
"blood tight". The problem is to make the graft blood tight during
the initial surgery and for the immediate few hours afterwards. The
original approach taken was to "pre clot" the graft before
implantation. A small amount of blood was taken from the patient
before the operation, and the graft was soaked in this blood so as
to fill all the pores of the fabric with clots. The porous
structure ensured that the clotted blood was firmly attached. This
procedure was, however, time consuming, and it was and is very
difficult to properly pre-clot those materials with high
porosities. Because of these problems, the soft and very compliant
fabric grafts, which heal better than stiff woven grafts, were not
considered suitable for areas of high pressure such as thoracic
arteries near the heart.
[0058] Subsequent to the development of fabric grafts, a new
development was introduced, which was the invention of a graft made
from polytetrafluoroethylene (PTFE). PTFE is a material that is
generally well tolerated in the body. A chief advantage with a PTFE
graft is that it does not require pre clotting. However, PTFE
material does not heal as well as warp fabric grafts. Modern PTFE
prostheses are made of expanded material in order to imitate the
cellular structure of fabric grafts, but this is only partially
satisfactory.
[0059] Fabric grafts are now available which do not require
pre-clotting. They are coated with a bio-absorbable material such
as gelatin or collagen. The coating material is gradually adsorbed
and tissue grows to replace it. Such grafts are not only simpler to
use because there is no requirement for pre-clotting, but they also
tend to give better healing and performance.
[0060] All of these conventionally used grafts have a common
disadvantage in that they cannot be used for small diameter
applications. Synthetic vascular grafts with a diameter of less
than approximately 6 mm will not remain functional over a
clinically significant period of time.
[0061] The reason for the failure of conventional small diameter
vascular grafts is thought to be related to the flow rate and type
of blood flow within the graft. With a large inner diameter graft,
there is a high volume of blood passing though the vessel. Any
small tissue growth on the inside wall is insignificant and does
not disrupt flow. With small inner diameter grafts, a small tissue
build up is more significant in relation to the overall diameter of
the vessel. A small build up will cause flow turbulence, which,
because of the already low volume flow, tends to cause even more
tissue growth, which leads to stenosis.
[0062] Conventional medical clinicians urgently need a small
diameter synthetic graft to cope with a range of small caliber
replacement requirements. The only procedure conventionally
available is an autologous transplant of the saphenous vein in the
leg. The problem with this approach is that the amount of graft
material available is very limited. In addition, the removal of the
saphenous vein causes severe discomfort to the patient. One of the
most important of these small diameter applications is the
replacement or bypass of coronary arteries in cases of coronary
stenosis. Another use is for the replacement of stenosed or
occluded infragenticulate arteries.
[0063] In order to replace the smaller caliber vessels using a
small diameter vascular graft, the implant should be highly
biocompatible and not thrombogenic. The biocompatibility should be
such that little tissue growth is stimulated and the blood and body
accept the prosthesis in a similar way that they accept the natural
artery.
[0064] Many polymers have been tested for the small diameter
vascular graft application. A polymer is a single molecule built up
by the repeated reaction of molecules that may be referred to as
monomers. Monomers are molecules that may be reacted with other
monomers to make a polymer. For example, a methylmethacrylate
monomer represented by "A" may be used to make
polymethylmethacrylate, which would be the polymer "AAAAA". A
polymer made of monomers A and B could have a random structure of
ABAAABAABA and could be called a polymer or a copolymer of A and B.
Polymer AAAAA and BBBBB could be joined to form copolymer
AAAAABBBBB. A molecule that is derivatized is a molecules that has
been chemically changed; a molecules that has been decorated is a
molecules that has had a chemical unit attached.
[0065] A macromer, as used herein, is a monomer or a polymer that
is polymerizable and is a convenient term for referring to monomers
or polymers that have been decorated with a monomer or used as
decorations. Polysaccharide macromers include multiple
polysaccharides that are polymerizable. For example, several
macromers may be polymerized together to form a larger
polymerizable group that is a macromer. Or several polymers, e.g.,
polysaccharides, may be joined together and decorated with
polymerizable groups to form a macromer. Thus a heparin macromer is
a heparin molecule that is polymerizable, for example after being
decorated with a monomer. The term polymer, as used herein,
includes oligomers and chains of at least two monomers in length.
Polymers can be assembled into larger materials; for example, many
polymers may be linked together to form a hydrogel.
[0066] A variety of hydrogels are blood compatible. Examples that
are commercially useful are made from
polyhydroxyethylmethylacrylate (PHEMA), polyacrylamides,
polyacrylic acid, N-vinyl-2-pyrrolidone (NVP), methacrylic acid,
methyl methacrylate, and maleic anhydrides, each of which have been
proven to be polymerizable from monomers. Further examples of
biocompatible materials include hydrogels made from polyvinyl
alcohol, methacrylates in general, acrylates in general,
polyethylene glycol (PEG), hyaluronic acid, and alginates.
[0067] The term hydrogel, as used herein, is a cross-linked
material that can absorb or imbibe a water and is produced by the
cross linking of one or more monomers or polymers. The cross-links
in a hydrogel may be the result of covalent bonding or of
association bonds, for example hydrogen bonds, charge-charge
interactions, or strong van der Waals interactions between chains
(Ratner et al., pages 60-64). A hydrogel cannot be suspended in
water nor does it dissolve in water; instead, it remains intact
water. For example, a material can shrink or swell and still remain
intact without dissolving. For example, a contact lens shrinks and
swells in water but does not dissolve therein.
[0068] Hydrogels have been used for a myriad of applications, such
as artificial tendon materials, wound-healing bioadhesives, wound
dressings, artificial kidney membranes, articular cartilage, knee
cartilage replacement, artificial skin, maxillofacial and sexual
organ reconstruction, tissue engineering scaffolds, and vocal cord
replacement materials. There are many types of hydrogels known to
those skilled in these arts, such as aerogels, xerogels,
equilibrium-swollen hydrogels, solvent-activated hydrogels, and
swelling-controlled relapse hydrogels (e.g., Ratner et al., page
60-64). These types of hydrogels may be used with certain
embodiments as described herein. Moreover, all of the uses for
hydrogels described in this application may be used in embodiments
described herein.
[0069] Polysaccharides are polymers made from monomers that are
sugars. Alginate is a polysaccharide. Glycosaminoglycans are a
subcategory of polysaccharides that are made from repeats of
disaccharide units. Glycosaminoglycans include hyaluronic acid,
chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin,
chitin, chitosan, and keratan sulfate. Polysaccharides and
glycosaminoglycans can also be found in a related proteoglycan
form; proteoglycans are polysaccharides unified with a protein.
Methods, compositions, and uses as described herein for
polysaccharides are applicable to proteoglycans,
glycosaminoglycans, and natural or synthetic derivatives or
fragments thereof.
[0070] Heparin is a polysaccharide polymer with an important
property: it interferes with key molecules in the blood clotting
mechanism such that the blood will not clot. Coating the inside of
a tube with heparin tends to increase the amount of time that the
tube remains open to blood flow but, to date, small diameter
vascular grafts coated with heparin have failed to resist blockage
by blood coats for a clinically useful length of time. Many
researchers have tried to use heparin to coat the inside of
vascular grafts. Heparin is a molecule that belongs to a group of
molecules called polysaccharides that are molecules made from
combinations of smaller molecules called sugars. Polysaccharides
are naturally-occurring polymers but certain embodiments are
directed to synthetic, derivitized, man-made, and semi-synthetic
polysaccharides.
[0071] Heparin has been applied to materials in many ways. General
strategies have included adsorption, making charge-charge bonds
with the surface, covalent immobilization, and release from a
surface. Photoactivatable chemical groups have been put onto
heparin so that if heparin is put close to the surface and the
surface is bathed in light to make the photoactive groups make
permanent covalent chemical bonds with the surface. Similarly,
heparin has been reacted with polymerizable monomers that have then
been reacted to achieve covalent bonding to the surface.
[0072] Despite the great amount of research effort that has been
expended in the field of biomaterials, including research with
hydrogels, heparin, and polysaccharides, there is a continued need
for improved biomaterials. Biomaterials that may be used in
blood-contacting applications are especially required.
[0073] Embodiments are provided that include an improved
biomaterial that successfully combines the advantages of
polysaccharides and hydrogels. One embodiment is a hydrogel made of
polysaccharides. Another embodiment is a linear or multi-armed
polysaccharide or polyvinylpyrrolidone polymer that is absorbable
to a surface. Multi-armed means a soluble polymer that is branched
or cross-linked. The hydrogels and the coatings may be used for the
many applications for which a hydrogel may be used, e.g., as
already described. There are other uses for hydrogels and the
linear or multi-armed polymers that include coatings for stents,
catheter coatings, cardiac valves or leaflets, cartilage
replacement, replacement knee cartilage, organ scaffolds, lumbar
disks, cell encapsulation, wound healing, nerve guides or tubes,
and postoperative adhesions. A hydrogel may be used to make, coat,
or encapsulate such devices. A coating may be used to such devices
to improve their performance. Another hydrogel use is for a wound
dressing for large, shallow wounds on animals so that a scab does
not form over the wound but prevents blood clotting at the surface,
thereby preventing scar formation.
[0074] The hydrogel may be made by mixing polysaccharide macromers,
e.g., heparin macromer, with other macromers or monomers to make a
mixture. The mixture is poured into a mold and polymerized. After
polymerization, the mold is removed and the polymerized
macromers/monomers are hydrated. Various shapes, e.g., sheets,
tubes, spheres, rods, may be formed by using suitable molds.
[0075] The resultant shape is not covalently or otherwise bonded to
other materials: the exterior and luminal surfaces are "free". The
free surfaces are not attached to other surfaces. A free surface
may be decorated with moieties, e.g., drugs, polymers, and other
agents. Such decorations do not cause the free surface to thereby
be attached to other materials. Further, the resultant shape is
formed during the polymerization process. This shape-forming
process is distinct from processes that build up a coating on the
inside of, e.g., a tube, in part, because the coating on the tube
is essentially inseparable from the tube, especially if it is
ionically or covalently bonded thereto.
[0076] Moreover, the prior art methods of applying a coating to a
tube and building up the coating is not equivalent to the present
process. First, the prior art coating procedure does not create the
tubular shape. But polymerizing macromers into a tubular shape
during the polymerization process does create the tubular shape.
Making a shape during a polymerization process is difficult because
the polymerization reaction must be effective enough to make a
solid material, with the effectiveness depending on polymerization
variables known to those skilled in these arts. For example, an
effective process requires using a macromer that can be provided in
sufficient concentration. Not all macromers are sufficiently
soluble to be present in solution with a high enough concentration
to make a solid. The polymerization mixture must have be
crosslinkable for crosslinks to form. The kinetics of the
polymerizable groups must be suitable.
[0077] Many prior art processes have not overcome these limitations
and instead dry polymerizable groups onto a surface and then
crosslinking them. The drying step results in drastically different
structures than those made with polymerization from a solution (or
a melt). If proteins or polysaccharides are dried, they aggregate
and form clumps on the molecular level. In contrast, polymerization
from a solution gives structures that are not aggregated but
instead have a network of unaggregated polysaccharides. Since the
macromers are not aggregated, the density of materials polymerized
from solution can be lower. Moreover, a true polymerization process
may take place wherein the polymerizable groups react with each
other to form a polymeric backbone. In contrast, dried solutions
have little mobility and the polymerizable groups react with the
chemical structures closest to them instead of reacting with other
polymerizable groups.
[0078] In short, chemical crosslinking is not equivalent to
polymerization. The present materials and methods provide for
polymerization methods and for polymerized materials as opposed to
coatings built up on surfaces, gelled structures, and merely
aggregated, chemically crosslinked, or surface-immobilized
materials. The advantages of polymerization are numerous and well
known to ordinary artisans.
[0079] One advantage of a polysaccharide covalently polymerized
with a hydrogel is that the polysaccharide may be stably
incorporated into the hydrogel so that it is not released over
time. This stability is useful for a long-term implant because the
hydrogel would otherwise dissipate over time and eventually fail.
The heparin hydrogels are hypothesized to function by reversibly
binding antithrombin III. The antithrombin III is bound by the
heparin and thereby changes its shape so that it reacts with and
inactivates both thrombin and Factor X(a), which are key enzymes
required for blood to clot. The antithrombin III is hypothesized to
stay on the heparin hydrogel temporarily so that it attaches,
reacts with thrombin and Factor X(a), and departs back into the
bloodstream so that a new antithrombin III molecule may be bound to
the heparin.
[0080] Another advantage of the polysaccharide hydrogel is that it
can be made as a thick film. Thick films may be handled by
surgeons, grasped with tools such as forceps, punctured by sutures,
and suffer scratches and damages to their surface without losing
their favorable blood-contacting properties. The thickness of the
film and the three-dimensional structure of the film allows it to
suffer minor damage while continuing to cover the surface with
heparin molecules. In contrast, damage to a thin coating or a
synthetic material that has been merely reacted with a
polysaccharide can entirely remove the polysaccharide and expose
the underlying material to the body. For example, a surgeon that
uses forceps to firmly grasp a plastic tube covered with a layer of
heparin that has been reacted with the tube's surface might
accidentally scratch the tube and remove the heparin thereby
exposing the underlying plastic material of the tube. In contrast,
a surgeon might accidentally scratch a plastic tube encapsulated
with a thick film heparin coating but would not thereby expose the
underlying plastic because a scratch in the thick film would expose
only more of the heparin hydrogel.
[0081] Further, the thickness of the hydrogel film is hypothesized
to minimize blood contact with the synthetic material that the
thick film is encapsulating. Blood or its components must penetrate
through the entire thickness of the hydrogel prior to reacting with
the encapsulated synthetic material. In contrast, a thin coating,
especially a coating of a few molecules' thickness, presents a
shorter distance between the blood and the encapsulated synthetic
material. This distance is important because the efficiency of
surface chemistry reactions used for conventional techniques is
hypothesized to typically provide a surface coverage of less than
100%, i.e., not every space on a surface coated with heparin is
completely covered with a heparin molecule. In contrast, a thick
film provides more than 100% coverage because any molecule that
would react with the surface must pass through a thick coating that
has a thickness of many molecules.
[0082] One embodiment is a tubular member encapsulated by a
polysaccharide hydrogel. The encapsulation may be achieved by a
number of processes, one such process being placing tubular member
into a mold and charging the mold with the desired formulation of
polysaccharide macromers and polymerized by conventional techniques
at room or at elevated temperature and/or by electromagnetic
radiation. A material that encapsulates a member is termed an
encapsulant.
[0083] Certain embodiments involve polymerization processes,
including polymerization of polysaccharide macromers. The
polysaccharide macromers may be polymerized using conventional
techniques, for example using initiators, carriers, accelerators,
retardants, viscosifiers, and/or cross-linkers. The polysaccharide
macromers may also be copolymerized with and other monomers and/or
macromers and/or polymerizable polymers. In another embodiment, a
tubular member is covered with a mixture of polysaccharide
macromers and/or monomers and/or polymers. The polymerizable groups
are subsequently polymerized to form a crosslinked hydrogel. It may
be desired to placed the tubular member on a rotating mandrel and
apply the mixture so as to ensure that the tubular member is
encapsulated uniformly.
[0084] The polysaccharide macromers and polymers made thereof may
also be copolymerized, blended, mixed, and/or cross-linked with
other monomers and/or macromers, and/or polymers including
engineering polymers, blood compatible polymers, hydrogel polymers,
natural polymers (e.g., deoxyribonucleic acid, polysaccharides, and
proteins and bioactive fragments thereof) and/or fillers. The type
of initiation is not limited and may include thermal, X-ray,
ultraviolet, infrared, visible light, free radical, addition,
sonic, and condensation initiation.
[0085] Monomers, i.e., for mixing with the polysaccharide
macromers, can include, but are not limited to, monomers with
hydroxyl groups (e.g., hydroxyethyl methacrylate), monomers with
glycerol groups (e.g., glycerol monomethacrylate, glycerol
dimethacrylate, glycerol trimethacrylate), monomers with
polyoxyalkylene ether groups (e.g., polyethylene glycol
methacrylate, polypropylene glycol methacrylate), monomers with
vinyl groups (e.g., N-vinyl pyrrolidone), monomers with
zwitterionic groups (e.g., 2-methacryloyloxyethyl-2-(trimethyl
ammonium) phosphate, monomers with silicone groups (e.g.,
methacryloxypropyl tris (trismethyl-siloxy) silane and other
silicone methacrylate or acrylates), monomers having sulphate
groups (e.g., vinyl sulphonic acid), monomers having sulphonate
groups (e.g., ammonium sulphatoethyl methacrylate), heparin monomer
as cited in the patent PCT GB9701173 and U.S. Pat. No. 6,096,798,
which are hereby incorporated herein by reference.
[0086] Polymers for mixing, blending, and/or copolymerization with
polysaccharide macromers include derivatized polymers, for example,
derivatized polyoxyalkylene ether groups (e.g., polyethylene oxide
terminating in hydroxyl group, carboxylic groups and/or isocyanate
groups and polypropylene oxide terminating in hydroxyl group, amino
groups, carboxylic groups and/or isocyanate groups), polyvinyl
pyrrolidone functionalized with methacrylate groups, methacrylate
terminating dimethysiloxone, vinyl terminating dimethylsiloxone,
polyurethane terminating in isocyanate, polyester terminating in
isocyanate and also other polymers that can be derivatized with
methacrylate, acrylate, isocyanate, carboxylic acid, amino,
hydroxyl and/or vinyl groups.
[0087] Polymers mixed, blended and/or copolymerized with
polysaccharide macromers may also be used to enhance the viscosity
of the mixture formulation for the application to the rotary
mandrel and hence the polymerization of the mixture formulation.
This technique may be used to give the encapsulated tubular member
a homogenous and smooth surface, a feature that enhances vascular
prosthesis biocompatibility. The encapsulated tubular member and
hence the biocompatible vascular prosthesis has a smooth surface
containing non-thrombogenic or anti-thrombogenic properties or both
and preferably has a water content ranging from about 30% to about
90%.
[0088] In one embodiment, a tubular member is encapsulated by the
hydrogel, e.g., as in FIGS. 1 and 2, the hydrogel having
cross-linked polymers made from polysaccharide macromers and
copolymerized with monomers from at least three of these classes,
as discussed in patent application PCT GB97 01173, U.S. Pat. No.
6,096,798: (a) monomers having sulphate groups, (b) monomers having
sulphonate groups, (c) monomers having sulphamate groups, (d)
monomers having polyoxyalkylene ether groups and (e) monomers
having zwitterionic groups. The polysaccharide macromers are
preferably heparin macromers. Hydrogel encapsulation of the tubular
member is performed by placing the tubular member into a mold,
adding a macromer and/or monomer formulation and then polymerizing
to make a hydrogel. The monomer constituents may vary from 10% to
90% by weight and are preferably polymerized with a bifunctional
monomer, e.g., ethylene glycol dimethacrylate. This formulation
provides the prosthesis with a smooth surface, prevents the leakage
of blood, is non-thrombogenic and/or anti-thrombogenic, and has a
water content ranging from 30% to 90% when hydrated. When hydrated,
the biocompatible vascular prosthesis is soft and pliable so it
will not compromise the mechanical properties of the
prosthesis.
[0089] FIG. 1 depicts a longitudinal cross section of a small
diameter vascular graft 10. FIG. 2 shows an end view of a radial
cross section of FIG. 1. The loops of synthetic material 12 are
completely encapsulated within hydrogel 14. This embodiment is
suitable for porous members that allow passage of the macromer
and/or monomer constituents through the pores of the tubular
member, e.g., a fabric, in order to provide binding between the
inner and outer faces of the encapsulant.
[0090] An alternative embodiment uses approximately the same
materials and methods but a tubular blood vessel member 13 is used
which has sufficiently low porosity so that blood leakage is not a
consideration. e.g., a tightly knitted or woven fabric, or a
plastic extrusion. With this kind of tubular member, the basic
porosity is low. Referring to FIG. 3, instead of encapsulating
tubular member 13, it is covered with a hydrogel layer 14 of
polysaccharide macromer and/or monomers. In the case of a fabric
tubular member, the hydrogel coats the individual yams and fibers.
At the same time, the hydrogel may be used to cover the pores
completely or partially. The loops of knitted fabric 13 are coated
by hydrogel 14. This embodiment is simpler to make than the
encapsulation process as the covering is applied by dip process,
spraying technique or by other conventional process.
[0091] Another embodiment uses approximately these same materials
and methods but uses a porous tubular member 15, such as one made
from a fabric, which is pre-coated (a primary coating layer 16)
with a polymeric material in order to prevent blood leakage, as the
layer provides a strong "leak proof" security layer (FIG. 4). The
leak proof layer is essentially impermeable to blood, meaning that
it generally prevents flow of blood in surgical applications.
Alternatively, the barrier may be permeable to blood, and control
the flow of blood. Primary coating layer 16 may be made from a
number of flexible polymers, e.g., silicone polymer, polypropylene,
polyester, polyurethane, polytetrafluoroethylene (PTFE) or
elastomeric polymer such as silicone rubber. The total composite is
then further coated with hydrogel 14 containing polysaccharides.
This structure imparts an extremely thin, flexible, and compliant
wall to vascular prosthesis 10. Each of the coating processes may
be applied by dip process, spraying technique or by other
conventional coating process. FIG. 4 depicts a longitudinal cross
section of a knitted tubular member coated according to this
embodiment. The fabric loop of porous tubular member 15 is inside
primary coating 16, which in turn is inside hydrogel 14.
[0092] Referring to FIG. 5, another embodiment takes advantage of
the manufacturing processes of woven vascular prostheses. A tubular
member made from knitted fabric has a different surface texture on
the internal face and the external face. The technical face of the
fabric tends to be smoother than the technical back. In the case of
the knitted tubular member, the technical back is on the internal
face of the fabric, whereas the technical face is on the external
face. When used as a vascular prosthesis, the knitted tubular
member can be inverted so that the smoother face is on the internal
face of the prosthesis. In addition, the internal face has very
shallow grooves, which run longitudinally. These grooves may help
to smooth the flow of the blood and reduce turbulence.
[0093] FIG. 5 shows a schematic longitudinal cross section of a
porous tubular member 15 made of a knitted material that is coated
with the fabric inverted. The fabric loop of the porous tubular
member 15 is inside the primary coating 16, which in turn is inside
the hydrogel 14. A tubular vascular vessel made from knitted fabric
has a different surface texture on the internal face and the
external face. The technical face of the fabric tends to be
smoother than the technical back. In the case of the knitted
tubular member, the technical back of the fabric is on the internal
face of the vessel, whereas the technical face is on the external
face of the vessel. The fabric loop of the porous tubular member 15
is inside the primary coating 16, which in turn is inside the
hydrogel 14.
[0094] A most preferred tubular member is a warp knitted or weft
knitted seamless fabric tube. In the warp knitted form, the most
preferred structure is reverse locknit, but tricot can also be
used. The fabric tube can also be weft knitted or woven. The tube
may be continuous or it may be bifurcated in order to fulfill the
needs of a graft designed to replace the Aorto-Iliac
bifurcation.
[0095] FIG. 6 shows a portion of a vascular graft 10 with surface
18 with a thick film of hydrogel 24. The thickness of film 24
protects surface 18 from being exposed as a result of damage caused
by handling the vascular graft 10. The film is preferably at least
25 .mu.m thick, more preferably from about 5 to about 1500 .mu.m
thick, and even more preferably about 500 to about 800 .mu.m
thick.
[0096] Alternatively, a very thin coating or hydrogel may be
applied to a graft or other structure. The coating is applied,
e.g., by spraying, so that the coating or hydrogel is present on
the fibers of the graft. The interstices between the fibers are not
coated by this technique. For example, a wire mesh stent may be
coated with a hydrogel without the hydrogel filling the interstices
of the mesh. Such a hydrogel or coating is preferably less than
about 10 .mu.m in thickness.
[0097] FIG. 7 depicts vascular graft 10 being made by molding
hydrogel 14 around mandrel 20 and within outer mold 22 while
entrapping synthetic material 12 in annulus 26 created by mandrel
20 and outer mold 22. The monomers and/or macromers used to make
hydrogel 14 are poured into annulus 26 and then polymerized around
synthetic material 12. FIG. 8 depicts cross-section 8-8 of FIG. 7;
hydrogel 14 is shown in phantom lines.
[0098] A tubular member may also be a plastic tubular extrusion of
a polymeric material. Such materials could be, for example,
silicone polymers, polyester, polyurethane, polypropylene, silicone
elastomer, polytetrafluoroethylene (PTFE) or other suitable
materials. The tubular member may also be porous or have a defined
permeability, e.g., as a hollow tube fiber with a defined molecular
weight cut-off. Porosity/permeability may be incorporated into a
tube by the selection of the material or by adding pores or holes,
e.g., by lasers, and punctures.
[0099] Another embodiment is a method of making a vascular graft. A
first polysaccharide hydrogel tube is made and introduced inside of
a tubular member that has an exterior side and an inner side that
faces the lumen of the tubular member. A second polysaccharide
hydrogel tube is made and introduced around the outside of the
tubular member to form a sandwich of a tubular member between two
hydrogel tubes. The two hydrogel tubes are then treated to form one
unit. One suitable treatment is to swell the hydrogel tubes in a
solvent to bring them in to contact with each other and then to
chemically react them. Examples of suitable chemical reactions
include polymerization, polymeric cross-linking with ultraviolet,
heat, or sonic initiators, and chemical cross-linking with
gluteraldehyde, or diisocyantes. The cross-linking agents may be
present in the tubes prior to swelling or may be introduced with
the solvent. Suitable solvents include aqueous solvents, organic
solvents, and low boiling point and/or low dielectric constant
organic solvents. One option for forming one unit of the hydrogels
is to use a tubular member that is shorter than the two hydrogel
tubes so that the two hydrogel tubes are joined around the tubular
member. Another option for forming one unit of the hydrogels is to
use a tubular member that is porous so that the hydrogels are
forced into the pores during swelling so that the two hydrogel
tubes contact each other through the pores. As a result, the
hydrogels may become cross-linked through the pores.
[0100] Polymers and hydrogels as described herein, whether
encapsulating or coating the tubular member, may if desired,
incorporate and slowly release growth factors, thrombolytic drugs,
thrombotic drugs, enzymes, restenosis-preventing drugs, inhibitors
and other agents used to treat diseased tissues. Further, gene
therapy delivery may be performed by complexing gene therapy
victors to the polymer or hydrogel, e.g., by complexing DNA and a
polysaccharide together with a positively charged ion or polymer.
Other functions, uses, applications, formulations, and technologies
of hydrogels known those skilled in the art may be used to create
further alternative embodiments.
[0101] Another embodiment is related to making a heparin macromer
by reacting heparin with a quaternary ammonium salt to form a
heparin-quaternary ammonium salt complex; dissolving the
heparin-quaternary ammonium salt complex in an organic solvent with
a dielectric constant less than the dielectric constant of
dimethylsulfoxide; and decorating the heparin in the
heparin-quaternary ammonium salt complex with a polymerizable
monomer. Further, a vacuum removal step of removing the organic
solvent with a vacuum may be used, preferably at room
temperature.
[0102] An embodiment is a method of making a heparin macromer by
reacting heparin with a quaternary ammonium salt to form a
heparin-quaternary ammonium salt complex; dissolving the
heparin-quaternary ammonium salt complex in an organic solvent that
has a boiling point of less than 190 degree Centigrade at
atmospheric pressure; and decorating the heparin in the
heparin-quaternary ammonium salt complex with a polymerizable
monomer. The step of dissolving the heparin-quaternary ammonium
salt complex in an organic solvent is alternatively performed with
an organic solvent with a boiling point of less than 114 degrees
Centigrade at atmospheric pressure.
[0103] Certain embodiments include an optional additional step of
decomplexing the heparin quaternary ammonium salt from the
heparin-quaternary ammonium salt complex by mixing the
heparin-quaternary ammonium salt complex with a salt that is not a
quaternary ammonium salt.
[0104] Another embodiment is a method of making a heparin polymer
by reacting heparin with a quaternary ammonium salt to form a
heparin-quaternary ammonium salt complex; dissolving the
heparin-quaternary ammonium salt complex in an organic solvent that
has a boiling point of less than 190 degree Centigrade at
atmospheric pressure; decorating the heparin in the
heparin-quaternary ammonium salt complex with a polymerizable
monomer; and polymerizing the monomer to make a polymer.
[0105] Another embodiment is a method of making a heparin hydrogel
by reacting heparin with a quaternary ammonium salt to form a
heparin-quaternary ammonium salt complex; dissolving the
heparin-quaternary ammonium salt complex in an organic solvent with
a dielectric constant less than the dielectric constant of
dimethylsulfoxide; decorating the heparin in the heparin-quaternary
ammonium salt complex with a polymerizable monomer to make a
heparin macromer; and polymerizing the heparin macromer to form a
polymer and cross-linking the polymers to form a hydrogel.
[0106] Another embodiment is a method of making a polysaccharide
macromer, the method comprising: reacting a polysaccharide with a
quaternary ammonium salt to form a polysaccharide-quaternary
ammonium salt complex; dissolving the polysaccharide-quaternary
ammonium salt complex in an organic solvent that has a boiling
point of less than 190 degree Centigrade at atmospheric pressure;
and decorating the polysaccharide in the polysaccharide-quaternary
ammonium salt complex with a polymerizable monomer. The step of
dissolving the polysaccharide-quaternary ammonium salt complex in
an organic solvent may also be performed with an organic solvent
with a boiling point of less than 114 degrees Centigrade at
atmospheric pressure.
[0107] Another embodiment is a method of making a material from a
polysaccharide by reacting a polysaccharide with a quaternary
ammonium salt to form a polysaccharide-quaternary ammonium salt
complex; dissolving the polysaccharide-quaternary ammonium salt
complex in an organic solvent that has a boiling point of less than
190 degree Centigrade at atmospheric pressure; and decorating the
polysaccharide in the polysaccharide-quaternary ammonium salt
complex with a polymerizable monomer to make a polysaccharide
macromer; decorating the polysaccharide in the
polysaccharide-quaternary ammonium salt complex with a
polymerizable monomer to make a polysaccharide macromer. Moreover
there may be included a step of polymerizing the polysaccharide
macromer to make a polysaccharide polymer. There may further be
included a step of polymerizing the polysaccharide macromer to form
a hydrogel.
[0108] Another embodiment is a material for use in a medical
context, the material including a hydrogel made of a material
including polymers, the polymers including heparin polymers made of
polymerizable heparin macromers, the hydrogel having covalently
cross-linked polymers such that the hydrogel remains intact in
water. The heparin macromers may be macromers that are
polymerizable while in a solution or in a suspension. The hydrogel
may include polymerizable heparin macromers polymerizable in
aqueous solvent and/or polymerizable heparin macromers are
polymerizable in organic solvent. The amount of heparin in the
heparin hydrogel may be least 1% as measured by dividing the dry
weight of heparin macromers by the total dry weight of the
hydrogel. And the amount of water in the heparin hydrogel may be at
least 5% as measured by dividing the weight of water in the
hydrogel by the total weight of the hydrated hydrogel and is
preferably in the range of 10%-90% and more preferably 60%-80%
water.
[0109] Another embodiment is a material for use in a medical
context, the material including a hydrogel made of a material
including polymers, the polymers including polysaccharide polymers
made of polymerizable polysaccharide macromers, the hydrogel having
covalently cross-linked polymers such that the hydrogel remains
intact in water, and the polysaccharide macromers being macromers
that are polymerizable while in a solution or in a suspension.
[0110] Another embodiment is a material for use in a medical
context, the material including a hydrogel including polymers, the
polymers including heparin polymers made of polymerizable heparin
macromers, the hydrogel having covalently cross-linked polymers
such that the hydrogel remains intact in water, the heparin
macromers being heparin molecules decorated with a monomer chosen
from the group consisting of monomers polymerizable by free-radical
polymerization, monomers polymerizable by addition polymerization,
and monomers polymerizable by condensation polymerization.
[0111] Another embodiment is a material for use in a medical
context, the material including a hydrogel including polymers, the
polymers including polymers made of polysaccharide macromers, the
hydrogel being covalently cross-linked such that the hydrogel
remains intact in water, the polysaccharide macromers being
polysaccharides decorated with a monomer chosen from the group
consisting of monomers polymerizable by free-radical
polymerization, monomers polymerizable by addition polymerization,
and monomers polymerizable by condensation polymerization.
[0112] Another embodiment is a vessel for use in a medical context,
the vessel comprising: a tubular member with an inside wall defined
by an inner diameter and an outside wall defined by an outside
diameter joined by a thickness, a portion of the cylinder having
its inner wall and outer wall covered with a hydrogel, the hydrogel
including polymers, the polymers including heparin polymers made of
polymerizable heparin macromers, with the hydrogel having
covalently cross-linked polymers such that the hydrogel remains
intact in water.
[0113] The hydrogel for the small diameter vascular graft and other
such vessels is preferably at least several .mu.m thick, and more
preferably is at least about 50 .mu.m thick, and even more
preferably about 500-800 .mu.m thick. The vessel's polysaccharide
macromers may be polysaccharide molecules decorated with a monomer
chosen from the group consisting of monomers polymerizable by
free-radical polymerization, monomers polymerizable by addition
polymerization, and monomers polymerizable by condensation
polymerization. In contrast to certain conventional processes, the
polysaccharide macromers may be macromers that are polymerizable
while in a solution or in a suspension.
[0114] Another embodiment is a vessel wherein the diameter of the
minimum cross-sectional area available for blood flow through the
vessel after the vessel is covered with hydrogel is less than
approximately 6.0 mm. The vessel may be a fabric vessel that has
pores and the hydrogel is continuous through a portion of the pores
of the fabric vessel.
[0115] Another embodiment is a coated stent. Another embodiment is
a tissue engineering matrix. Another embodiment is a medical device
covered to make a biomaterial covering around the device.
[0116] The medical device may be coated on one surface, or a
portion thereof. Alternatively, the device may be completed coated
on all exterior surfaces. An encapsulated device is coated on all
surfaces with an essentially continuous material. If the material
is a hydrogel, the hydrogel is preferably crosslinked so as to have
an increased strength. A continuous hydrogel is distinguished from
a thin coating because the coating is attached or adsorbed to the
coated surface and is stable so long as that attachment is
maintained. But a hydrogel forms a coherent structure that has
stability independent of its attachment to the encapsulated
surface. The term encapsulated, as used herein, means to cover. In
the case of an encapsulated medical device, the covering is
essentially total. In the case of a hydrogel encapsulating a tube,
the inside and outside of the tube are covered. The ends of the
tube are not necessarily covered.
[0117] Embodiments include coated devices, for example, medical
devices or components thereof, and includes medical devices that
contact a bodily fluid. For example, springs, wires, guide wires,
pacemaker leads, stents, implants, antennae, sensors, glucose
sensors, tubing, blood bypass tubing, syringes, catheters, i.v.
bags, needles, oxygen tubing, ventricular assist device components,
and trochars.
[0118] Improved Processes for Preparing Polysaccharides and Uses
Thereof
[0119] Synthetic materials have gained wide-ranging acceptance as
suitable materials for medical devices. The extent of their
application has extended from simple disposable devices, like
syringes, blood bags, catheters, also products like extracorporeal
devices, artificial blood vessels, stents, stent grafts to complex
artificial organs, such as kidneys, lung, liver, heart assist
devices and implantable devices. These medical devices are required
to have the appropriate functional properties, durability, and
biological safety.
[0120] There is now emerging an additional requirement for medical
devices, especially implantable devices, to have improved
biocompatibility with the biological environment, with reduced or
no tissue rejection or reaction. Anti-thrombogenicity is a
biocompatibility property that is important in many cases. Further,
it is often desirable to make medical devices with a lubricious
exterior. Coatings may be used to impart lubricity and
biocompatibility. Polysaccharide coatings, in particular, can
impart these properties. Heparin is a natural polysaccharide with
desirable properties.
[0121] Conventional techniques for applying a heparin coating to
medical devices consist primarily of two routes: (1) complexing
heparin with a polymer for attaching a mucopolysaccharide (e.g.,
heparin) to a surface, and, alternatively, (2) chemical
modification to introduce groups onto the mucopolysaccharides or
the surface to make them hydrophilic, zwitterionic and/or charged,
(e.g., anionic or cationic). Route (1) has been achieved by: (I)
blending or attaching an organic-soluble polymer to heparin so that
the heparin goes into solution in organic solvent; alternatively by
(II) treating heparins to dissolve them into an organic solvent and
using the organic solution to coat a medical device, alternatively
by (III) electrostatic binding of heparin to a surface, and
alternatively by (IV) chemically linking the heparin to the
surface.
[0122] To cite a few examples of these methods, Pusineri et al
disclose in U.S. Pat. No. 4,469,827 polymer compositions containing
quaternized amino groups that ionically bind to heparin. Hsu
discloses ionic heparin coating in U.S. Pat. No. 5,047,020, where
alkylbenzl ammonium cations are used to complex with heparin. U.S.
Pat. No. 5,541,167, describes a coating composition consisting of
stearyldimetylbenzyl ammonium heparin complex with antifoaming
agents. Hsu et al in U.S. Pat. No. 5,417,969 inform processes for
coating the surface of polyvinylchloride with an organic solvent
soluble solution of heparin complexed with an organic cation. EP 0
769 503 A2, patent application discloses a heparin complex coating
that contains stable ionic bonding and where reduction in
anticoagulant activity is minimized. The preferred quaternary ion
is alkyldimethylammonium. Yokota and et al have described (in EP 0
781 566), an organic soluble heparin complex coating for medical
devices, where the cation consists of a quaternary phosphonium
moiety. In another disclosure, U.S. Pat. No. 5,270,046, a monomer
is formed containing quaternary ammonium groups, which are
complexed with heparin. The monomeric complexed heparin is
polymerized with other monomers. In general, however, these
coatings fail under prolonged use in physiological conditions. The
reason for failure is that ions generally decomplex from the
heparin, causing the release of the heparin and the cation.
[0123] Polysaccharide Processing by Formation of Polysaccharide
Complexes with Cations
[0124] In contrast to the other approaches, materials and methods
are set forth herein that allow for improved processing of
polysaccharides. In particular, the complexation of polysaccharides
with cations to make them soluble in organic solvents enables for
improved chemical processes to be used for polysaccharide
derivitization and reaction. Polysaccharides carry negative charges
that can be neutralized, at least partially, by selected cations so
that the solubility of the polysaccharide complex is different than
the solubility of the polysaccharide by itself. An association of
cations with a polysaccharide may be referred to as a complexed
polysaccharide or a polysaccharide complex. Natural, synthetic, and
derivitized polysaccharides may all be complexed with cations and
dissolved in an organic solvent. The polysaccharide part of the
organic soluble complex can subsequently undergo a variety of
chemical reactions. After completion of the chemical reaction, the
polysaccharide may be de-complexed. The term soluble traditionally
refers a substance that can be dissolved into molecular units. In
the case of polymers and biological macromolecules, however, it is
appreciated that dissolution may be more complex. Scientists refer
to a polymer as being soluble in a solvent when the polymer is
substantially removed from the solid phase and dispersed when
exposed to that particular solvent.
[0125] A polysaccharide complex may be formed by reacting a
polysaccharide with a quaternary salt, e.g., a quaternary ammonium
salt, to form a polysaccharide-quaternary ammonium salt complex. A
quaternary ammonium salt has four substituents on the nitrogen so
that the resulting moiety has a positive charge. Examples of
quaternary ammonium salts include, e.g., cetyltrimethylammonium
chloride, dodecyldimethylbenzylammonium chloride, benzalkonium
chloride, didecyldimethylammonium chloride, benzethonium chloride,
hexyl trimethyl ammonium, decyl trimethyl ammonium, lauryl
trimethyl ammonium, myristyl trimethyl ammonium, cetyl trimethyl
ammonium, stearyl trimethyl ammonium, didecyl dimethyl ammonium,
dilauryl dimethyl ammonium, and distearyl dimethyl ammonium.
[0126] Decomplexing a quaternary salt from a polysaccharide complex
may be accomplished by mixing the polysaccharide complex with a
salt that is not a quaternary ammonium salt. For example, a sodium
chloride solution may be used for decomplexation. Decomplexation
may be accomplished at room temperature, or other any suitable
temperatures. As shown in, e.g., Example 14, exposure to a
saturated NaCl solution for about a minute may be used to perform
the decomplexation.
[0127] Examples of organic solvents include dimethylformamide,
dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric
triamide, formic acid, acetonitrile, methanol, ethanol, acetone,
acetic acid, dichloromethane, pyridine, and formamide. Some
solvents for forming a polysaccharide complex or for reacting a
polysaccharide or polysaccharide complex are solvents with a
boiling point of less than approximately 115 degrees Centigrade and
a dielectric constant that is less than that of DMSO. Other
embodiments use an organic solvent that has a boiling point of less
than approximately 70.degree. C. at atmospheric pressure and a
dielectric constant that is less than that of DMSO. These solvent
properties have certain advantages; for example, they allow for
expedited heat-and-vacuum removal of the solvents with minimal
denaturation of the polysaccharides. Certain mebodiemtns inlcludea
mixture of at least 50% by volume of a particular organic solvent
or a particular combination of organic solvents.
[0128] Polysaccharide complexes may be formed with a native
polysaccharide or with a polysaccharide that previously has
undergone chemical reaction(s) to decorate it with a functional
group or otherwise modify the native polysaccharide; examples of
such reactions are set forth in FIGS. 9 and 10. FIGS. 9 and 10 show
schemes that involve formation of polysaccharide complexes at
various points in the chemical processing of a polysaccharide from
a first chemical state to a second chemical state. Referring to
FIG. 9, which depicts scheme I, certain embodiments of chemical
reactions involving complexed polysaccharides are set forth. FIG. 9
depicts the complexing of a polysaccharide with cations to make a
polysaccharide complex that comprises the polysaccharide and
multiple cations. The polysaccharide complex is soluble in an
organic solvent as a result of the formation of the complex. A
molecule that is an organic solvent has at least one carbon in its
structure. The organic-solvent soluble complex can then undergo
chemical reaction in an organic solvent to chemically modify the
polysaccharide. A chemically modified polysaccharide that has
undergone modification in an organic solvent is abbreviated as
O-MPSAC, i.e., organic-solvent reaction modified polysaccharide.
Many chemical processes are feasible only in organic solvent so
that the processes could not take place if the polysaccharide were
not complexed. Provided herein are numerous examples of a reaction
of a complexed polysaccharide in organic solvent, e.g., as in the
Examples. An O-MPSAC may be decomplexed from its cations and is
typically water soluble.
[0129] Referring to FIG. 10, which depicts scheme II, additional
embodiments of chemical reactions involving complexed
polysaccharides are set forth. A polysaccharide undergoes chemical
reaction and is soluble in water or mixtures of water with other
solvents, e.g., DMSO. A polysaccharide derivitized in water is
herein referred to as a W-MPSAC, i.e., a polysaccharide modifiable
in a solvent of water or water mixed with other solvents. The
W-MPSAC is then complexed with a cationic moiety to form a complex
that is organic soluble, and which can undergo further chemical
reaction. After the further reactions, the W-MPSAC may then be
de-complexed.
[0130] Reaction of Polysaccharides with Surfaces
[0131] Polysaccharides may be attached to a surface using the
materials and methods set forth herein. A polysaccharide may be,
for example, natural, synthetic, derivitized, or processed
according the methods described herein. The surface, the
polysaccharide, or both the surface and the polysaccharide may be
modified to accomplish the polysaccharide attachment.
[0132] The surface that is reacted with a polysaccharide may be any
surface, and may be a surface of a medical device. The surface may
be of any material, for example, polymeric, metallic, natural,
synthetic, or biological. Surfaces of a medical device that contact
a bodily fluid are suitable for modification with polysaccharides
using materials and methods described herein. Such surfaces are
essentially any surface that is exposed to a tissue after
implantation in a body or patient. Such surfaces also include
extracorporeal devices, e.g., catheters, trochars, pumps,
blood-contacting devices, stents.
[0133] Modifying a polysaccharide and/or a surface may involve
processing the polysaccharide and/or surface to associate a
functional group with the polysaccharide and/or surface. The
functional group is subsequently involved in a chemical reaction to
thereby attach to polysaccharide and surface to each other. The
functional groups could be all of a single type, or could be a
variety of types. The functional group may be introduced by adding
new chemical moieties to the modified material, or the material may
be modified to remove some chemical moieties so as to create the
functional groups.
[0134] The modification of a surface or a polysaccharide is often
advantageous. For example, new functional groups can be introduced
that are capable of forming covalent bonds with other functional
groups. Or the new functional groups may allow for more efficient
chemistries to be used. Or the new functional groups may allow for
a greater degree of bonding. For example, a polymeric surface may
be modified to express primary amines. The primary amines may then
be reacted with carboxyl groups on a polysaccharide to make
covalent bonds. In some cases the reaction between the amines and
carboxyls can be efficiently performed only in an organic
solvent.
[0135] Certain embodiments involve the chemical reaction between a
polysaccharide complex and a surface in the presence of organic
solvent. Referring to FIGS. 9 and 10, for example, the
polysaccharide complex may have a functional group on the
polysaccharide that is capable of reacting with a functional group
on the surface in the presence of an organic solvent to thereby
form a bond. After reaction of the polysaccharide complex with the
surface, the polysaccharide is de-complexed, and the polysaccharide
remains bonded to the surface, e.g., by a covalent bond. Thus, an
O-MPSAC may be chemically reacted to a surface; with the chemical
reaction in step 2 of FIG. 9 denoting the binding of the
polysaccharide to the surface. Or a W-MPSAC may be reacted with a
surface, with the chemical reaction of step 3 of FIG. 10 denoting
the binding of the polysaccharide to the surface. Thus, the O-MPSAC
or W-MPSAC may be complexed as needed to complete the reaction and
decomplexed to leave the polysaccharide in association with the
surface without the presence of the complexing cations.
[0136] Certain embodiments involve the chemical reaction between a
polysaccharide complex and a surface in the presence of water,
DMSO, or a comparable solvent. Referring to FIGS. 9 and 10, for
example, the polysaccharide may have a functional group that is
capable of reacting with a functional group on the surface in the
presence of a such a solvent to thereby form a bond. After reaction
of the polysaccharide complex with the surface, the polysaccharide
is bonded to the surface, e.g., by a covalent bond. Thus an O-MPSAC
may be chemically reacted to a surface after it has been
de-complexed, as shown in step 3 of FIG. 9. And a W-MPSAC may be
reacted with a surface, with the binding of the polysaccharide to
the surface being denoted as the first chemical reaction in step 1
of FIG. 10. Alternatively, the W-MPSAC may be reacted with the
surface after it has been de-complexed. Thus the O-MPSAC or W-MPSAC
may be complexed as needed to complete a reaction and decomplexed
to leave a polysaccharide in association with the surface without
the presence of the complexing cations.
[0137] A chemical reaction between a polysaccharide complex, e.g.,
O-MPSAC or W-MPSAC, and a surface may take place as a result of the
activation of the surface, the polysaccharide, or a combination of
both. For example, a surface that has been derivitized with
electrophilic functional groups is thereby activated to react with
nucleophiles on a polysaccharide. Or a polysaccharide may be
activated with electrophilic functional groups to thereby react
with nucleophiles on the surface. Or a monomer may be attached to
both a surface and a polysaccharide so that they polymerize
together when polymerization of the monomers is initiated. Such
reactions may be performed in an organic solvent or other solvents,
with the polysaccharide being complexed or decomplexed as needed to
make the polysaccharide in the solvent.
[0138] Chemical Reactions Involving Polysaccharides and/or
Polysaccharide Complexes
[0139] A tremendous variety of chemical reactions are available for
use with the various embodiments of polysaccharide and
polysaccharide complexes set forth herein. Polysaccharides often
have hydroxyls and carboxyls in their native states; these chemical
groups are particularly suitable for further modification. An
advantage of certain chemistries, e.g., some photoactivation
chemistries, is that reactions may be undertaken with other
chemical groups besides hydroxyls and carbosyls. Some chemical
reactions may involve reacting a polysaccharide or polysaccharide
complex with a surface, other polysaccharides, polysaccharide
complexes, polymers, or other molecules. Such reactions may
include, for example, a free radical process, a photo initiated
reaction, an electrophilic-nucleophilic reaction, and Sn2
substitution, an elimination reaction, chemical coupling reaction
to various polymers, and other reactions that are known to those of
skill in these arts. These reactions may be performed with the
polysaccharides in complexed or uncomplexed form, as needed to
adapt to the appropriate solvent and chemical reaction
conditions.
[0140] For example, a polysaccharide may incorporate or be
decorated with functional groups. The functional groups may be used
to enhance or enable the reaction of the polysaccharide with other
functional groups. Functional groups could be, for example, groups
that are commonly found to be useful in chemical reactions in the
life sciences, e.g., amines, carboxyls, hydroxyls, and sulfhydryls.
Functional groups could be, for example, groups that are commonly
useful in the polymer sciences, e.g., monomers, free radical
monomers, photoinitiated monomers, thermally initiated monomers,
chemically initiated monomers, acrylates, and methacrylates.
Functional groups could be, for example, groups that are reactable
with nucleophiles, e.g., isocyanates, epoxides, sulfhydryls,
succinimide esters, and N-hydroxy succinimide esters. Functional
groups could be, for example, groups that are photoactivatable,
e.g., azides. Other examples of functional groups are maleimides,
carbodiimides, carbonyl diimidazole, and acid anhydrides.
[0141] For example, the reaction depicted in FIG. 9 may involve the
incorporation of a functional group to the O-MPSAC that can undergo
a further chemical reaction by a photo initiated reaction. Or, for
example, the second chemical reaction in FIG. 10 may include
chemically attaching the W-MPSAC to the surface of a material that
contains reactive species. Or the second chemical reaction in FIG.
10 may involve the incorporation of a functional group to the
W-MPSAC that can undergo a further chemical reaction by free
radical process or by a photo initiated reaction or chemical
coupling reaction to various polymers. The first chemical reaction
in FIG. 10 could alternatively involve the incorporation of a
functional group to the polysaccharide that can undergo a further
chemical reaction by free radical process or by photo initiated
reaction. The first chemical reaction in FIG. 10 could also involve
chemical coupling reactions to various other chemical moieties.
[0142] Other embodiments involve activating a surface by decorating
the surface with functional groups that are reactive towards
functional groups on a polysaccharide or polysaccharide complex.
For example, a surface may be activated with a photoactivatable or
polymerizable group. Examples include azide, methacrylate,
isocyanate, and epoxide. Alternatively, a polysaccharide or
polysaccharide complex may be activated by decorating the
polysaccharide with a functional group that is reactive towards a
functional group on a surface. For example, a polysaccharide may be
activated with a photoactivatable or polymerizable group; examples
include azide, methacrylate, isocyanate, and epoxide. Alternative
functional groups are, e.g., amines, hydroxyls, carboxyls,
sulfhydryls, isocyanates, carbodiimides, carbonyl diimidazoles, and
acid anhydrides. The reactions may be performed in organic and/or
non-organic solvents, with the polysaccharides being complexed or
uncomplexed as needed for the particular chemical reaction.
[0143] Some embodiments relate to the use of photoactivatable
groups. Photoactivatable groups respond to specific applied
external stimuli to undergo active specie generation with resultant
covalent bonding to a nearby chemical structure. Photoactivatable
groups retain covalent bonds unchanged under conditions of storage
but, upon activation by an external energy source, form covalent
bonds with other molecules. Photoactivatable groups may generate
active species such as free radicals and particularly nitrenes,
carbenes, and excited states of ketones upon absorption of
electromagnetic energy. Photoactivatable groups can be chosen to be
responsive to various portions of the electromagnetic spectrum,
e.g., ultraviolet and visible portions of the spectrum.
[0144] Photoactivatable groups may be, e.g., aryl ketones are
preferred, such as acetophenone, benzophenone, anthraquinone,
anthrone, and anthrone-like heterocycles (e.g., heterocyclic
analogs of anthrone), or their substituted (e.g., ring substituted)
derivatives. Examples of aryl ketones include heterocyclic
derivatives of anthrone, including acridone, xanthone, and
thioxanthone, and their ring substituted derivatives.
[0145] The azides constitute a class of photoactivatable groups and
include derivatives based on arylazides such as phenyl azide and
particularly 4-fluoro-3-nitrophenyl azide, acyl azides, azido
formates (e.g., ethyl azidoformate), phenyl azidoformate, sulfonyl
azides (e.g., benzenesulfonyl azide), and phosphoryl azides (e.g.,
diphenyl phosphoryl azide and diethyl phosphoryl azide). Also,
diazo compounds are contemplated, including diazoalkanes (e.g.,
diazomethane and diphenyldiazomethane), diazoketones (e.g.,
diazoacetophenone and 1-trifluoromethyl-1-diazo-2-pentanon),
diazoacetates (e.g., t-butyl diazoacetate and phenyl diazoacetate),
and beta-keto-alpha-diazoacetates (e.g., t-butyl alpha
diazoacetoacetate). Other photoactivatable groups include the
diazirines (e.g., 3-trifluoromethyl-3-phenyldiazirine), and ketenes
(e.g., as ketene and diphenylketene).
[0146] Formation of Polysaccharide Polymers
[0147] Polysaccharide polymers are made of at least two
polysaccharides that have been synthetically reacted to form the
polysaccharide polymer. Polysaccharide polymers may also include
monomers, oligomers, polymers, or macromers. For example,
polyesters, polyamines, polyethylenes, polyethylene oxides, and
polyurethanes may be incorporated in to the polysaccharide
polymers. Such polysaccharide-polymers may include functional
groups that are capable of further reaction, for example, monomers,
electrophiles, photoactivatable, or photopolymerizable groups. The
polysaccharide-polymers may be branched and/or cross-linked. Some
embodiments have a molecular weight of at least about 25,000,
100,000, 250,000, or 500,000. Other embodiments have a molecular
weight in the range of about 50,000 to about 5,000,000; a person of
ordinary skill will in the art will understand that all molecular
weights and ranges within the explicit ranges are contemplated, and
are within this disclosure. Embodiments include a molecular weight
range of about 200,000 to about 2,000,000, from 300,000 to
1,000,000, and from 400,000 to 800,000. Other embodiments have a
molecular weight outside of these explicit ranges. A plurality of
polymers typically have a range of molecular weights that are
distributed about an average molecular weight for that group of
polymers. The molecular weight ranges herein may be directed to
average molecular weights for a plurality of polymers. Thus, for
some embodiments, a plurality of polymers having an average
molecular weight that falls within a range is contemplated.
[0148] Chemical reactions, use of functional groups, and solvents
may all be chosen as needed to form the desired structure. O-MPSAC
and/or W-MPSAC may be used in such reactions to form
polysaccharide-polymers. The polysaccharides may be complexed or
decomplexed as needed to perform the chemical reactions. Specific
examples are presented below.
[0149] Polysaccharide-polymers made of a plurality of
polysaccharide macromers are distinct from a polysaccharide that
has been derivitized with a functional group to form a macromer.
The polymers are made of more than one macromer. The
polysaccharide-polymers have a synthetic polymeric backbone formed
by the polymerization of the polymerizable groups. The
polysaccharide-polymers have a higher molecular weight than the
macromers because they are the product of joining at least two, and
possibly multiple, macromers. The increased molecular weight is a
factor that affects their solubility and their stability when
adsorbed or otherwise attached to a surface. The
polysaccharide-polymers may have a linear, branched (multi-armed),
or cross-linked structure, with the structure being dependent upon
the reaction conditions.
[0150] A polymer such as a polysaccharide-polymer has different
properties than the unpolymerized starting material, or a typical
polysaccharide; these properties can be, e.g., molecular weight,
presence or degree of branching, cross-linking, and the type of
bond between the polysaccharides. These properties may be
manipulated to achieve a polymer that has desired adsorptive
properties. An unbranched, uncrosslinked polymer is typically
poorly adsorptive. A multi-armed crosslinked or branched polymer,
however, is highly adsorptive and stable. But a polymer that is too
highly crosslinked may become insoluble such that it comes out of
solution. An insoluble polymer may be difficult to use in coating
techniques.
[0151] Selection of Molecular Weight, Cross-linking, and Branching
of Polymers and Polysaccharide Polymers
[0152] A suitable degree of branching or cross-linking that is
appropriate is determinable by empirical processes. Techniques for
readily determining the molecular weight of large crosslinked
polymers are not readily available. Therefore, it is usually
necessary to perform empirical procedures to develop multi-armed
polymers with appropriate branching or crosslink densities. For
example, a 100,000 molecular weight polysaccharide that has been
decorated with between two to ten polymerizable groups can be
placed into solution in five samples that vary in concentration by
a factor of ten. Each sample is exposed to initiating conditions to
react all of the polymerizable groups. A surface or portion thereof
that is to be coated, e.g., a wire or tube, is exposed to the
samples for a set time, such as between about 2-10 hours. The
surface is removed, rinsed in aqueous solution, and tested for
adsorption. The sample that causes the highest amount of adsorption
is identified and the procedure is repeated with a new
concentration range built around the initially selected solution.
Samples wherein the polymers fall out of solution are rejected as
having polymers that are too highly crosslinked. A range of
parameters may be varied to ascertain desirable conditions,
including, for example, starting polymeric molecular weight, number
of polymerizable groups per polymer, and solution concentrations.
This optimization procedure is applicable for making polymeric,
linear, high-molecular weight, and multi-armed polysaccharides as
well as linear, multi-armed, and high molecular weight
vinylpyrrolidones (as described below). Other approaches can be
used by a person of ordinary skill in the art based on the
disclosure herein, such as by varying the number of solutions in
the empirical procedure or other reasonable modification in the
empirical procedure.
[0153] Polysaccharide Complexes in a Layer on a Surface
[0154] Polysaccharide complexes may be used as part of a process
for creating a layer on a surface or selected portion thereof. A
layer refers to a coating, hydrogel, or other material that is in
intimate association with a surface or another layer. Thus a layer
could be a coating of molecules on a surface or a hydrogel or other
three-dimensional structure that is associated with a surface.
Polysaccharide complexes may be part of the process of preparing a
polysaccharide that is subsequently layered onto a surface.
Alternatively, a polysaccharide complex may be coated onto a
surface and the surface may subsequently be decomplexed, leaving
the polysaccharide associated with the coating. Polysaccharide
polymers may be used in a layer, with the polymers being in a
complexed or uncomplexed form. Alternatively, polysaccharides may
be used in a layer in a complexed on uncomplexed form. Components
of a layer may include, e.g., a polysaccharide, polysaccharide
complex, non-polysaccharide polymers, and combinations thereof.
[0155] Certain embodiments are layers of polysaccharide and
non-polysaccharide polymers, e.g., branched polymers. A
polysaccharide may be combined with other polysaccharides or
polymers to make a modified polysaccharide polymer. The polymer may
be added by covalent bonding, cross-linking, ionic attraction, or
by the creation of other associations. The addition of polymers to
the polysaccharide may be advantageously used, e.g., to increase it
molecular weight, adsorptive proprieties.
[0156] Layers may be of uniform, non-uniform, or continuously
varying thicknesses. Layers may be of any suitable thickness. For
example, a layer may have a thickness of the order of less than a
micron, a micron, tens of microns, hundreds of microns, a
millimeter, or other thicknesses. Layers may fully or partially
cover a surface. Multiple layers may be built up on a surface. All
of the layers could comprise a polysaccharide, e.g., a modified
polysaccharide, or polysaccharide-polymer. Alternatively, layer(s)
that comprise a polysaccharide could be interspersed or otherwise
mixed with other materials, objects, or layers of other
materials.
[0157] Layers may be formed using, e.g., a spray process, a dip
process, or other processes known in the art. A dip process entails
dipping an object into a solution or melt of the layer components
and removing the object. A spray process entails preparing a
solution or melt of the layer components and spraying them onto an
object. A mold may be used to prepare a layer, especially a thick
hydrogel or coating. The components of a layer at least partially
solidify on the object to create the layer. Solvents that evaporate
at low temperatures and/or pressures can are advantageous in that
they can typically be efficiently removed.
[0158] Layers may be associated with a surface by a variety of
physical or chemical processes. Certain embodiments are directed to
forming layers on surfaces that are at least a part of a medical
device. Adsorption, ionic attraction, and covalent bonding are
possible mechanisms that can be used by choosing suitable
functional groups. Certain embodiments entail associating a layer
with a surface and subsequently stabilizing the layer by activating
functional groups that are in the layer or on the surface. Examples
of such functional groups are thermally initiatable monomers,
photoinitiatable monomers, photoactivatable groups, methacrylates,
isocyanates, and epoxides. Alternatively, the layer may be
simultaneously formed and stabilized; for example, by allowing
functional groups on a surface to react with functional groups on a
component of a layer. The simultaneous processes could involve
immobilization of a polysaccharide or polysaccharide complex to a
surface. The simultaneous processes could further involve reactions
between functional groups on the components with each and with the
surface; for example, polysaccharide complexes comprising
polymerizable monomers could be reacted with each other and
simultaneously with a surface decorated with suitable monomers.
[0159] Additional Embodiments Related to Polysaccharide
Complexation
[0160] An O-MPSAC may be chemically reacted with a surface of a
medical device that contains reactive functional groups. The
surface's reactive functional groups are able to react with the
mucopolysaccharide, which is followed by decomplexation, leaving
the mucopolysaccharide bound to the surface. This process is
exemplified by forming an organic solvent soluble heparin complex,
which can be reacted with but not limited to, isocyanate or epoxide
groups, which have been incorporated to the surface of the medical
device. The isocyanate or epoxide groups are able to react with
free hydroxyl of the heparin to form urethane or ether linkages,
respectively. In another manner the isocyanate or epoxide groups
are able to react with the free amino groups of the heparin to form
urea or substituted amine linkage. On completion of the surface
reaction the heparin is decomplexed with salt solution, leaving the
heparin chemically bound to the surface in its active form. In the
case of heparin, the complexed, chemically modified, and
de-complexed heparin is produced in its active anti-thrombogenic
form. The organic soluble heparin complex can be applied to the
medical device by, e.g., dip coating, spray coating or any other
coating process. Alternatively, the surface could be activated with
photoactivatable groups that are triggered to react with the
polysaccharides.
[0161] Another embodiment is to chemically modify a
mucopolysaccharide component of a organic solvent soluble complex
(see FIG. 9), to produce chemically activated O-MPSAC, which is
activated to be able to undergo further chemical reactions. This
process is exemplified by forming an organic solvent soluble
heparin complex, which can be reacted with, e.g., isocyanatoethyl
methacrylate or methacryloyl chloride. The isocyanatoethyl
methacrylate or methacryloyl chloride is able to react with free
hydroxyl of the heparin to form methacrylate urethane or
methacrylate ester linkage with the heparin. In another manner the
isocyanatoethyl methacrylate or methacryloyl chloride is able to
react with the free amino groups of the heparin to form
methacrylate urea or methacrylate amide linkage with the heparin.
Other functional groups may be substituted for methacrylates, e.g,
polymerizable or photoactivatable groups.
[0162] The complexed methacrylate heparin of the form described
above can undergo free radical polymerization with other macromers
and/or monomers, either in solid state, gel state, in solution, in
emulsion, or in suspension. The final polymer, where the heparin
complex is attached to the polymer backbone, can be used to coat
medical devices. The heparin is then decomplexed with salt
solution, leaving the active heparin coated onto the medical
device. Other polysaccharides or proteoglycans may be substituted
for heparin. And other polymerizable groups may be substituted for
methacrylates.
[0163] A complexed methacrylated heparin macromer may be
decomplexed with salt solution, giving a methacrylated heparin
macromer that can undergo polymerization with other macromers
and/or monomers, by e.g., solution, emulsion, or suspension
polymerization. The final polymer, where the active heparin is
attached to the polymer backbone, can be used to coat medical
devices. Thus the macromers may be polymerized to form larger
macromers, polymers, and three-dimensional structures. Or they may
be polymerized to form a three-dimensional hydrogel.
[0164] Another embodiment is a chemically modified O-MPSAC, which
is able to undergo photochemical reactions. This embodiment is
exemplified by forming an organic solvent soluble heparin complex,
which can be chemically modified to contain photochemical reactive
groups that are able to link to the surface of medical devices. The
photochemical reactive groups may be photopolymerizable or
photoactivatable, e.g., allyl, vinyl, acrylates, methacrylates,
azides, nitrenes, carbenes and excited states of ketones, diazo,
azo compounds and peroxy compounds, and such groups as are cited in
and those cited in WO 90/00887, which is hereby incorporated herein
by reference. An advantage of this method is that photochemical
reactive groups may be bound to the heparin complex in organic
solvents, and the resultant product may then be dissolved in
organic solvent and coated onto the medical device. Then, by
applying the appropriate electromagnetic radiation to carry out the
photochemical reaction, the photoactivated groups bond to the
surface to form the desired coating. Photoactivated bonding is
followed by decomplexation, leaving the active heparin bound to the
surface.
[0165] Another embodiment comprises of the chemical modification of
the mucopolysaccharide in water or DMSO or another equivalent
solvent or solvent mixtures. This is exemplified by the reaction of
the activated imidazole carbonate of polyethyleneglycol
methacrylate (see WO 97/41164, hereby incorporated by reference
herein) with heparin to form the heparin-polyethyleneglycol
methacrylate. The heparin-polyethyleneglycol methacrylate is then
complexed (W-MPSAC, Scheme 2). The W-MPSAC can then undergo further
chemical reaction in an organic solvent, e.g., by free radical
process or by photo-initiated reaction. Alternatively, the
heparin-polyethyleneglycol methacrylate can undergo chemical
reactions by free radical process or by photo initiated reaction
without the complexation step. The resultant product may then be
complexed to form an organic soluble heparin complex.
[0166] An advantage of the modified polymers and the polysaccharide
macromers is that they may be reacted with a surface while in
solution. For example, modified polymers with polymerizable groups
may be polymerized while in solution. Or photoactivatable groups or
electrophilic groups may be activated while the polymer or macromer
is in solution. These approaches are particularly effective when
organic solvents are used because many chemical reactions are much
more efficient in organic solvents as compared to aqueous solvents,
e.g., electrophile-nucleophile reactions. The present disclosure
provides numerous techniques for bringing polysaccharides and
modified polymers into solution so that an effective reaction with
the surface may be performed.
[0167] Polymers of Vinylpyrrolidone
[0168] Another embodiment is a polymer (or macropolymer) of
vinylpyrrolidone. Vinylpyrrolidone polymers or oligomers may be
decorated with a polymerizable group using techniques known to
those of ordinary skill in these arts to make a vinylpyrrolidone
macromer that is polymerizable. The vinylpyrrolidone macromer may
be polymerized to make a three-dimensional cross-linked structure.
Or the vinylpyrrolidone macromer may be polymerized to make a
larger polymer. Further, cross-links may be incorporated into the
larger polymer. As discussed above, structures that are branched,
cross-linked, and/or have a relatively high MW have advantageous
properties for use as a coating.
[0169] The vinylpyrrolidone polymer (or macropolymer) is useful for
making lubricious coatings. The coatings may be made on essentially
any surface for a medical device. The coatings may be made, for
example, by drying a solution of vinylpyrrolidone polymer,
multi-armed polymer, or macromer onto an object. The macromer may
subsequently be polymerized. Alternatively, the object may be
covered with the macromer and the macromer polymerized to make a
coating or encapsulating membrane. The vinylpyrrolidone
macropolymer or the macromer may be combined with other
monomers/polymer/macromers, especially those described herein.
EXAMPLE 1
Heparin Complex
[0170] 5 g sodium heparin (Celsus Laboratories, Inc, USP
lyophilized from porcine intestinal mucosa) was dissolved in 80 ml
de-ionized water and allowed to stir for 1 hour in a 250 ml
beaker.
[0171] 8 g benzalkonium chloride (Aldrich Chemical Company, Inc)
was allowed to dissolve in 80 ml de-ionized water with gentle
warming (40-50.degree. C.) on a magnetic stirrer hotplate for 1
hour and then allowed to reach room temperature.
[0172] To the above vigorously stirred solution of sodium heparin,
the benzalkonium chloride solution was added. A white precipitate
immediately formed and the suspension was further stirred for 1
minute. The precipitate was filtered through a Whatman qualitative
filter paper (grade 1).
[0173] The white precipitate was collected from the filter paper
and re-suspended in 400 ml de-ionized water and allowed to stir for
20 minutes. The suspension was filtered as above and re-suspended
in 400 ml de-ionized water and filtered again. The precipitate was
once again suspended in 400 ml de-ionized water and then poured
into a dialysis membrane Cellu Sep:MWCO 3,500 and dialyzed against
10 L de-ionized water for a minimum of 16 hours.
[0174] The precipitate was collected and dried on a glass dish in a
vacuum oven at 60.degree. C. for 12 hours.
[0175] Dry gray-yellow crystals were obtained with a yield of 10
g.
EXAMPLE 2
[0176] 3 g 4, 4'-methylenebis (phenyl isocyanate) (MDI) (Aldrich
Chemical Company, Inc) was dissolved in 100 ml anhydrous
tetrahydrofuran (THF). Polyurethane tubing was dipped in to the
above solution for 30 seconds and was then allowed to stir-dry at
60.degree. C. for 1 hour.
[0177] 5 g of dry crystals of complexed heparin from Example 1 were
dissolved in 100 ml anhydrous dichloromethane (DCM). The MDI coated
polyurethane tubing was dipped into the DCM solution of complexed
heparin for 30 seconds and then allowed to air-dry for 2 hours.
[0178] The tubing was dyed with 0.075% w/v pH 8.5 toludine blue
aqueous solution for 30 seconds and washed with de-ionized water. A
very faint purple color due to the complexed heparin was observed.
The tubing was then immersed in 25% w/v solution of sodium chloride
at 40.degree. C. for 30 minutes. The tubing was washed with
de-ionized water and again dyed. An intense dark purple color due
to complexed heparin was observed.
[0179] In a similar experiment where the polyurethane tubing was
not initially coated with MDI and was de-complexed in sodium
chloride solution (as above) no purple coloration due to the
heparin was observed.
EXAMPLE 3
[0180] 1. Heparin Methacrylate (Methacryloyl Chloride)
[0181] 5 g of dry crystals of complexed heparin from Example 1 were
dissolved in 100 ml anhydrous DCM in a 250 ml quickfit conical
flask. To this was added 0.1265 g (1.25.times.10.sup.-3 moles)
triethylamine.
[0182] Methacryloyl chloride (Aldrich Chemical Company, Inc) was
distilled under reduced pressure to obtain a very pure sample.
0.1306 g (1.25.times.10.sup.-3 moles) of the above distilled
methacryloyl chloride was dissolved in 30 ml anhydrous DCM and
placed in a stoppered quickfit pressure equalizing funnel above the
vigorously stirred solution of DCM containing the complexed
heparin. The methacryloyl chloride solution was added drop-wise
over a period of 30 minutes to the complexed heparin solution in
DCM.
[0183] The DCM was rotary evaporated and the complexed heparin
methacrylate was dried in a vacuum oven at 40.degree. C. for 2
hours.
[0184] Complexed methacrylate was characterized by .sup.1H and
.sup.13C.
[0185] 0.2 g of the above complexed heparin methacrylate was
dissolved in 10 ml 2-hydroxyethylmethacrylate and to this was added
0.02 g ethylene gluol dimethacrylate and 0.02 g 2,2'-azobis
(2,4-dimethylvaleronitrile) (Dupont). The above clear solution was
degassed for 30 minutes.
[0186] The above polymerization mixture was poured into a
polypropylene concave mold and then a polypropylene convex mold was
placed onto the concave mold allowing the excess solution to
overflow, thereby uniformly filling the space between the concave
and convex molds. The sealed molds were then heated to a
temperature of 65.degree. C. for 4 hours and then at 110.degree. C.
for 1 hour.
[0187] The molds were cooled and opened to obtain a clear
dehydrated rigid hydrogel. These were then hydrated in de-ionized
water for 10 hours, after which they were placed in boiling
solution of 25% w/v sodium chloride aqueous solution for 1 hour and
then equilibrated in de-ionized water. The hydrogel was dyed (as in
Example 2) and a uniform intense dark purple coloration was
observed throughout the hydrogel.
[0188] In a similar experiment where no methacrylate of the heparin
was formed, a hydrogel of the complexed heparin alone was formed.
After boiling in 25% w/v sodium chloride aqueous solution and
equilibrating in water the hydrogel was dyed. Dark purple
precipitated particles of heparin could be observed on the surface
of the hydrogel and were easily washed away with de-ionized water,
leaving a blue coloration to the hydrogel. This coloration is
identical to the hydrogels formed without any complexed
heparin.
[0189] 2. Heparin Methacrylate (Isocyanatoethylmethacrylate)
[0190] 5 g of dry crystals of complexed heparin from Example 1 were
dissolved in 100 ml anhydrous DCM in a 250 ml thick-walled glass
bottle with cap. To this was added 0.194 g (1.25.times.10.sup.-3
moles) 2-isocyanatoethylmethacrylate (Aldrich Chemical Company,
Inc) and 0.05 g dibutyltin dilaurate (Aldrich Chemical Company,
Inc). The cap was screwed on tight and the solution was stirred for
16 hours at 40.degree. C.
[0191] The DCM was rotary-evaporated off and the product dried in a
vacuum at 40.degree. C. for 2 hours.
[0192] As in Example 3(1), hydrogels were made and the heparin was
decomplexed and dyed. Again, a uniform intense dark purple
coloration was observed throughout the hydrogel whereas the
complexed heparin with no methacrylate coupling heparin particles
precipitated on the surface of the hydrogel and were easily washed
away with de-ionized water.
EXAMPLE 4
[0193] 5 g of Heparin methacrylate from example 3 i) was dissolved
in 100 ml of 2-propanol. To this was added 20 g
methoxypolyethlyeneglycol 2000 methacrylate (MPEG 2000 MA) (Inspec
U.K.) and 3 g of 2-hydroxyethylmethacrylate.
[0194] A 250 ml, 3-necked reaction vessel equipped with stirrer,
thermometer, condenser and nitrogen inlet tube was charged with 100
ml 2-propanol. To the 2-propanol was added 5 g of heparin
methacrylate [from example 3 (i)], 20 g methoxypolyethyleneglycol
2000 methacrylate (MPEG 2000 MA) (Inspec U.K.) and 3 g
2-hydroxyethylmethoxylate. (HEMA) The 250 ml, 3 necked reaction
vessel was placed in a silicone oil bath at 120.degree. C. and the
2-propanol was stirred gently and nitrogen was bubbled through the
solution (100 cm.sup.3/min).
[0195] When the temperature in the 250 ml, 3-necked reaction vessel
reached 75.degree. C., 0.25 g 2,-2'-azobis (2,
4-dimethylvaleronitrile) was added and the stirrer speed was
increased to 750 rpm. After approximately 15 minutes a very viscous
solution was obtained and the reaction was allowed to continue for
30 minutes, periodically added 30 ml 2-proponal to dilute and
reduce the viscosity of the solution. In total four 30 ml aliquots
of 2-propanol was added.
[0196] The polymer was cooled down to room temperature and the
isopropanol rotary evaporated off and the polymer dried in a vacuum
oven at 40.degree. C. for 8 hours.
[0197] GPC (Gel permeation chromatography) showed that the average
molecular weight of the polymer was approximately 400,000 when
using polyethylene glycols as standards.
EXAMPLE 5
[0198] 3 g MDI was dissolved in 100 ml of anhydrous THF. A 150 mm
long and 2 mm diameter polyurethane tube was dipped into the above
solution for 30 seconds and was then allowed to air dry at
60.degree. C. for 1 hour.
[0199] 5 g of heparin copolymer from Example 4 was dissolved in
anhydrous DCM. The MDI coated polyurethane tubing was dipped into
the DCM solution of copolymer for 30 seconds and was then allowed
to air at 60.degree. C. for 30 minutes and then at room temperature
for 16 hours.
[0200] The tubing was immersed in 25% w/v sodium chloride solution
at 40.degree. C. for 30 minutes. The tubing was washed with
de-ionized water and dried with toludine blue (example 2). A
homogenous intense dark purple coloration was obtained on the
tubing. In addition the polyurethane tubing was completely wetted
and very lubricious. The lubricity did not diminish even when it
was rubbed between forefingers and thumb 20 times. The tubing was
then immersed in phosphate buffered saline at 50.degree. C. for 16
hrs and then rubbed between the forefinger and thumb. Again there
was no observable discharges in lubricity.
EXAMPLE 6
[0201] As in Example 4, 5 g heparin methacrylate was copolymerized,
except that instead of MPEG 2000 MA and HEMA, 20 g
N-vinylpyrrolidone was used as the co-monomer in 2-propanol. The
polymerization was allowed to continue for 1 hour.
[0202] The average molecular weight of the copolymer was
approximately 300,000 as determined by GPC.
[0203] As in Example 5 a 150 mm long and 2 mm diameter polyurethane
tubing was dipped into a 3% w/v MDI in THF solution and air dried
at 60.degree. C. for 1 hour.
[0204] The tubing was then dipped in a 5% w/v
heparin--vinylpyrrolidone copolymer in DCM for 30 seconds and then
air dried at 60.degree. C. for 2 hours.
[0205] The tubing was then immersed in 25% w/v sodium chloride
solution at 40.degree. C. for 30 minutes. The tubing was washed
with de-ionized water and dyed with toludine blue. A homogenous
intense dark purple colorization was obtained. The polyurethane
tubing was completely wetted and extremely lubricious. The
lubricity was equivalent to that obtained for in Example 5.
EXAMPLE 7
[0206] 5 g heparin methacrylate was copolymerized with 20 g acrylic
acid in 2-proponal. The reaction conditions were the same as in
Example 6. The average molecular weight was determined to be
400,000 using GPC and polyacrylic acids as standards.
[0207] As in Example 5 a 150 mm long and 2 mm diameter polyurethane
tubing was dipped into a 3% w/v MDI in THF solution and air dried
at 60.degree. C. for 1 hour.
[0208] The tubing was dipped into a 5% w/v heparin-acrylic acid
copolymer in methanol/dimethylacetamide solution (90:10) for 30
seconds and the air dried at 60.degree. C. for 3 hours.
[0209] The lubricity of the surface of the polyurethane tubing was
very similar to that in Example 5 and 6 after washing in 25% w/v
sodium chloride solution (as performed in Example 5 and 6).
[0210] XPS confirmed the presence of heparin on the surface as
SO.sub.4 groups be detached on the surface of the polyurethane
tubing.
EXAMPLE 8
[0211] PVC tubing 150 mm long 2 mm in diameter were coated with the
heparin copolymers synthesized in Example 4, 6 and 7. The coating
conditions for the respective heparin copolymers were identical to
the Examples 5, 6 and 7 respectively.
[0212] In all cases a very durable lubricious coating (when wet)
was obtained and the presence of heparin on the surface of the PVC
was detected either using toludine blue or XPS.
EXAMPLE 9
[0213] A polyurethane tube (150 mm long, 2 mm diameter) was dipped
into a 2% w/v solution of poly [1,4-phenylenediisocyanate-co-poly
(1,4-butanediol)] diisocyanate (Aldrich Chemical Co.) in anhydrous
THF and allowed to air dry at 60.degree. C. for 2 hours.
[0214] 2 g of heparin complex (from Example 1), 2 g polyethylene
oxide (M. W. 100,00) (Aldrich Chemical Co.) and 0.25 g MDI were
dissolved in 100 ml anhydrous DCM. The polyurethane tubing was
dipped with the above solution for 30 seconds and allowed to air
dry at 60.degree. C. for 1 hour and then at 22.degree. C. for 16
hours.
[0215] The polyurethane tubing was immersed in 25% w/v sodium
chloride solution at 40.degree. C. for 30 minutes and then washed
with de-ionized water and then dyed with toludine blue. An intense
homogenous dark purple color developed on the tubing and when wet
the tubing was highly lubricious. The lubricity was comparable to
in Example 5, 6 and 7.
EXAMPLE 10
[0216] A similar experiment to the one in Example 9 was conducted
with polyvinylpyrrolidone (M. W. 1,300,000) (Aldrich Chemical Co.)
with all the experimental conditions the same. Again the results
showed that heparin was present on the surface and the polyurethane
tubing was highly lubricious and comparable to the coating in
Example 9.
EXAMPLE 11
[0217] A PTFE tube measuring 3.8 mm O.D; length 8 cm was placed on
a rotatable mandrel. Placed over the PTFE was a knitted fabric tube
measuring 4.0 mm I.D; length of 7 cm.
[0218] A methacrylated polyvinylpyrrolidone (MPVP) was made by
dissolving 6 g of polyvinylpyrrolidone (PVP) in dichloromethane. A
solution of isocyanato ethyl methacrylate (0.8 g dissolved in 20 ml
of dichloromethane) was added drop wise to the stirred solution of
PVP. The reaction was allowed to proceed for a further 2 hours.
Dichloromethane was then rotary evaporated and the MPVP formed was
used in the vascular graft formulation as per the following:
Hydoxyethyl Methacrylate 18 g; Heparin Methacrylate (as from
example 3) 1 g; MPVP 0.6 g; Ethylene glycol dimethacrylate 0.08 g;
thermal initiator 0.12 g (Vazo 52).
[0219] The vascular graft formulation was then added drop wise onto
the rotating knitted fabric until a homogeneous viscous film was
formed, which totally encapsulated the fabric. Then the graft was
exposed to UV light from a medium pressure mercury arch lamp for 10
minutes; then the graft was placed in a vacuum oven for 3 hours at
70.degree. C.
[0220] The heparin contained in the graft was de-complexed with
saturated NaCl solution. The final vascular graft had a hydrogel
that totally encapsulated the fabric, which had a water content of
50%. Heparin activity was measured by antithrombin binding assay
and was found to be 5 units per 100 mm.sup.2.
EXAMPLE 12
[0221] This example shows that vascular grafts made as described
herein are effective for use with patients. A 28 day animal study
was carried out on two pigs. The vascular grafts as made according
to Example 11 were implanted in the carotid artery of each animal
using aseptic surgical techniques known to those skilled in the
art. The carotid arties were visualized at day nine, and day 28
using a medical X-ray arteriogram. The arteriogram showed that the
grafts were patent with endothelial cells, were clean, and showed
no evidence of thrombus at both days.
EXAMPLE 13
[0222] This Example describes the production of an
azide-polysaccharide complex, which is exemplified by the
production of a heparin-azide complex.
[0223] 5 g of sodium heparin, end-aminated (containing a terminal
amine group; Celsus Laboratories, Inc., Cincinnati, Ohio) was
complexed with benzalkonium chloride and purified as in Example 1,
except that the product was dried by freeze-drying with a yield of
10 g. The complexed heparin (10 g) was dissolved in anhydrous
dichloromethane (100 ml). 0.3 g of 4-azidophenyl isothiocyanate
(Aldrich Chemical Company, Inc.) was dissolved in 50 ml anhydrous
dichloromethane, and this solution was added drop-wise to the
solution containing the heparin complex. After the addition had
been completed, the solution was kept in the dark to prevent the
reaction of the azide group. Infrared spectroscopy showed the
disappearance of the isothiocyanate at 2000 cm.sup.-1 due to the
reaction of the isothiocyanate with the amine group of the heparin
complex.
EXAMPLE 14
[0224] This example shows how an azide-polysaccharide complex can
be used to coat a variety of surfaces, e.g., by dipping or
spraying. The process is exemplified using tubing and stents. From
Example 13, the azide-heparin complex dichloromethane solution was
used to coat a variety of surfaces by dipping or spraying.
[0225] In particular, a polyurethane tube was dipped into the
azide-heparin complex dichloromethane solution, dried, and then
exposed to UV light from a medium pressure mercury arc lamp for one
minute. The polyurethane tubing was then immersed into a saturated
sodium chloride solution for one minute to de-complex the heparin
from the benzalkonium chloride. Any heparin not covalently bonded
to the surface via the azide group was thereby dissolved in the
saturated sodium chloride solution.
[0226] The polyurethane tubing was then washed with de-ionized
water and dyed in toluidine blue. A homogenous deep purple color
was observed indicative of heparin being bound to the surface.
[0227] Similarly, polyethylene, polypropylene, polyamide and
polyester tubing was coated with azide-heparin as above and then
exposed to UV. The heparin was then de-complexed in saturated
sodium chloride solution and dyed in toluidine blue. The appearance
of a homogenous deep purple coloration showed that heparin was
chemically bound to the surface.
[0228] Expanded PTFE tubing was sprayed with the above
azide-heparin complex solution and then processed similarly. A
homogenous but lighter purple coloration was observed after dying
with toluidine blue. However, when the process was repeated onto
the same PTFE tubing, a deep-purple coloration was observed after
dying in toluidine blue.
[0229] Stents were coated with a variety of different polymer
coatings that are used as drug delivery systems, such as
polyethylene-vinyl acetate, polyethylene-vinyl alcohol,
polyurethane and polydimethyl siloxane. These stents were then
sprayed with the azide-heparin complex from a solution of
dichloromethane and isopropanol (50:50). The sprayed stents were
exposed to UV light and then decomplexed, washed and dried.
[0230] The stents were then crimped on to a Percutaneous
Transluminal Coronary Angioplasty (PTCA) catheter, which was then
expanded. Light microscopy showed that the polymers contained no
cracks or any imperfection upon expansion of the stents. Dying the
stents with toluidine blue gave a homogenous deep purple coloration
indicative of chemically linked heparin.
EXAMPLE 15
[0231] This example shows that an azido-polymer, e.g., an
azide-polysaccharide complex, can be used in combination with a
second polymer, e.g., a hydrophilic polymer, to create a coating on
surface that includes the azido-polymer and the second polymer. 0.5
g of polyethylene oxide (MW 4,000,000) was added to a 150 ml
solution of the azide-heparin complex in dichloromethane from
Example 13, and allowed to dissolve.
[0232] A polyurethane tubing was dipped coated with the above
solution and then exposed to UV light for one minute. The heparin
was de-complexed, as described previously, and the tubing was
washed with de-ionized water and dyed with toluidine blue. The
stained stent had a homogenous deep-purple coloration and was found
to be very lubricious. The above procedure was repeated with
polyvinylpyrrolidone (5 g; MW=1,000,000) and it was again found
that heparin was chemically linked to the surface, which was also
lubricious.
[0233] The association of polyvinylpyrrolidone or polyethylene
oxide with a surface gives the surface a lubricious character. The
lubricious character of the surfaces therefore showed that
polyethylene oxide or polyvinylpyrrolidone was associated with the
surface.
EXAMPLE 16
[0234] This example shows that an azido-polymer can be complexed
with monomers or macromers to make a layer of a hydrogel on a
surface. 20 g hydroxyethylmethacrylate (HEMA) HEMA, 10 g MPEG2000MA
(PEG with MW 2000 having a methyl on one end and a methacrylate on
the other end), 0.3 g ethylene glycol dimethacrylate, and 0.2 g
benzoin methyl ether (an UV initiator) were added to a 50 ml
solution of azide-heparin complex in dichloromethane (from Example
13).
[0235] This solution was then dip coated onto a polyurethane tubing
and exposed to UV light for 5 minutes. Then, the heparin was
de-complexed (as described previously), washed and exposed to
toluidine blue dye. The tubing surface was found to stain with a
homogenous deep-purple coloration. Scanning electron microscopy
(SEM) showed that a layer of about 10 microns in thickness was
present. The presence and deep color of the stain after the washing
step indicated that the heparin was present in a high concentration
in the layer. Moreover, the SEM results showed that a
three-dimensional structure was built up on the surface, indicating
the monomeric groups were polymerized to form a hydrophilic
polymer.
[0236] The embodiments set forth herein are exemplary of the
inventions and not intended to be limiting in scope. Patents,
patent applications, and articles mentioned in this application are
hereby incorporated herein by reference.
* * * * *