U.S. patent application number 13/973530 was filed with the patent office on 2014-02-27 for pva-paa hydrogels.
The applicant listed for this patent is Jeeyoung Choi, Orhun K. Muratoglu. Invention is credited to Jeeyoung Choi, Orhun K. Muratoglu.
Application Number | 20140058009 13/973530 |
Document ID | / |
Family ID | 39876197 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140058009 |
Kind Code |
A1 |
Choi; Jeeyoung ; et
al. |
February 27, 2014 |
PVA-PAA Hydrogels
Abstract
The invention provides fabricated PVA-hydrogels,
PVA-hydrogel-containing compositions, and methods of making the
same. The invention also provides methods of implanting or
administering the PVA-hydrogels, or the PVA-hydrogel-containing
compositions to treat a subject in need. Methods of cross-linking
pre-solidified or pre-gelled hydrogel particles and making
cross-linked PVA-hydrogels, and cross-linked
PVA-hydrogel-containing compositions also are disclosed herein.
Inventors: |
Choi; Jeeyoung;
(Spartanburg, SC) ; Muratoglu; Orhun K.;
(Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Choi; Jeeyoung
Muratoglu; Orhun K. |
Spartanburg
Cambridge |
SC
MA |
US
US |
|
|
Family ID: |
39876197 |
Appl. No.: |
13/973530 |
Filed: |
August 22, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12597056 |
Dec 9, 2009 |
8541484 |
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PCT/US08/61388 |
Apr 24, 2008 |
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13973530 |
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60969831 |
Sep 4, 2007 |
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60913618 |
Apr 24, 2007 |
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Current U.S.
Class: |
523/113 ;
525/57 |
Current CPC
Class: |
A61L 27/52 20130101;
C08L 29/04 20130101; C08L 71/02 20130101; C08J 3/075 20130101; C08J
2329/04 20130101; C08L 29/04 20130101; A61L 27/26 20130101; A61L
27/26 20130101; A61L 27/16 20130101; A61L 27/16 20130101; C08L
33/02 20130101; C08L 29/04 20130101; C08L 2666/02 20130101; C08L
29/04 20130101 |
Class at
Publication: |
523/113 ;
525/57 |
International
Class: |
A61L 27/26 20060101
A61L027/26; A61L 27/52 20060101 A61L027/52 |
Claims
1. A method of making a PVA-hydrogel comprising: a) contacting an
aqueous solution of poly(vinyl alcohol) (PVA) with an aqueous
solution of poly(acrylic acid) (PAA) at a temperature above room
temperature, thereby forming a homogenous PVA-PAA solution; b)
cooling the PVA-PAA solution down to room temperature, thereby
allowing formation of the PVA-hydrogel; c) cooling the PVA-hydrogel
by freezing at a temperature below 0.degree. C.; and d) thawing the
PVA-hydrogel to a temperature above 0.degree. C.
2. The method of claim 1, further comprising dehydrating the
PVA-hydrogel to remove part or all of the water content.
3. The method of claim 2, wherein the dehydration is carried out at
about 40.degree. C., about 80.degree. C., about 90.degree. C.,
about 100.degree. C., about 150.degree. C., about 160.degree. C.,
about 180.degree. C., about 200.degree. C., or above 200.degree. C.
for about an hour.
4. The method of claim 2, wherein the dehydration is carried out by
heating the hydrogel in air or in inert atmosphere to an elevated
temperature, wherein a heating rate ranges from about 0.01.degree.
C./minute to about 10.degree. C./minute.
5. The method of claim 2, wherein the dehydrated hydrogel is
re-hydrated by placing the dehydrated hydrogel: i) in water, saline
solution, Ringer's solution, salinated water, buffer solution, and
the like, ii) in a humid chamber, or iii) at room temperature or at
an elevated temperature.
6. A PVA-hydrogel made by a process comprising: a) contacting an
aqueous solution of poly(vinyl alcohol) (PVA) with an aqueous
solution of poly(acrylic acid) (PAA) at a temperature above room
temperature, thereby forming a homogenous PVA-PAA solution; b)
cooling the PVA-PAA solution down to room temperature, thereby
allowing formation of the PVA-hydrogel; c) cooling the PVA-hydrogel
by freezing at a temperature below 0.degree. C.; and d) thawing the
PVA-hydrogel to a temperature above 0.degree. C., wherein the
PVA-hydrogel comprises one or more hydrophilic polymers selected
from the group consisting of: PVA-PAA copolymer, poly(ethylene
oxide)(PEO)--PAA copolymer, poly(methacrylic acid) (PMAA),
polyvinylpyrrolidone (PYP), hyaluronic acid (HA), and
poly(allylamine hydrochloride) (PAH).
7. The PVA-hydrogel of claim 6, wherein the hydrogel comprises
water and/or one or more other ingredients.
8. The PVA-hydrogel of claim 7, wherein the ingredient is PVA, PAA,
PEG, and/or salt, proteoglycan, water soluble polymer, amino acid,
alcohol, DMSO, or water soluble vitamin, and wherein the ingredient
is partially or completely soluble in water.
9. The PVA-hydrogel of claim 7, wherein the ingredient is PEG,
wherein the PEG is in a solution of water, ethanol, ethylene
glycol, DMSO, or a suitable solvent.
10. The PVA-hydrogel of claim 7, wherein the ingredient is
non-volatile.
11. The PVA-hydrogel of claim 7, wherein the ingredient is at least
partially miscible in water.
12. The PVA-hydrogel of claim 7, wherein the ingredient is selected
from the group consisting of PEG, salt, NaCl, KCl, CaCl.sub.2,
vitamins, carboxylic acids, hydrocarbons, esters, and amino
acids.
13. The PVA-hydrogel of claim 7, wherein the ingredient is PEG of
different molecular weights or a blend of PEGs of different
molecular weights.
14. The PVA-hydrogel of claim 7, wherein the ingredient is a water
miscible polymer.
15. The PVA-hydrogel of claim 14, wherein the water miscible
polymer is PEO, Pluronic, amino acids, proteoglycans,
polyvinylpyrrolidone, polysaccharides, dermatin sulfate, keratin
sulfate, chondroitin sulfate, or dextran sulfate.
16. A medical implant comprising a PVA-hydrogel according to claim
6.
17. The medical implant of claim 16 wherein the medical implant is
an interpositional device.
18. The medical implant of claim 17, wherein the interpositional
device a unispacer, wherein the unispacer is a free floating
articular implant in a human joint.
19. The medical implant of claim 18, wherein the human joint is a
knee, a hip, a shoulder, an elbow, or an upper or an extremity
joint.
Description
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 60/913,618, filed Apr. 24, 2007, and U.S.
Provisional Application Ser. No. 60/969,831, filed Sep. 4, 2007,
the entireties of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention relates to manufacture of creep resistant and
lubricious poly(vinyl alcohol)(PVA)-hydrogels, creep resistant and
lubricious PVA-hydrogel-containing compositions, and methods of
making fabricated PVA-hydrogels and PVA-hydrogel-containing
compositions. The invention also relates to methods of using the
fabricated creep resistant PVA-hydrogels and creep resistant
PVA-hydrogel-containing compositions for osteochondral defect
repair that require mechanical integrity, high water content, and
excellent lubricity in order to fully function under the high
stress environment in the joint space and withstand high loads of
human joints.
BACKGROUND OF THE INVENTION
[0003] Biocompatible hydrogels as synthetic materials for
osteochondral defect repair require mechanical integrity, high
water content, and excellent lubricity to fully function under the
high stress environment in the human joint spaces. PVA hydrogels
are good candidates for such purposes, but currently available
formulations do not provide enough mechanical strength and
lubricity compatible to that of natural articular cartilage.
[0004] Most hydrogels systems available for articular cartilage
replacement applications do not have required mechanical strength
to withstand the high loads of the human joint. Various dehydration
methods, described below, can be used together in combinations to
alter the properties of hydrogels.
[0005] Solvent dehydration of hydrogels is described by Bao (U.S.
Pat. No. 5,705,780). Bao describes immersion of PVA hydrogel into
solvents such as ethanol/water mixture at room temperature to
dehydrate PVA hydrogel without shape-distortion.
[0006] Hyon and Ikada (U.S. Pat. No. 4,663,358) and Bao (U.S. Pat.
No. 5,705,780) describe the use of water and organic solvent
mixture to dissolve PVA powder and subsequently cooling the
solution below room temperature and heating back up to room
temperature to form a hydrogel. The hydrogel is then immersed in
water to remove the organic solvent. Hyon and Ikada claim that PVA
hydrogels thus formed are transparent, as opposed to the ones
formed by freeze-thaw method that uses water only as the solvent to
dissolve the PVA powder.
[0007] Bao (U.S. Pat. No. 5,522,898) describes dehydration methods
that use air dehydration, vacuum dehydration, or partial humidity
dehydration to control the rate of dehydration and prevent shape
distortion of PVA hydrogels for use as prosthetic spinal devices to
replace the nucleus pulposus. The starting gels of Bao are the
freeze-thaw gels described in the U.S. Pat. No. 5,705,780.
[0008] Ku et al. (U.S. Pat. No. 5,981,826) describes a freeze-thaw
method to form a PVA hydrogel by subjecting a PVA aqueous solution
to freeze-thaw followed by immersion in water and additional cycles
of freeze-thaw while immersed in water.
[0009] The creep resistance of PVA is currently achieved in the
field by reducing the equilibrium water content (EWC) of the
hydrogel, but which also reduces the lubricity of the hydrogel.
Therefore, there remain long felt but an unmet need for, among
other things, a creep resistant PVA-hydrogel, which also would
retain the lubricity. Such a creep resistant PVA-hydrogel and
methods of making such a composition was not known until the
instant invention.
SUMMARY OF THE INVENTION
[0010] The present invention relates generally to creep resistant
PVA-hydrogels, PVA-hydrogel-containing compositions, and methods of
making PVA-hydrogels and PVA-hydrogel-containing compositions. The
invention also relates to methods of using the creep resistant
PVA-hydrogels and creep resistant PVA-hydrogel-containing
compositions in treating a subject in need, for example, for
osteochondral defect repair that require mechanical integrity, high
water content, excellent lubricity to fully function under the high
stress environment in the joint space and withstand high loads of
human joints.
[0011] One aspect of the invention provides methods of making a
PVA-hydrogel comprising: a) contacting an aqueous solution of
poly(vinyl alcohol) (PVA) with an aqueous solution of poly(acrylic
acid) (PAA) at a temperature above the room temperature, thereby
forming a homogenous PVA-PAA solution; b) contacting the PVA-PAA
solution with an aqueous solution of polyethylene glycol (PEG),
thereby forming a homogenous PVA-PAA-PEG solution; and c) cooling
the PVA-PAA-PEG solution to room temperature or below, thereby
forming a PVA-hydrogel.
[0012] Another aspect of the invention provides methods of making a
PVA-hydrogel comprising: a) contacting an aqueous solution of
poly(vinyl alcohol) (PVA) with an aqueous solution of poly(acrylic
acid) (PAA) at a temperature above the room temperature, thereby
forming a homogenous PVA-PAA solution; b) pouring the PVA-PAA
solution onto a mold (optionally pre-heated) followed by cooling
down to room temperature, thereby allowing formation of the
PVA-hydrogel; c) cooling the PVA-hydrogel by freezing at a
temperature below 0.degree. C.; d) thawing the PVA-hydrogel to a
temperature above 0.degree. C.; and e) immersing PVA-hydrogel in a
PEG solution, thereby allowing diffusion of the PEG into the
PVA-hydrogel.
[0013] Another aspect of the invention provides methods of making a
PVA-hydrogel comprising: a) contacting an aqueous solution of
poly(vinyl alcohol) (PVA) with an aqueous solution of poly(acrylic
acid) (PAA) at a temperature above the room temperature, thereby
forming a homogenous PVA-PAA solution; b) contacting the PVA-PAA
solution with an aqueous solution of polyethylene glycol (PEG),
thereby forming a homogenous PVA-PAA-PEG solution; c) pouring the
PVA-PAA-PEG solution onto a mold (optionally pre-heated) followed
by cooling down to room temperature, thereby allowing formation of
the PVA-hydrogel; d) cooling the PVA-hydrogel by freezing at a
temperature below 0.degree. C.; and e) thawing the PVA-hydrogel to
a temperature above 0.degree. C.
[0014] According to one aspect of the invention, the mold is
pre-heated to a temperature between about 1 and about 200.degree.
C., preferably between about 25.degree. C. and about 150.degree.
C., more preferably about 90.degree. C.
[0015] According to another aspect, the invention provides methods
as described above, wherein the hydrogel comprises PVA-hydrogel,
wherein the hydrogel comprises water and/or one or more other
ingredients. The ingredients are FAA, PEG, and/or salt,
proteoglycan, water soluble polymer, amino acid, alcohol, DMSO,
water soluble vitamin, wherein in the ingredients are partially or
completely soluble in water.
[0016] According to another aspect, the ingredients are PAA, and/or
salt, proteoglycan, water soluble polymer, amino acid, alcohol,
DMSO, water soluble vitamin, wherein in the ingredients are
partially or completely soluble in water.
[0017] According to another aspect, the ingredients are PEG,
wherein the PEG is in a solution of water, ethanol, ethylene
glycol, DMSO, or another suitable solvent.
[0018] According to another aspect, the ingredients are
non-volatile.
[0019] According to another aspect, the ingredients are at least
partially miscible in water.
[0020] According to another aspect, the ingredients are selected
from the group consisting of PEG, salt, NaCl, KCl, CaCl.sub.2,
vitamins, carboxylic acids, hydrocarbons, esters, and amino acids,
PEG of different molecular weights or a blend of PEGs of different
molecular weights, or any combination of the above.
[0021] According to another aspect, the water miscible polymer is
PEO, Pluronic, amino acids, proteoglycans, polyvinylpyrrolidone,
polysaccharides, dermatin sulfate, keratin sulfate, chondroitin
sulfate, or dextran sulfate, or any combination of the above.
[0022] According to another aspect, at least 0.1% of the hydrogel's
weight constitutes one or more non-volatile ingredient.
[0023] According to another aspect, the dehydration is carried out
by placing the hydrogel in: a) a non-solvent, wherein i) the
non-solvent is PEG, alcohols, acetones, saturated salinated water,
vitamin, or carboxylic acid, aqueous solution of a salt of an
alkali metal, or a combination thereof, and ii) the non-solvent
contains more than one ingredients including water, PEG, vitamin,
polymer, ester, proteoglycan, and carboxylic acid, or b) in a
supercritical fluid.
[0024] According to another aspect, the dehydration is carried out
by leaving the hydrogel in air, by placing the hydrogel in a vacuum
at room temperature or at an elevated temperature, for example, at
40.degree. C., above about 40.degree. C., about 80.degree. C.,
above 80.degree. C., about 90.degree. C., about 100.degree. C.,
above 100.degree. C., about 150.degree. C., about 160.degree. C.,
above 160.degree. C., about 180.degree. C., about 200.degree. C.,
or above 200.degree. C.
[0025] According to another aspect, the dehydration is carried out
by heating the hydrogel in air or inert atmosphere (in presence of
inert gas, such as nitrogen, argon, neon, or helium), or under
vacuum at an elevated temperature, wherein the heating rate is slow
or fast or the heating follows the vacuum or air dehydration.
[0026] According to another aspect, the dehydration is carried out
in an atmosphere containing 100% air, 100% inert gas, a mixture of
one or more inert gases containing 0.1% to 99.9% air, or a mixture
of one or more inert gases mixed with 0.1% to 99.9% oxygen.
[0027] According to another aspect, the dehydrated hydrogel is
re-hydrated by placing the dehydrated hydrogel: i) in water, saline
solution, Ringer's solution, salinated water, buffer solution, and
the like, or a combination thereof, ii) in a humid chamber, or iii)
at room temperature or at an elevated temperature.
[0028] According to another aspect, the PVA-hydrogels made by above
disclosed methods are re-hydrated to reach an equilibrium, wherein
the PVA-hydrogels are re-hydrated in water or a salt solution.
[0029] In one aspect, the invention provides PVA-hydrogels
comprising a polymer and water, wherein the PVA-hydrogels contain
at least about 1% to about 50% equilibrium water content.
[0030] In another aspect, the invention provides PVA-hydrogels made
by any of the above described processes, wherein the PVA-hydrogel
is capable of re-hydration following dehydration, wherein the
dehydration reduces the weight of the hydrogel; and the
re-hydration results in increase in equilibrium water content in
the re-hydrated hydrogel.
[0031] In another aspect, the PVA-hydrogels are of a biaxial
orientation or of a uniaxial orientation, wherein the PVA-hydrogel
has a high ultimate tensile strength.
[0032] Yet another aspect of the invention provides medical
implants comprising a PVA-PAA-hydrogel, for example, an
interpositional device, wherein the interpositional device a
unispacer, wherein the unispacer is a free floating articular
implant in human joints such as a knee, a hip, a shoulder, an
elbow, or an upper or an extremity joint.
[0033] Yet another aspect of the invention provides medical
implants comprising a PVA-PAA-PEG-hydrogel, for example, an
interpositional device, wherein the interpositional device a
unispacer, wherein the unispacer is a free floating articular
implant in human joints such as a knee, a hip, a shoulder, an
elbow, or an upper or an extremity joint.
[0034] According to another aspect, the invention provides
PVA-hydrogels made by any of the above described processes, wherein
pH-induced phase-separation of PVA-PAA solutions into the PVA-rich
and PAA-rich domains prior to gelation increases creep resistance
of PAA-containing PVA hydrogels.
[0035] According to another aspect, the invention provides
PVA-hydrogels made by any of the above described processes, wherein
certain pH value (which is the "miscibility transition inducing" pH
(pH.sub.mt)) varies depending on factors selected from the group
consisting of the total polymer concentration, molecular weight of
each polymer, PVA:PAA ratio, salt concentration or the ionic
strength of the solution, and the like.
[0036] According to another aspect, the invention provides
PVA-hydrogels made by any of the above described processes, wherein
miscibility of PVA-PAA solutions prior to gelation is controlled by
adjusting pH values of the PVA-PAA solutions below or above
pH.sub.mt.
[0037] According to another aspect, the invention provides
PVA-hydrogels made by any of the above described processes, wherein
the certain pH value (which is the "miscibility transition
inducing" pH (pH.sub.mt)) of a PVA-PAA solution containing 1.654
w/w % aqueous PAA solution and 25% total polymer having a PVA:PAA
ratio of 19:1 is between about 3.0 and about 5.5.
[0038] According to another aspect, the invention provides
PVA-hydrogels made by any of the above described processes, wherein
the certain pH value (which is the "miscibility transition
inducing" pH (pH.sub.mt)) of a PVA-PAA solution containing 0.332
w/w % aqueous PAA solution and 25% total polymer having a PVA:PAA
ratio of 99:1 is between about 1.5 and about 5.5.
[0039] Unless otherwise defined, all technical and scientific terms
used herein in their various grammatical forms have the same
meaning as commonly understood by one of ordinary skill in the art
to which this invention belongs. Although methods and materials
similar to those described herein can be used in the practice or
testing of the present invention, the preferred methods and
materials are described below. In case of conflict, the present
specification, including definitions, will control. In addition,
the materials, methods, and examples are illustrative only and are
not limiting.
[0040] Further features, objects, advantages, and aspects of the
present invention are apparent in the claims and the detailed
description that follows. It should be understood, however, that
the detailed description and the specific examples, while
indicating preferred aspects of the invention, are given by way of
illustration only, since various changes and modifications within
the spirit and scope of the invention will become apparent to those
skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] FIG. 1 shows the PVA-PAA hydrogels formed from 15% solid
PVA-PAA-PEG blends with 15% PEG by 3 cycle freeze-thawing after
various processing described in Examples 1-3: 1(A) After
re-hydration in saline (Example 1), 1(B) After vacuum dehydration
followed by re-hydration in saline (Example 2), and 1(C) After
vacuum dehydration and subsequent heating followed by re-hydration
in saline (Example 3).
[0042] FIG. 2 depicts the PVA-PAA hydrogels formed from 15% solid
PVA-PAA blends by 3 cycle freeze-thawing after various processing
described in Examples 5-8: 2(A) After re-hydration in saline
(Example 5), 2(B) After vacuum dehydration followed by re-hydration
in saline (Example 6), 2(C) After vacuum dehydration and subsequent
heating followed by re-hydration in saline (Example 7), and 2(D)
After immersing in 100% PEG400 followed by re-hydration in saline
(Example 8).
[0043] FIG. 3 illustrates creep behavior in Strain vs. Time plots
for the 10 hour loading and 10 hour unloading cycles
respectively.
[0044] FIG. 4 shows creep behavior in Strain vs. Time plots for the
10 hour loading and unloading cycles, respectively, for the samples
1-3 as shown in Table 7.
[0045] FIG. 5 shows creep behavior in Strain vs. Time plots for the
10 hour loading and unloading cycles, respectively, for samples 4-6
refer as shown in Table 7.
[0046] FIG. 6 illustrates creep behavior in Strain vs. Time plots
for the 10 hour loading and unloading cycles, respectively, for the
samples 7-10 as shown in Table 7.
[0047] FIG. 7 shows total creep strain of PVA hydrogels obtained
from creep test as described in Example 24 and is plotted as a
function of equilibrium water content.
[0048] FIG. 8 depicts a confocal micrograph of rehydrated PVA
hydrogel made by a method (example 1) where PEG was present in the
PVA and PAA solution during the time of gelling process (scale
bar=20 .mu.m).
[0049] FIG. 9 depicts a confocal micrograph of rehydrated PVA
hydrogel made by a method (example 8) where PEG was sequentially
incorporated in pre-made PVA-PAA gels (scale bar=20 .mu.m).
[0050] FIG. 10 shows the creep resistance of "The PVA-PAA-PEG gel"
where PEG was present during PVA gelling and "PVA-PAA gel with PEG
incorporated" where PEG was incorporated after PVA gelling. Both
gels were thermally treated and rehydrated in saline prior to creep
deformation test.
[0051] FIG. 11 shows DePEG PVA hydrogels after PAA diffusion by
immersion in six different PAA aqueous solutions including; 11(A)
25% PAA (MW-200K) solution, 11(B) 5% PAA (MW=200K), 11(C) 5% PAA
11(D) 25% PAA 11(E) deionized water with no PAA (control), and
11(F) about 50% PAA (MW=5K).
[0052] FIGS. 12A and 1213 show equilibrium water content (EWC) of
the FAA-containing PVA hydrogels. "PVA only; NA" indicates the
non-annealed hydrogel made with only PVA without PAA. The hydrogels
were equilibrated at 25.degree. C. (12A) or 40.degree. C. (12B)
prior to drying for EWC measurement.
[0053] FIG. 13 shows the typical creep behavior of the
PAA-containing PVA gels with various PVA-PAA ratios made by type 1
gel method. (1) PVA only, non-annealed (2) 7:3 PVA:PAA, (3) 8:2
PVA:PAA, (4) 9:1 PVA:PAA, and (5) PVA only.
[0054] FIG. 14 shows the typical creep behavior of the
PAA-containing PVA gels with various PVA-PAA ratios made by type 2
gel method. (1) PVA only, non-annealed (2) 8:2 PVA:PAA, (3) 7:3
PVA:PAA, (4) 9:1 PVA:PAA, and (5) PVA only.
[0055] FIG. 15 illustrates total creep strain of the PAA-containing
PVA hydrogels. Average numbers of 3 values and standard deviation
are shown except for the case of *, for which the average of 2
values were presented.
[0056] FIG. 16 shows Coefficient of Friction (COF) of the
FAA-containing PVA gels made by type I gel method.
[0057] FIG. 17 illustrates Coefficient of Friction (COF) of the
PAA-containing PVA gels made by type 2 gel method.
[0058] FIG. 18 shows equilibrium water content (EWC) and the total
creep strain of 25% total polymer hydrogels of 7:3 PVA:PAA ratio
made with or without the PEG doping step as described in Example
30. The hydrogels were equilibrated 40.degree. C. prior to drying
for EWC measurement.
[0059] FIG. 19 shows the typical creep behavior of 25% total
polymer hydrogels of 7:3 PVA:PAA ratio made with or without the PEG
doping step as described in Example 30. (1) PEG-doped and (2) non
PEG-doped
[0060] FIG. 20 Coefficient of Friction (COF) of 25% total polymer
hydrogels of 7:3 PVA:PAA ratio made with or without the PEG doping
step as described in Example 30.
[0061] FIG. 21 shows the equilibrium water content (EWC) and
coefficient of friction (COF) of the 25% total polymer content
PAA-containing PVA gels with various PVA:PAA ratios made by type 1
gel method as described in Examples 31-34. EWC was measured after
equilibrating the gels at 40.degree. C. prior to measurement. COF
under 7N normal force was taken as the representative COF for each
gel. All gels were annealed for 1 hour at 160.degree. C. under
argon gas. PVA:PAA ratio is indicated followed by the pH value at
which each gelling solution was made. "PVA only" indicates the PVA
gels with no PAA. "Miscible" and "immiscible" indicate the
miscibility state of each PVA-PAA solution prior to gelling: (1)
PVA only, (2) 99:1 PVA:PAA, pH 3.3, (3) 99:1 PVA:PAA, pH 1.5, (4)
19:1 PVA:PAA, pH 5.5, and (5) 19:1 PVA:PAA, pH 3.0.
[0062] FIG. 22 shows the equilibrium water content of the
PAA-containing PVA gels with 9:1 PVA:PAA ratio made by type 1 gel
method under various annealing conditions as described in Example
36. EWC was measured after equilibrating the gels at 40.degree. C.
prior to measurement. (A) 1 hour heating at 160.degree. C. under
argon gas, (13) 1 hour heating at 160.degree. C. in air (without
argon gas purging), (C) 16 hour heating at 160.degree. C. under
argon gas, and (D) 1 hour heating at 200.degree. C. under argon
gas.
[0063] FIG. 23 shows the total creep strain of the FAA-containing
PVA gels with 9:1 PVA:PAA ratio made by type 1 gel method under
various annealing conditions as described in Example 36. (A) 1 hour
heating at 160.degree. C. under argon gas, (B) 1 hour heating at
160.degree. C. in air (without argon gas purging), (C) 16 hour
heating at 160.degree. C. under argon gas, and (D) 1 hour heating
at 200.degree. C. under argon gas.
[0064] FIG. 24 depicts the coefficient of friction (COF) of the
PAA-containing PVA gels with 9:1 PVA:PAA ratio made by type 1 gel
method under various annealing conditions as described in Example
36. (A) 1 hour heating at 160.degree. C. under argon gas, (B) 1
hour heating at 160.degree. C. in air (without argon gas purging),
(C) 16 hour heating at 160.degree. C. under argon gas, and (D) 1
hour heating at 200.degree. C. under argon gas.
[0065] FIG. 25 shows the coefficient of friction (COF) of the
PAA-containing PVA gels with 9:1 PVA:PAA ratio made by type 1 gel
method under various annealing conditions as described in Example
36. COF under 7N normal force was taken as the representative COF
for each gel. (A) 1 hour heating at 160.degree. C. under argon gas,
(B) 1 hour heating at 160.degree. C. in air (without argon gas
purging), (C) 16 hour heating at 160.degree. C. under argon gas,
and (D) 1 hour heating at 200.degree. C. under argon gas.
[0066] FIG. 26 shows the coefficient of friction (COF) of the
PAA-containing PVA gels with various PVA:PAA ratio made by type 1
gel method. All gels were annealed for 1 hour at 160.degree. C.
under argon gas except for "PVA only; Non-annealed", which
indicates the non-annealed hydrogels made with only PVA without
PAA. "PVA only" indicates the annealed PVA gels made with only PVA
without PAA. (A) PVA only, (B) 9:1 PVA:PAA, (C) 8:2 PVA;PAA, (D)
7:3 PVA:PAA, (E) PVA only; non-annealed.
[0067] FIG. 27 shows the coefficient of friction (COF) of the
PAA-containing PVA gels with various PVA:PAA ratio made by type 1
gel method. All gels were annealed for 1 hour at 160.degree. C.
under air except for "PVA only; Non-annealed", which indicates the
non-annealed hydrogels made with only PVA without PAA. "PVA only"
indicates the annealed PVA gels made with only PVA without PAA. (A)
PVA only, (B) 9:1 PVA:PAA, (C) 8:2 PVA; PAA, (D) 7:3 PVA:PAA, (E)
PVA only; non-annealed.
[0068] FIG. 28 shows the equilibrium water content (EWC) of the
PAA-containing PVA gels with various PVA:PAA ratio made by type 1
gel method followed by annealing for 1 hour at 160.degree. C. under
argon gas or in air. "PVA only" indicates the annealed PVA gels
made with only PVA without PAA. (A) PVA only, (B) 9:1 PVA:PAA, (C)
8:2 PVA;PAA, (D) 7:3 PVA:PAA.
[0069] FIG. 29 shows the total creep strain (TCS) of the
PAA-containing PVA gels with various PVA:PAA ratio made by type 1
gel method followed by annealing for 1 hour at 160.degree. C. under
argon gas or in air. "PVA only" indicates the annealed PVA gels
made with only PVA without PAA. (A) PVA only, (B) 9:1 PVA:PAA, (C)
8:2 PVA;PAA, (D) 7:3 PVA:PAA.
DETAILED DESCRIPTION OF THE INVENTION
[0070] The present invention provides creep resistant
PVA-hydrogels, which also retain lubricity, and methods of making
creep resistant PVA-hydrogel for osteochondral defect repair, which
possesses one or more of mechanical integrity, high water content,
excellent lubricity to fully function under the high stress
environment in the joint space and the ability to withstand high
loads of human joints.
[0071] According to one embodiment of the invention, a second
polymer is incorporated by physically blending with PVA and/or
chemically tethering the molecules of the second polymer to PVA
molecules in the hydrogel. The second polymer also can be
polymerized in the presence of PVA molecules. A number of
post-processing methods such as freeze-thaw, vacuum dehydration,
solvent dehydration, heating, also can be used.
[0072] Increased hydrophilicity achieved by the addition of this
second polymer results in increased water uptake, which improves
surface lubricity of the PVA hydrogels. In cases where the second
polymer has high ionic strength, electrostatic repulsion provides
increased elasticity under compressive or tensile loading, similar
to cartilage. The second polymer also can have chemical functional
groups that can cross-link with each other or with the PVA
molecules to form an interpenetrating network to reinforce the
original PVA network structure. Polymers with weak acid or weak
base functional groups also can be used to impart pH-sensitivity to
the originally non-ionic PVA hydrogels. This is useful for
pH-induced volume transition and complexation with dyes, drugs,
and/or biological molecules.
[0073] In another embodiment, the invention provides methods of
designing such systems. With PVA-hydrogels as a base hydrogel
system, the newly incorporated hydrophilic entities are
macromolecules with ionic chemical functionality or hydrogen
bonding capability, namely, poly(acrylic acid) (PAA) and
poly(allylamine hydrochloride) (PAH), PVA-PAA copolymer,
poly(ethylene oxide) (PEO)-PAA copolymer, Poly(methacrylic acid)
(PMAA), hyaluronic acid (HA), and polyvinylpyrrolidone (PVP).
Methods for incorporating the new hydrophilic moieties include
blends with PVA before gel formation and diffusion into PVA after
gel formation. Methods for stabilizing the introduced new moieties
inside the original gel network include, chemical cross-linking,
irradiation, dehydration, and thermal treatment and combinations
thereof. The incorporation of the second polymer in PVA can be
non-uniform to impart, for example, non-uniform gradient properties
to the final implant, such as different water content, creep
strength, mechanical properties, and cross-link density, and the
like.
[0074] Methods of Making PVA-PAA-PEG Gels:
[0075] 1. Blending of PVA and PAA in Solution with PEG
Addition.
[0076] In one embodiment, aqueous poly(acrylic acid) (PAA) solution
is mixed with an aqueous solution of poly(vinyl alcohol) (PVA) at
an elevated temperature above room temperature to form a homogenous
PVA-PAA solution. PVA:PAA ratio can be about 99.9:0.1 to 5:5, for
example, 99.5:0.5, 99:1, 79:1, 59:1, 39:1, 19:1, 9:1, 8:2, 7:3,
6:4, 5:5, or any ratio thereabout, or therebetween, with the total
polymer content in the mixture at about 10%, 15%, 20%, 25%, 27%,
30%, 35%, 40%, 45%, 50%, or any value thereabout, therebetween, or
higher. Polyethylene glycol (PEG) is added to the PVA-PAA hot (for
example, about 90.degree. C.) mixture to form a homogenous
PVA-PAA-PEG solution and poured into a mold (optionally pre-heated)
followed by cooling down to a lower temperature to form a gel.
[0077] 2. Freeze-Thawing of PVA-PAA-PEG Gels.
[0078] In another embodiment, aqueous poly(acrylic acid) (PAA)
solution is mixed into an aqueous solution of poly(vinyl alcohol)
(PVA) at an elevated temperature above room temperature to form a
homogenous PVA-PAA solution. PVA:PAA ratio can be about 99.9:0.1 to
5:5, for example, 99.5:0.5, 99:1, 79:1, 59:1, 39:1, 19:1, 9:1, 8:2,
7:3, 6:4, 5:5, or any ratio thereabout, or therebetween, with the
total polymer content in the mixture at about 15%, 20%, 25%, 27%,
30%, 35%, 40%, 45%, any value thereabout, therebetween, or higher.
Polyethylene glycol (PEG) is added to the PVA-PAA hot (for example,
about 90.degree. C.) mixture to form a homogenous PVA-PAA-PEG
solution and poured into a mold (optionally pre-heated) followed by
freezing at a temperature below 0.degree. C. followed by thawing
above 0.degree. C. In some embodiments the freeze thaw cycles are
repeated.
[0079] 3. Freeze-Thawing of PVA-PAA Gels with PEG-Doping.
[0080] In another embodiment, aqueous poly(acrylic acid) (PAA)
solution is mixed into an aqueous solution of poly(vinyl alcohol)
(PVA) at an elevated temperature above room temperature to form a
homogenous PVA-PAA solution. PVA:PAA ratio can be about 99.9:0.1 to
5:5, for example, 99.5:0.5, 99:1, 79:1, 59:1, 39:1, 19:1, 9:1, 8:2,
7:3, 6:4, 5:5, or any ratio thereabout, or therebetween, with the
total polymer content in the mixture at about 10%, 15%, 20%, 25%,
27%, 30%, 35%, 40%, 45%, 50%, or any value thereabout,
therebetween, or higher. The mixture is poured into a mold
(optionally pre-heated) followed by freezing at a temperature below
0.degree. C., followed by thawing above 0.degree. C. The PVA-PAA
gel is immersed in PEG to diffuse PEG into the gel. The gel either
used in this form after re-hydration in water or saline, or it is
subjected to further processing such as heating.
[0081] 4. Diffusion of PEG into PVA-PAA Gels.
[0082] In another embodiment, aqueous polyacrylic acid (PAA)
solution is mixed into an aqueous solution of poly(vinyl alcohol)
(PVA) at an elevated temperature above room temperature to form a
homogenous PVA-PAA solution. PVA:PAA ratio can be about 99.9:0.1 to
5:5, for example, 99.5:0.5, 99:1, 79:1, 59:1, 39:1, 19:1, 9:1, 8:2,
7:3, 6:4, 5:5, or any ratio thereabout, or therebetween, with the
total polymer content in the mixture at about 10%, 15%, 20%, 25%,
27%, 30%, 35%, 40%, 45%, 50%, or any value thereabout,
therebetween, or higher. The mixture is poured into a mold
(optionally pre-heated) followed by freezing at a temperature below
0.degree. C. followed by thawing above 0.degree. C. The
PVA-hydrogel is immersed in PEG to diffuse PEG into the gel while
extracting some or all of the water.
[0083] 5. Freeze-Thawing of PVA Gels Followed by Diffusion of PAA
into PVA Gels.
[0084] In another embodiment, an aqueous poly(vinyl alcohol) (PVA)
solution at an elevated temperature above room temperature is
poured into a mold (optionally pre-heated) and cooled down below
0.degree. C., followed by thawing at a temperature above 0.degree.
C. to form a PVA cryogel. The total PVA content in the gel can be
about 10%, 15%, 20%, 25%, 27%, 30%, 35%, 40%, 45%, or any value
thereabout, therebetween, or higher. The PVA cryogel is immersed in
an aqueous solution of PAA to diffuse PAA into the gel. Vigorous
agitation and/or elevated temperature is used to increase the
diffusion rate. The diffusion rate also can be increased by
immersing the gel in a supercritical fluid.
[0085] 6. PAA Incorporated PVA Cyrogel Followed by PEG-Doping.
[0086] In another embodiment, an aqueous poly(vinyl alcohol) (PVA)
solution at an elevated temperature above room temperature is
poured into a mold (optionally pre-heated) and cooled down below
0.degree. C., followed by thawing at a temperature above 0.degree.
C. to form a PVA cryogel. The total PVA content in the gel can be
about 10%, 15%, 20%, 25%, 27%, 30%, 35%, 40%, 45%, or any value
thereabout, therebetween, or higher. The PVA cryogel is immersed in
an aqueous solution of PAA to diffuse PAA into the gel. Vigorous
agitation and/or elevated temperature is used to increase the
diffusion rate. The diffusion rate also can be increased by
immersing the gel in a supercritical fluid. The gel then can be
immersed in PEG to diffuse PEG into the gel while extracting some
or all of the water out.
[0087] The hydrophilic entity incorporated in the PVA gels by any
of the methods described above is not limited to PAA homopolymer,
but can be other types of hydrophilic polymers with chemical
functionality, namely, PVA-PAA copolymer, poly(ethylene
oxide)(PEO)-PAA copolymer, Poly(methacrylic acid) (PMAA),
polyvinylpyrrolidone (PVP), hyaluronic acid (HA), and
poly(allylamine hydrochloride) (PAH). The freeze-thaw methods
described in the above gels do not need to be limited to 1 cycle of
freeze/thaw but can be more than one cycle, for example, 2, 3, 4,
5, 8, 10 or more cycles. In any of the above embodiments the final
gel device can be dehydrated in a solvent or under vacuum and/or
subsequently heated prior to final re-hydration in water or
physiologic saline solution.
[0088] According to one embodiment, the mold in any of the above
methods, is pre-heated to a temperature between about 1 and about
200.degree. C., preferably between about 25.degree. C. and about
150.degree. C., more preferably about 90.degree. C.
[0089] 7. Mixing PVA Solutions with Other Ingredients.
[0090] Mixing can be done in various ways, for example, [0091] a)
PVA solutions can be blended by mixing/stirring with other
ingredients, as described herein, in a container, such as a beaker;
and [0092] b) PVA solutions can be blended with other ingredients,
as described herein, using a compounder.
[0093] In another embodiment, aqueous poly(acrylic acid) (PAA)
solution is mixed with an aqueous solution of poly(vinyl alcohol)
(PVA) at an elevated temperature above room temperature to form a
homogenous PVA-PAA solution by blending in a container or by using
a compounder along with other ingredients. According to one aspect
of the invention, the hydrogel comprises water and/or one or more
other ingredients, such as PAA, PEG (PEG is in a solution of water,
ethanol, ethylene glycol, DMSO, or another suitable solvent), PEG
of different molecular weights or a blend of PEGs of different
molecular weights, salt, NaCl, KCl, CaCl.sub.2, vitamins,
carboxylic acids, hydrocarbons, esters, amino acids, proteoglycan,
water soluble polymers, alcohol, wherein in the other ingredients
are at least partially miscible or soluble in water.
[0094] The ingredients for mixing can be of any forms, such as
powder, pellets, liquid, wax, paste, micro or nano-particles, or
already gelled substances. Already gelled substances can be
previously processed by post-gelling methods such as dehydration,
rehydration, solvent-immersion, heat treatment, irradiation, and/or
freeze-thawing.
[0095] Gelation:
[0096] According to some embodiments, gelation can be done by
cooling down in presence of a gellant such as PEG; and/or
freeze-thaw (for one or more cycles); and/or irradiation.
[0097] According to one aspect of the invention, irradiation of the
solution is done to cause gelation. During irradiation, the solvent
in the gel solution can be in any medium such as water, DI-water,
saline, DMSO, ethanol, PEG, another suitable solvents, and any
mixture of any of the above.
[0098] Irradiation:
[0099] According to another aspect, irradiation can be done on
already gelled substances by mixing with gellants, or
freeze-thawing. Gelled substances can be immersed in a medium such
as water, DI-water, saline, DMSO, ethanol, PEG, and any suitable
solvents, and any mixture of any of the above prior to or during
irradiation. Gelled substances can be placed in an atmosphere
containing air, inert gas, or vacuum for dehydration and further
treated with annealing after irradiation.
[0100] According to another aspect, gelled substances can be
dehydrated in air or in vacuum, after soaking in a medium such as
water, DI-water, saline, DMSO, ethanol, PEG, and any suitable
solvents, and any mixture of any of the above, then irradiated.
Irradiated substances can be further dehydrated in air or in a
vacuum at room temperature or at an elevated temperature.
[0101] According to another aspect, gelled substances can be
dehydrated, and/or thermally annealed before irradiation.
[0102] According to another aspect, irradiation can be of any type,
such as MIR, CISM, CIMA, WIAM, and the like, and sequential with
any of the steps with annealing in between.
Methods and Sequence of Irradiation:
[0103] The selective, controlled manipulation of polymers and
polymer alloys using radiation chemistry can, in another aspect, be
achieved by the selection of the method by which the polymer is
irradiated. The particular method of irradiation employed, either
alone or in combination with other aspects of the invention, such
as the polymer or polymer alloy chosen, contribute to the overall
properties of the irradiated polymer.
[0104] Gamma irradiation or electron radiation may be used. In
general, gamma irradiation results in a higher radiation
penetration depth than electron irradiation. Gamma irradiation,
however, generally provides low radiation dose rate and requires a
longer duration of time, which can result in more in-depth and
extensive oxidation, particularly if the gamma irradiation is
carried out in air. Oxidation can be reduced or prevented by
carrying out the gamma irradiation in an inert gas, such as
nitrogen, argon, neon, or helium, or under vacuum. Electron
irradiation, in general, results in more limited dose penetration
depth, but requires less time and, therefore, reduces the risk of
extensive oxidation if the irradiation is carried out in air. In
addition if the desired dose levels are high, for instance 20 Mrad,
the irradiation with gamma may take place over one day, leading to
impractical production times. On the other hand, the dose rate of
the electron beam can be adjusted by varying the irradiation
parameters, such as conveyor speed, scan width, and/or beam power.
With the appropriate parameters, a 20 Mrad melt-irradiation can be
completed in for instance less than 10 minutes. The penetration of
the electron beam depends on the beam energy measured by million
electron-volts (MeV). Most polymers exhibit a density of about 1
g/cm.sup.3, which leads to the penetration of about 1 cm with a
beam energy of 2-3 MeV and about 4 cm with a beam energy of 10 MeV.
If electron irradiation is preferred, the desired depth of
penetration can be adjusted based on the beam energy. Accordingly,
gamma irradiation or electron irradiation may be used based upon
the depth of penetration preferred, time limitations and tolerable
oxidation levels.
[0105] According to certain embodiments, the cross-linked polymeric
material can have a melt history, meaning that the polymeric
material is melted concurrently with or subsequent to irradiation
for cross-linking. According to other embodiments, the cross-linked
polymeric material has no such melt history.
[0106] Various irradiation methods including IMS, CIR, CISM, WIR,
and WIAM are defined and described in greater detail below for
cross-linked polymeric materials with a melt history, that is
irradiated with concurrent or subsequent melting:
[0107] (i) Irradiation in the Molten State (IMS):
[0108] Melt-irradiation (MIR), or irradiation in the molten state
("IMS"), is described in detail in U.S. Pat. No. 5,879,400. In the
IMS process, the polymer to be irradiated is heated to at or above
its melting point. Then, the polymer is irradiated. Following
irradiation, the polymer is cooled.
[0109] Prior to irradiation, the polymer is heated to at or above
its melting temperature and maintained at this temperature for a
time sufficient to allow the polymer chains to achieve an entangled
state. A sufficient time period may range, for example, from about
5 minutes to about 3 hours.
[0110] Gamma irradiation or electron radiation may be used. In
general, gamma irradiation results in a higher radiation
penetration depth than electron irradiation. Gamma irradiation,
however, generally provides low radiation dose rate and requires a
longer duration of time, which can result in more in-depth
oxidation, particularly if the gamma irradiation is carried out in
air. Oxidation can be reduced or prevented by carrying out the
gamma irradiation in an inert gas, such as nitrogen, argon, neon,
or helium, or under vacuum. Electron irradiation, in general,
results in more limited dose penetration depth, but requires less
time and, therefore, reduces the risk of extensive oxidation if the
irradiation is carried out in air. In addition if the desired dose
levels are high, for instance 20 Mrad, the irradiation with gamma
may take place over one day, leading to impractical production
times. On the other hand, the dose rate of the electron beam can be
adjusted by varying the irradiation parameters, such as conveyor
speed, scan width, and/or beam power. With the appropriate
parameters, a 20 Mrad melt-irradiation can be completed in for
instance in less than 10 minutes. The penetration of the electron
beam depends on the beam energy measured by million electron-volts
(MeV). Most polymers exhibit a density of about 1 g/cm.sup.3, which
leads to the penetration of about 1 cm with a beam energy of 2-3
MeV and about 4 cm with a beam energy of 10 MeV. The penetration of
e-beam is known to increase slightly with increased irradiation
temperatures. If electron irradiation is preferred, the desired
depth of penetration can be adjusted based on the beam energy.
Accordingly, gamma irradiation or electron irradiation may be used
based upon the depth of penetration preferred, time limitations and
tolerable oxidation levels.
[0111] The temperature of melt-irradiation for a given polymer
depends on the DSC (measured at a heating rate of 10.degree. C./min
during the first heating cycle) peak melting temperature ("PMT")
for that polymer. In general, the irradiation temperature in the
IMS process is at least about 2.degree. C. higher than the PMT,
more preferably between about 2.degree. C. and about 20.degree. C.
higher than the PMT, and most preferably between about 5.degree. C.
and about 10.degree. C. higher than the PMT.
[0112] Exemplary ranges of acceptable total dosages are disclosed
in greater detail in U.S. Pat. Nos. 5,879,400, and 6,641,617, and
International Application WO 97/29793. For example, preferably a
total dose of about or greater than 1 MRad is used. More
preferably, a total dose of greater than about 20 Mrad is used.
[0113] In electron beam IMS, the energy deposited by the electrons
is converted to heat. This primarily depends on how well the sample
is thermally insulated during the irradiation. With good thermal
insulation, most of the heat generated is not lost to the
surroundings and leads to the adiabatic heating of the polymer to a
higher temperature than the irradiation temperature. The heating
could also be induced by using a high enough dose rate to minimize
the heat loss to the surroundings. In some circumstance, heating
may be detrimental to the sample that is being irradiated. Gaseous
by-products, such as hydrogen gas when the polymer is irradiated,
are formed during the irradiation. During irradiation, if the
heating is rapid and high enough to cause rapid expansion of the
gaseous by-products, and thereby not allowing them to diffuse out
of the polymer, the polymer may cavitate. The cavitation is not
desirable in that it leads to the formation of defects (such as air
pockets, cracks) in the structure that could in turn adversely
affect the mechanical properties of the polymer and in vivo
performance of the device made thereof.
[0114] The temperature rise depends on the dose level, level of
insulation, and/or dose rate. The dose level used in the
irradiation stage is determined based on the desired properties. In
general, the thermal insulation is used to avoid cooling of the
polymer and maintaining the temperature of the polymer at the
desired irradiation temperature. Therefore, the temperature rise
can be controlled by determining an upper dose rate for the
irradiation.
[0115] In embodiments of the present invention in which electron
radiation is utilized, the energy of the electrons can be varied to
alter the depth of penetration of the electrons, thereby
controlling the degree of cross-linking following irradiation. The
range of suitable electron energies is disclosed in greater detail
in U.S. Pat. Nos. 5,879,400, 6,641,617, and International
Application WO 97/29793. In one embodiment, the energy is about 0.5
MeV to about 12 MeV. In another embodiment the energy is about 1
MeV to 10 MeV. In another embodiment, the energy is about 10
MeV.
[0116] (ii) Cold Irradiation (CIR):
[0117] Cold irradiation is described in detail in U.S. Pat. No.
6,641,617, U.S. Pat. No. 6,852,772, and WO 97/29793. In the cold
irradiation process, a polymer is provided at room temperature or
below room temperature. Preferably, the temperature of the polymer
is about 20.degree. C. Then, the polymer is irradiated. In one
embodiment of cold irradiation, the polymer may be irradiated at a
high enough total dose and/or at a fast enough dose rate to
generate enough heat in the polymer to result in at least a partial
melting of the crystals of the polymer.
[0118] Gamma irradiation or electron radiation may be used. In
general, gamma irradiation results in a higher dose penetration
depth than electron irradiation. Gamma irradiation, however,
generally requires a longer duration of time, which can result in
more in-depth oxidation, particularly if the gamma irradiation is
carried out in air. Oxidation can be reduced or prevented by
carrying out the gamma irradiation in an inert gas, such as
nitrogen, argon, neon, or helium, or under vacuum. Electron
irradiation, in general, results in more limited dose penetration
depths, but requires less time and, therefore, reduces the risk of
extensive oxidation. Accordingly, gamma irradiation or electron
irradiation may be used based upon the depth of penetration
preferred, time limitations and tolerable oxidation levels.
[0119] The total dose of irradiation may be selected as a parameter
in controlling the properties of the irradiated polymer. In
particular, the dose of irradiation can be varied to control the
degree of cross-linking in the irradiated polymer. The preferred
dose level depends on the molecular weight of the polymer and the
desired properties that will be achieved following irradiation. In
general, increasing the dose level with CIR would lead to an
increase in wear resistance.
[0120] Exemplary ranges of acceptable total dosages are disclosed
in greater detail in U.S. Pat. Nos. 6,641,617 and 6,852,772,
International Application WO 97/29793, and in the embodiments
below. In one embodiment, the total dose is about 0.5 MRad to about
1,000 Mrad. In another embodiment, the total dose is about 1 MRad
to about 100 MRad. In yet another embodiment, the total dose is
about 4 MRad to about 30 MRad. In still other embodiments, the
total dose is about 20 MRad or about 15 MRad.
[0121] If electron radiation is utilized, the energy of the
electrons also is a parameter that can be varied to tailor the
properties of the irradiated polymer. In particular, differing
electron energies will result in different depths of penetration of
the electrons into the polymer. The practical electron energies
range from about 0.1 MeV to 16 MeV giving approximate iso-dose
penetration levels of 0.5 mm to 8 cm, respectively. A preferred
electron energy for maximum penetration is about 10 MeV, which is
commercially available through vendors such as Studer (Daniken,
Switzerland) or E-Beam Services (New Jersey, USA). The lower
electron energies may be preferred for embodiments where a surface
layer of the polymer is preferentially cross-linked with gradient
in cross-link density as a function of distance away from the
surface.
[0122] (iii) Warm Irradiation (WIR):
[0123] Warm irradiation is described in detail in U.S. Pat. No.
6,641,617 and WO 97/29793. In the warm irradiation process, a
polymer is provided at a temperature above room temperature and
below the melting temperature of the polymer. Then, the polymer is
irradiated. In one embodiment of warm irradiation, which has been
termed "warm irradiation adiabatic melting" or "WIAM." In a
theoretical sense, adiabatic heating means an absence of heat
transfer to the surroundings. In a practical sense, such heating
can be achieved by the combination of insulation, irradiation dose
rates and irradiation time periods, as disclosed herein and in the
documents cited herein. However, there are situations where
irradiation causes heating, but there is still a loss of energy to
the surroundings. Also, not all warm irradiation refers to an
adiabatic heating. Warm irradiation also can have non-adiabatic or
partially (such as about 10-75% of the heat generated is lost to
the surroundings) adiabatic heating. In all embodiments of WIR, the
polymer may be irradiated at a high enough total dose and/or a high
enough dose rate to generate enough heat in the polymer to result
in at least a partial melting of the crystals of the polymer.
[0124] The polymer may be provided at any temperature below its
melting point but preferably above room temperature. The
temperature selection depends on the specific heat and the enthalpy
of melting of the polymer and the total dose level that will be
used. The equation provided in U.S. Pat. No. 6,641,617 and
International Application WO 97/29793 may be used to calculate the
preferred temperature range with the criterion that the final
temperature of polymer maybe below or above the melting point.
Preheating of the polymer to the desired temperature may be done in
an inert (such as under nitrogen, argon, neon, or helium, or the
like, or a combination thereof) or non-inert environment (such as
air).
[0125] In general terms, the pre-irradiation heating temperature of
the polymer can be adjusted based on the peak melting temperature
(PMT) measure on the DSC at a heating rate of 10.degree. C./min
during the first heat. In one embodiment the polymer is heated to
about 20.degree. C. to about PMT. In another embodiment, the
polymer is pre-heated to about 90.degree. C. In another embodiment,
the polymer is heated to about 100.degree. C. In another
embodiment, the polymer is pre-heated to about 30.degree. C. below
PMT and 2.degree. C. below PMT. In another embodiment, the polymer
is pre-heated to about 12.degree. C. below PMT.
[0126] In the WIAM embodiment of WIR, the temperature of the
polymer following irradiation is at or above the melting
temperature of the polymer. Exemplary ranges of acceptable
temperatures following irradiation are disclosed in greater detail
in U.S. Pat. No. 6,641,617 and International Application WO
97/29793. In one embodiment, the temperature following irradiation
is about room temperature to PMT, or about 40.degree. C. to PMT, or
about 100.degree. C. to PMT, or about 110.degree. C. to PMT, or
about 120.degree. C. to PMT, or about PMT to about 200.degree. C.
These temperature ranges depend on the polymer's PMT--most
hydrogels melt below 100.degree. C. when fully hydrated but the PMT
is much higher with reduced level of hydration. In another
embodiment, the temperature following irradiation is about
145.degree. C. to about 190.degree. C. In yet another embodiment,
the temperature following irradiation is about 145.degree. C. to
about 190.degree. C. In still another embodiment, the temperature
following irradiation is about 150.degree. C.
[0127] In WIR, gamma irradiation or electron radiation may be used.
In general, gamma irradiation results in a higher dose penetration
depth than electron irradiation. Gamma irradiation, however,
generally requires a longer duration of time, which can result in
more in-depth oxidation, particularly if the gamma irradiation is
carried out in air. Oxidation can be reduced or prevented by
carrying out the gamma irradiation in an inert gas, such as
nitrogen, argon, neon, or helium, or under vacuum. Electron
irradiation, in general, results in more limited dose penetration
depths, but requires less time and, therefore, reduces the risk of
extensive oxidation. Accordingly, gamma irradiation or electron
irradiation may be used based upon the depth of penetration
preferred, time limitations and tolerable oxidation levels. In the
WIAM embodiment of WIR, electron radiation is used.
[0128] The total dose of irradiation may also be selected as a
parameter in controlling the properties of the irradiated polymer.
In particular, the dose of irradiation can be varied to control the
degree of cross-linking in the irradiated polymer. Exemplary ranges
of acceptable total dosages are disclosed in greater detail in U.S.
Pat. No. 6,641,617 and International Application WO 97/29793.
[0129] The dose rate of irradiation also may be varied to achieve a
desired result. The dose rate is a prominent variable in the WIAM
process. The preferred dose rate of irradiation would be to
administer the total desired dose level in one pass under the
electron-beam. One also can deliver the total dose level with
multiple passes under the beam, delivering a (equal or unequal)
portion of the total dose at each time. This would lead to a lower
effective dose rate.
[0130] Ranges of acceptable dose rates are exemplified in greater
detail in U.S. Pat. No. 6,641,617 and International Application WO
97/29793. In general, the dose rates will vary between 0.5
Mrad/pass and 50 Mrad/pass. The upper limit of the dose rate
depends on the resistance of the polymer to cavitation/cracking
induced by the irradiation.
[0131] If electron radiation is utilized, the energy of the
electrons also is a parameter that can be varied to tailor the
properties of the irradiated polymer. In particular, differing
electron energies will result in different depths of penetration of
the electrons into the polymer. The practical electron energies
range from about 0.1 MeV to 16 MeV giving approximate iso-dose
penetration levels of 0.5 mm to 8 cm, respectively. The preferred
electron energy for maximum penetration is about 10 MeV, which is
commercially available through vendors such as Studer (Daniken,
Switzerland) or E-Beam Services New Jersey, USA). The lower
electron energies may be preferred for embodiments where a surface
layer of the polymer is preferentially cross-linked with gradient
in cross-link density as a function of distance away from the
surface.
[0132] (iv) Subsequent Melting (SM)--Substantial Elimination of
Detectable Residual Free Radicals:
[0133] Depending on the polymer or polymer alloy used, and whether
the polymer was irradiated below its melting point, there may be
residual free radicals left in the material following the
irradiation process. A polymer irradiated below its melting point
with ionizing radiation contains cross-links as well as long-lived
trapped free radicals. Some of the free radicals generated during
irradiation become trapped in the crystalline regions and/or at
crystalline lamellae surfaces leading to oxidation-induced
instabilities in the long-term (see Kashiwabara, H. S. Shimada, and
Y. Hori, Radiat. Phys. Chem., 1991, 37(1): p. 43-46; Jahan, M. S,
and C. Wang, Journal of Biomedical Materials Research, 1991, 25: p.
1005-1017; Sutula, L. C., et al., Clinical Orthopedic Related
Research, 1995, 3129: p. 1681-1689). The elimination of these
residual, trapped free radicals through heating can be, therefore,
desirable in precluding long-term oxidative instability of the
polymer. Jahan M. S, and C. Wang, Journal of Biomedical Materials
Research, 1991, 25: p. 1005-1017; Sutula, L. C., et al., Clinical
Orthopedic Related Research, 1995, 319: p. 28-4.
[0134] Residual free radicals may be reduced by heating the polymer
above the melting point of the polymer used. The heating allows the
residual free radicals to recombine with each other. If for a given
system the preform does not have substantially any detectable
residual free radicals following irradiation, then a later heating
step may be omitted. Also, if for a given system the concentration
of the residual free radicals is low enough to not lead to
degradation of device performance, the heating step may be
omitted.
[0135] The reduction of free radicals to the point where there are
substantially no detectable free radicals can be achieved by
heating the polymer to above the melting point. The heating
provides the molecules with sufficient mobility so as to eliminate
the constraints derived from the crystals of the polymer, thereby
allowing essentially all of the residual free radicals to
recombine. Preferably, the polymer is heated to a temperature
between the peak melting temperature (PMT) and degradation
temperature (T.sub.d) of the polymer, more preferably between about
3.degree. C. above PMT and T.sub.d, more preferably between about
10.degree. C. above PMT and 50.degree. C. above PMT, more
preferably between about 10.degree. C. and 12.degree. C. above PMT
and most preferably about 15.degree. C. above PMT.
[0136] In certain embodiments, there may be an acceptable level of
residual free radicals in which case, the post-irradiation
annealing also can be carried out below the melting point of the
polymer, the effects of such free radicals can be minimized or
eliminated by an antioxidant.
[0137] (v) Sequential Irradiation:
[0138] The polymer is irradiated with either gamma or e-beam
radiation in a sequential manner. With e-beam the irradiation is
carried out with multiple passes under the beam and with gamma
radiation the irradiation is carried out in multiple passes through
the gamma source. Optionally, the polymer is thermally treated in
between each or some of the irradiation passes. The thermal
treatment can be heating below the melting point or at the melting
point of the polymer. The irradiation at any of the steps can be
warm irradiation, cold irradiation, or melt irradiation, as
described above. For example the polymer is irradiated with 30 kGy
at each step of the cross-linking and it is first heated to about
120.degree. C. and then annealed at about 120.degree. C. for about
5 hours after each irradiation cycle.
[0139] (vi) Blending and Doping:
[0140] As stated above, the cross-liked polymeric material can
optionally have a melt history, meaning it is melted concurrent
with or subsequent to irradiation. The polymeric material can be
blended with an antioxidant prior to consolidation and irradiation.
Also, the consolidated polymeric material can be doped with an
antioxidant prior to or after irradiation, and optionally can have
been melted concurrent with or subsequent to irradiation.
Furthermore, a polymeric material can both be blended with an
antioxidant prior to consolidation and doped with an antioxidant
after consolidation (before or after irradiation and optional
melting). The polymeric material can be subjected to extraction at
different times during the process, and can be extracted multiple
times as well.
[0141] Stabilization of PAA in System:
[0142] 1. Dehydration in air, vacuum, inert gas, and/or solvents.
[0143] Once PVA gels containing PAA are made using any of the above
methods described herein, the gels are dehydrated in one or
combination of the following environments: in air, vacuum, inert
gas, or organic solvents. For example, the gels are dehydrated in
an atmosphere containing 100% air, 100% inert gas, a mixture of one
or more inert gases mixed with 0.1% to 99.9% air, or a mixture of
one or more inert gases containing 0.1% to 99.9% oxygen.
Dehydration of PAA containing PVA gels can render PAA molecules
physically trapped inside the PVA gel network by densification,
pore collapse, or further PVA crystallization.
[0144] 2. Dehydration in air, vacuum, inert gas at elevated
temperature, such as below or above 80.degree. C., for example
above room temperature to about 100.degree. C.
[0145] Once PVA gels containing PAA are made using any of the above
methods, the gels are dehydrated in one or combination of the
following environments: in air, vacuum, and/or inert gas at an
elevated temperature below the melting point of the said gel. For
example, the gels are dehydrated in an atmosphere containing 100%
air, 100% inert gas, a mixture of one or more inert gases mixed
with 0.1% to 99.9% air, or a mixture of one or more inert gases
containing 0.1% to 99.9% oxygen. Dehydration of PAA containing PVA
gels can render PAA molecules physically trapped inside the PVA gel
network by densification, pore collapse, or further PVA
crystallization.
[0146] 3. Dehydration in air, vacuum, inert gas, solvents, followed
by thermal treatment in vacuum, inert gas at temperature above or
below 160.degree. C., for example, above about 80.degree. C. to
about 260.degree. C.
[0147] Once PVA gels containing PAA are made using any of the above
methods 1-6, the gels are dehydrated in one or combination of the
following environments: in air, vacuum, and/or inert gas, at an
elevated temperature below the melting point of the said gel. For
example, the gels are dehydrated in an atmosphere containing 100%
air, 100% inert gas, a mixture of one or more inert gases mixed
with 0.1% to 99.9% air, or a mixture of one or more inert gases
containing 0.1% to 99.9% oxygen. Dehydration of PAA containing PVA
gels can render PAA molecules physically trapped inside the PVA gel
network by densification, pore collapse, or further PVA
crystallization. Subsequent to dehydration, the said gel can be
thermally treated in vacuum, or inert gas at an elevated
temperature higher than 100.degree. C., preferably above or below
160.degree. C., for example, above about 80.degree. C. to about
260.degree. C., for about an hour up to about 20 hours or longer.
Such thermal treatments can improve mechanical strength of the gels
by further increasing PVA crystallinity.
[0148] 4. Thermal treatment under high pressure.
[0149] Thermal treatment method described above also can be done at
an elevated pressure than the ambient atmosphere.
[0150] 5. Cross-linking by anhydrides and esters.
[0151] Thermal treatment methods described above can chemically
cross-link PAA chains by forming anhydrides between carboxylic
acids thus making PAA-interpenetrating network with PVA network.
Hydroxyl groups in PVA and carboxylic acids in PAA also can form
esters during such thermal treatments.
[0152] 6. Cross-linking by gamma, e-beam irradiation.
[0153] In some embodiments radiation cross-linking in the PAA
containing PVA gels processed by methods described here are carried
by gamma or e-beam irradiation. The cross-linking increases the
wear resistance and creep resistance. The cross-linking can be
carried out at any step of the processing/methods described
herein.
[0154] 7. Cross-linking by cross-linking agents.
[0155] Another type of chemical cross-liking method is using
cross-linking agents such as ethyleneglycol dimethacrylate (EGDMA)
to cross-link PAA chains in the PVA-PAA gels processed by methods
described above. Cross-linkers such as glutaraldehyde and
epichlorohydrin can cross-link PVA chains in the said gel to
improve mechanical properties in addition to physical locking of
the incorporated FAA in the said gel.
[0156] 8. Cross-linking of PAA during pH-induced volume
transition.
[0157] The charge density of the PAA chains is pH-tunable which
enables systematic control of the electrostatic repulsion imparted
from the anionic charges. By adjusting the charge density by
lowering the pH of the PAA-containing gel well below its pKa
values, one can increase the number of protonated carboxylates in
PAA, which can bring PAA chains closer and also promote
intramolecular or intermolecular hydrogen bonding in PAA. PAA
chains at such a state are cross-linked among themselves or with
neighboring PVA chains by any of the methods described above.
Increasing the pH of the said gel back to physiological pH value
deprotonates the non-cross-linked acid groups in PAA, whose
electrostatic repulsion will benefit the mechanical integrity of
the gels under repetitive loading condition expected in the joint
space.
[0158] Structural Design for Gradient Properties from PAA
Incorporation:
[0159] 1. Controlled diffusion of PAA into the PVA cryogels for
gradient distribution of PAA in the recipient gel.
[0160] The effects of incorporated FAA into the PVA gels can be
controlled to result in a non-uniform gel with a gradient of
properties, i.e., larger effects from the presence of PAA on the
gel surface than the bulk of the gel by having a higher PAA
concentration on the surface than the bulk. This is achieved by
controlling and/or varying the diffusion rate. Diffusion rate will
be faster with lower the molecular weight of PAA, with larger pores
in the PVA, with increased porosity of PVA, with higher hydration
of the PVA, and the like.
[0161] 2. Layer-by-layer buildup to create "vertical" gradient
properties.
[0162] PVA-PAA gels or PVA-PAA-PEG gels can be built up in a
layer-by-layer fashion by sequentially molding different
concentration solution in the mold to achieve gradient properties.
The gradient is thus disposed in a direction perpendicular to the
direction of deposit. A hot (for example, about 90.degree. C.)
PVA-PAA-PEG mixture solution is poured into a container up to a
certain thickness to form the first layer. The solution in the mold
is gelled by cooling down to the room temperature or lower
temperature. Upon gelling, the first layer in the container is
heated to a temperature below the melting temperature with no
disruption of the formed layer. Another layer of solution is added
from a hot PVA-PAA-PEG mixture to the first layer to ensure
adhesion of the two layers. The second layer can be formed from
same or different composition of the polymer solution, or a new
component can be added in the mixture. The container is again
cooled down to form a layered gel structure. This procedure can be
repeated to the desired number of layers or thickness. Such
layer-by-layer gel formation can be applied to PVA-PEG gels or PVA
cryogel as well, followed by PAA diffusion.
[0163] 3. Gradient effects of thermal treatment.
[0164] Thermal treatment on the PAA containing PVA gels can be
deliberately controlled in a gradient manner by having one of the
surfaces of the dehydrated gel in contact with higher temperature
than the opposite surface of the said gel. The gel surface in
contact with higher temperature will be affected more by heating,
i.e., more cross-linking and higher crystallinity, lower water
content, than the other surface in contact with lower
temperature.
[0165] In other embodiments, creep resistant PVA-hydrogels can be
prepared by several different ways, following various processing
steps in different orders, for example: [0166] Incorporation of
acrylic acid (AA) monomer: [0167] Blending of PVA and AA in
solution with PEG addition; [0168] Diffusion of AA into PVA-PEG
gels; [0169] Freeze-thawing of PVA-AA gels; [0170] Freeze-thawing
of PVA-AA-PEG gels; [0171] Freeze-thawing of PVA gels followed by
diffusion of AA into PVA gels; and/or [0172] All of the above
wherein the AA monomer is polymerized in situ. [0173] Stabilization
of PAA in system: [0174] Densification, collapsing pores (in DP
samples) by dehydration. [0175] Stabilization of AA in system:
[0176] Dehydration in air, vacuum, inert gas, solvents; [0177]
Dehydration in air, vacuum, inert gas at elevated temperature, such
as below or above 80.degree. C., for example above room temperature
to about 100.degree. C.; [0178] Dehydration in air, vacuum, inert
gas, solvents, followed by thermal treatment in vacuum, inert gas
at temperature above or below 160.degree. C., for example, above
about 80.degree. C. to about 260.degree. C.; [0179] All of the
above under high pressure; [0180] Cross-linking by
heating--anhydrides, esters; [0181] Cross-linking by gamma, e-beam
irradiation; [0182] Cross-linking by chemical
agents--glutaraldehyde, epichlorohydrin, EGDMA; and/or [0183]
Densification, collapsing pores (in DP samples) by dehydration.
[0184] According to one embodiment, this invention provides
fabricated PVA-hydrogels, PVA-hydrogel-containing compositions, and
methods of making PVA-hydrogels and PVA-hydrogel-containing
compositions. The invention also provides methods of using the
fabricated PVA-hydrogels and PVA-hydrogel-containing compositions
in treating a subject in need.
[0185] Hydrogels described in the prior art (see for example, U.S.
Pat. Nos. 4,663,358, 5,981,826, and 5,705,780, US Published
Application Nos. 20040092653 and 20040171740) can be used as
starting materials for making PVA-hydrogels of the present
invention by employing methods described herein for the first time.
The PVA-hydrogels provided in the present invention can be used in
a body to augment or replace any tissue such as cartilage, muscle,
breast tissue, nucleus pulposus of the intervertebral disc, other
soft tissue, interpositional devices that generally serves as a
cushion within a joint, and the like.
[0186] PVA-hydrogels generally include polymer, polymer blends, or
copolymers of polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP),
poly ethylene oxide (PEO), Polyacrylic acid (PAA), Poly(methacrylic
acid) (PMAA), alginates, polysaccharides,
polyoxyethylene-polyoxypropylene co-polymers, poly-N-alkylacrylam
ides, poly-N-isopropyl acrylamide (PNIAAm), chondroitin sulfate,
dextran sulfate, dermatin sulfate, or combinations of two or more
thereof.
[0187] PVA-hydrogels, as disclosed herein, comprised of uniformly
distributed hydrogel molecules or hydrogel particles comprising
polyvinyl alcohol (PVA) copolymerized and/or blended with at least
one of the other polymers or gellants, for example, polyvinyl
pyrrolidone (PVP), poly-N-isopropyl acrylamide (PNIPAAm), poly
ethylene oxide (PEO), Polyacrylic acid (PAA), Poly(methacrylic
acid) (PMAA), chondroitin sulfate, dextran sulfate, dermatin
sulfate and the like, or combinations of two or more thereof.
[0188] According to one aspect of the invention, the PVA-hydrogels
comprise polyvinyl alcohol (PVA) copolymerized and/or blended with
at least one of the other polymers.
[0189] According to another aspect of the invention, the hydrogel
solutions comprise polyvinyl alcohol (PVA), Polyacrylic acid (PAA),
Poly(methacrylic acid) (PMAA), polyvinyl pyrrolidone (PVP), poly
ethylene oxide (PEO), poly-N-isopropyl acrylamide (PNIAAm), or
combinations of two or more thereof.
[0190] According to another aspect of the invention, the hydrogel
solution is a polyvinyl alcohol (PVA) solution.
[0191] PVA-hydrogels of the invention can be used in a variety of
fashions in joints in mammals such as human joints. For example, an
interpositional device can be manufactured from the PVA-hydrogels,
which meet required mechanical strength to withstand high loads of
human joints, and can be used in articular cartilage replacement
applications. The interpositional devices typically act as a
cushion within the joint to minimize the contact of the cartilage
surfaces to each other. This is beneficial in patients with
arthritic joints. Early arthritic joints with cartilage lesions can
be treated with such interpositional devices, which minimizes the
contact between the damaged cartilage surfaces of the patient. The
interpositional devices are described by Fell et al. (see U.S. Pat.
Nos. 6,923,831, 6,911,044, 6,866,684, and 6,855,165). These devices
can have a variety of shapes and sizes. For a hydrogel inter
positional device to perform in vivo in the long-term, the device
first needs to have a high creep resistance. This is to minimize
the changes to the shape of the interpositional hydrogel device
during in vivo use. PVA-hydrogel materials of the invention with
increased stiffness display increased creep resistance. The
hydrogel interpositional device according to the invention also
have superior mechanical properties, such as toughness, wear
resistance, high creep resistance, and the like.
[0192] Another method for the use of a hydrogel implant is through
the filling of a cavity in the joint. The cavity can be an existing
one or one that is prepared by a surgeon. A PVA-hydrogel plug can
be inserted into the cavity. The hydrogel plug can be of any shape
and size; for instance it can be cylindrical in shape. In some
embodiments the plug can be oversized to be elevated from the
surrounding cartilage surface. In other embodiments the plug can be
undersized to stay recessed in the cavity. The over-sizing or
under-sizing can be such that the plug can stand proud above the
surrounding cartilage surface or recessed from the surrounding
cartilage surface by about less than 1 mm, by about 1 mm, by more
than about 1 mm, by about 2 mm, by about 3 mm, or by about more
than 3 mm. In some embodiments the hydrogel plug can be slightly
dehydrated to shrink its size and to allow an easy placement into
the cavity. The hydrogel plug then can be hydrated and swollen in
situ to cause a better fit into the cavity. The dehydrated and
re-hydrated dimensions of the hydrogel plug can be tailored to
obtain a good fit, under-sizing, or over-sizing of the plug after
re-dehydration and re-swelling. The re-dehydration in situ can also
be used to increase the friction fit between the plug and the
cavity. This can be achieved by tailoring the dimensions and the
extent of dehydration such that upon re-dehydration the
cross-section of the plug can be larger than the cross-section of
the cavity; by for instance about 1 mm, less than 1 mm, or more
than 1 mm. In some embodiments the cavity can be filled with an
injectable hydrogel system known in the art, such as the one
described by Ruberti and Braithwaite (see US Published Application
Nos. 20040092653 and 20040171740), Muratoglu et al. (International
Application WO 2006/125082), Lowman (US Published Application No.
20040220296), and other injectable systems.
[0193] The present invention also provides methods of fabricating
PVA-hydrogel systems to obtain PVA-hydrogels that can maintain
shape under the high stress of human joints. According to one
aspect of the invention, the PVA-hydrogels are obtained by
improving the stiffness, toughness and strength of hydrogels to
increase resistance to creep and resistance to wear. The invention
provides dehydration methods useful for improving the mechanical
properties of the hydrogel. Various dehydration methods, described
above, can be used together in combinations to improve the
properties of hydrogels. Any of the dehydration methods can be used
either by itself or in combination with the other dehydration
methods to improve the mechanical properties of hydrogels.
[0194] In the case of extreme dehydration of the PVA-hydrogel, it
can be important for some of the applications to subsequently
re-hydrate the PVA-hydrogel at least to some extent to regain the
lubrication imparted by the presence of water for some of the
embodiments. If the heat dehydration is carried out starting with a
hydrogel that contains water and one or more other ingredient(s),
which are in most embodiments non volatile such as low molecular
weight PEG, and others such as PVP, PEO, FAA, PMAA, chondrotin
sulfate, the dehydrated hydrogel is easily re-hydrated to varying
levels. According to one aspect of the invention, the level of
re-hydration following heat dehydration depends on the
concentration of other ingredient(s) in the water phase of the
initial hydrogel before dehydration. In contrast, if the starting
hydrogel contains no other ingredients but water, then the extent
of re-hydration subsequent to heat dehydration is substantially
reduced compared to the re-hydration levels of the hydrogels
dehydrated in the presence other ingredient(s). The presence of the
other ingredient(s) other than water also has implication on the
creep behavior of the hydrogel following heat dehydration and
subsequent re-hydration. The hydrogel is more viscoelastic when it
is heat treated in the presence of other ingredient(s).
[0195] According to another aspect, PVA-hydrogels containing a low
molecular weight ingredient, such as PEG, retain their opacity
during heat dehydration. In contrast, PVA-hydrogels containing no
such ingredients and heat dehydrated under identical conditions
lose their opacity and turn transparent, an indication for the loss
of the molecular porosity. The molecular porosity is thought to be
the free space in the structure where the water molecules penetrate
the hydrogel, thus hydrating it. The loss of the opacity upon heat
dehydration of hydrogels not containing any such ingredient can be
the reason for their substantially reduced ability to re-hydrate.
According to one aspect on the invention, the non-volatile
ingredient remains in the hydrogel structure during heat
dehydration and prevents the collapse of the molecular porosity,
and thus allowing these hydrogels to re-hydrate following heat
dehydration.
[0196] The invention also provides freeze-thaw prepared PVA-PAA
(FT-PVA-PAA) hydrogels, wherein the PVA-PAA-hydrogel is further
treated by heating at around 160.degree. C. Upon re-hydration, the
heated gels remain transparent forming an elastic and tough, almost
rubber-like material. While this material is useful in some
application, it may not be for applications requiring high water
content in the hydrogel. The extent of re-hydration is further
tailored in the heated FT-PVA-PAA by adding an ingredient such as
PEG into the water phase prior to the heating.
[0197] In another embodiment, the PVA-hydrogel implant is packaged
and sterilized. The packaging can be such that the hydrogel device
is immersed in an aqueous solution to prevent dehydration until
implantation, such as during sterilization and storage. The aqueous
solution can be water, deionized water, saline solution, Ringer's
solution, or salinated water. The aqueous solution also can be a
solution of poly-ethylene glycol in water. The solution can be of
less than 5% (wt) in PEG, about 5% (wt), more than about 5% (wt),
about 10% (wt), about 15% (wt), about 20% (wt), about 30% (wt),
about 50% (wt), about 90% (wt) or about 100% (wt). The hydrogel
device also can be sterilized and stored in a non-volatile solvent
or non-solvent.
[0198] The sterilization of the PVA-hydrogel implant can be carried
out through gamma sterilization, heat, gas plasma sterilization, or
ethylene oxide sterilization, for example. According to one
embodiment, the hydrogel is sterilized by autoclave. The
sterilization is carried out at the factory; or alternatively, the
implant is shipped to the hospital where it is sterilized by
autoclave. Some hospitals are fitted with ethylene oxide
sterilization units, which also is used to sterilize the hydrogel
implant.
[0199] In one embodiment, the hydrogel implant is sterilized after
packaging. In other embodiments the hydrogel implant is sterilized
and placed in a sterile aqueous solution.
[0200] In another embodiment, PVA-PAA-hydrogel is prepared using
the freeze-thaw method starting with an aqueous PVA solution (at
least about 10% (wt) PVA, above about 15% (wt) PVA, about 20% (wt)
PVA, about 25% (wt) PVA, about 27% (wt) PVA, about 30% (wt) PVA,
about 35% (wt) PVA, about 40% (wt) PVA, about 45% (wt) PVA, above
about 50% (wt) PVA) and subjecting it to freeze-thaw cycles (at
least 1 cycle, more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more
cycles). The freeze-thaw cycle is defined as cooling the PVA
solution below 0.degree. C. and heating it back up above 0.degree.
C. The PVA-PAA-hydrogel is then subjected to dehydration.
Subsequently, the dehydrated hydrogel is placed in saline solution
for re-hydration. This process results in very little re-hydrated
PVA-PAA-hydrogel with high mechanical strength.
[0201] In another embodiment, the invention provides a process of
modification of PVA-hydrogels to increase water content, improve
lubricity, with least compromise with mechanical strength, such as
creep resistance by addition of hydrophilic ionic molecules such as
PAA by methods of blending prior to gelling and/or diffusion into
the formed gel.
[0202] In another embodiment, the invention provides a process
incorporation of solvents such as PEG during subsequent processing
on PVA-PAA gels to prevent loss of mechanical integrity and
maintain high water affinity by methods of blending PEG during
PVA-PAA gel formation; diffusing PEG into the PVA-PAA gels; and/or
diffusing PEG simultaneously or sequentially as PAA into the PVA
gels.
[0203] In one embodiment of the invention, the PVA:PAA ratio can be
about 99.9:0.1 to 5:5, for example, 99.5:0.5, 99:1, 79:1, 59:1,
39:1, 19:1, 9:1, 8:2, 7:3, 6:4, 5:5, or any ratio thereabout, or
therebetween, with the total polymer content in the mixture at
about 10%, 15%, 20%, 25%, 27%, 30%, 35%, 40%, 45%, 50%, or any
value thereabout, therebetween, or higher. In another embodiment,
the composition ratio of PAA to PVA in the final gel content can be
about 0.1% to 90%. In another embodiment, the polymer content of
the basal PVA-PAA hydrogel can be 10% up to 90%. Average molecular
weight of PAA for blending or diffusion can be about 2,000 up to 1
million.
[0204] According to one aspect of the invention, PAA diffusion can
be done by immersing basal PVA gels in aqueous PAA solutions or in
mixture solutions with PEG or other solvents such as alcohol, DMSO,
NaCl solution, CaCl.sub.2 solution, saline, ringer's solution,
phosphate buffered saline, supercritical fluid, and the like. PAA
diffusion can be done at an elevated temperature, such as below or
above 80.degree. C., for example above room temperature to about
100.degree. C. PAA diffusion can be done in PAA solutions with
concentrations ranging from about 0.1% to 70%.
[0205] In another embodiment, the invention provides a process of
controlled diffusion of PAA into the PVA gels for gradient
distribution of PAA in the recipient gel. PAA containing PVA gels
can be dehydrated in air, vacuum, inert gas, solvents for physical
fixation of PAA in the PVA gel at room temperature, or at an
elevated temperature, such as below or above 80.degree. C., for
example above room temperature to about 100.degree. C. Thermal
treatment following dehydration on PAA containing PVA gels can be
done in vacuum, inert gas, at an elevated temperature, for example,
higher than 100.degree. C., preferably above or below 160.degree.
C., for example, above about 80.degree. C. to about 260.degree. C.,
for 1 hour up to 20 hours or longer for irreversibly linking PAA in
the hydrogel network and improve creep resistance. Thermal
annealing following dehydration on PAA containing PVA gels in
vacuum or inert gas also can be done by heating at heating rates
such as about 0.01.degree. C./min, about 0.1.degree. C./min, about
1.degree. C./min, or about 10.degree. C./min, starting at room
temperature or at an elevated temperature, such as below or above
80.degree. C., for example above room temperature to about
100.degree. C., up to a final temperature higher than about
100.degree. C., preferably above or below 160.degree. C., for
example, above about 80.degree. C. to about 260.degree. C., for
about one hour up to 24 hours or longer.
[0206] Thermal annealing, a post-gelation toughening method to
improve the creep resistance in physically cross-linked PVA
hydrogels, can cause changes in the EWC and lubricity of PVA
hydrogels. By blending PAA in PVA solutions prior to gelation, thus
to form PAA-containing PVA hydrogels, hydrophilicity and
compressive strength of the PVA gels can be increased by imparting
negative charges into the non-charged PVA gel matrix. Thermal
annealing process on PVA-PAA hydrogels also can make gels brittle
due to thermally-induced cross-linking of the PAA and PVA chains,
especially when the annealing is carried out in air. However,
according to an aspect of the invention, the presence of low
molecular weight PEG, such as PEG400, during the thermal annealing,
can alleviate these problems. PEG400 molecules, for example,
residing in PAA-containing PVA hydrogels can alleviate or prohibit
esterification that occurs between the hydroxyl groups of PVA and
the carboxylic acids of PAA during thermal annealing by screening
such functional groups of PVA and PAA in the vicinity. According to
another aspect of the invention, presence of PEG during thermal
annealing can significantly improve the surface lubricity of the
PAA containing PVA hydrogels.
[0207] In another embodiment, presence of PEG during thermal
annealing can significantly improve the surface lubricity of the
PAA containing PVA hydrogels. PEG can protect the pores in the gels
from collapsing during the annealing process so that the preserved
pores can retain water content easily upon rehydration, which is
favorable for surface lubrication. PEG is known to undergo
thermo-oxidative degradation in the presence of air. During thermal
degradation in air, PEG reacts with oxygen and forms thermally
labile .alpha.-hydroperoxide, which can produce low molecular
weight esters such as formic ester. Such degradation process of PEG
in air can be further facilitated when carboxylic groups from other
polymeric components co-exist in the gel, which can be, for
example, poly(acrylic acid) in the present invention. Thermal
degradation products or derivatives of PEG can react with PVA or
PAA in the gels during the annealing process to create more
negatively charged groups on the gel, which can further improve
surface lubricity of the gels.
[0208] Two types of gels, for example, PEG-doped (Type 1) and
PEG-blended (Type 2) with different blending ratios of PVA:PAA can
be used.
[0209] Type 1--PEG-Doped Gels:
[0210] PVA-PAA solution is poured into pre-heated glass sheet molds
and subjected to three freeze-thaw cycles (about 16 hour-freezing
at -17.degree. C. and about 8 hour-thawing at room temperature).
Subsequently, the molded gels are immersed in 100% PEG (PEG-doping
by immersion) followed by vacuum dehydration and annealing at about
160.degree. C. under inert environment (such as in argon) in a
self-pressurized vessel or in air for about one hour or more.
[0211] Type 2--PEG-Blended Gels:
[0212] About 15 why % PEG (with respect to the total PEG and the
amount of water in the PVA-PAA mixture) is pre-heated at about
90.degree. C. and added to a hot PVA-PAA mixture to form
PVA-PAA-PEG homogeneous solution. Resulting homogeneous polymer
blend is poured into a pre-heated glass mold. Subsequently, the
molded gel is subjected to three freeze-thaw cycles followed by
vacuum dehydration and annealing at about 160.degree. C. under
inert environment (such as in argon) in a self-pressurized vessel
or in air for about one hour or more. Each gel sheet is immersed in
deionized (DI) water to remove residual PEG and to reach an
equilibrated rehydration.
[0213] The non-annealed "PVA only" (that is, PVA with no PAA) gels
in both Types 1 and 2 are made by rehydrating the gels in DI water
immediately upon removal from the molds after completion of the
freeze-thaw cycles.
[0214] According to another aspect of invention, combination of the
PEG doping step with the presence of PAA in the PVA hydrogels can
increase equilibrium water content and lower the coefficient of
friction in PVA hydrogels. For example, during the PEG-doping step
as described in Type 1 gels, PEG can diffuse in and fill the micro-
and nano-pores existing in the PAA-containing PVA hydrogel gels
upon gelation, subsequently protect the pores from collapsing
during annealing. Upon rehydration following the annealing process,
the preserved pores can accelerate water absorbency in the PVA-PAA
gels, resulting in higher EWC and improved surface lubricity than
non PEG-doped PVA-PAA gels where the pores are presumably
collapsed.
[0215] In another embodiment, PVA:PAA ratio can be in about
99.9:0.1 to 5:5, for example, 99.5:0.5, 99:1, 79:1, 59:1, 39:1,
19:1, 9:1, 8:2, 7:3, 6:4, 5:5, or any ratio thereabout, or
therebetween, with the total polymer content in the mixture at
about 10%, 15%, 20%, 25%, 27%, 30%, 35%, 40%, 45%, 50%, any value
thereabout, therebetween, or higher.
[0216] According to another aspect of invention, pH-induced
phase-separation of PVA-FAA solutions into the PVA-rich and
PAA-rich domains prior to gelation can increase creep resistance of
PAA-containing PVA hydrogels. FAA is known to lower crystallization
of PVA due to hindrance of carboxylic groups when coexisting with
PVA in the molecular level. Since the mechanical strength of the
PVA hydrogel comes from degree of PVA crystallinity in the
physically crosslinked PVA hydrogels, the presence of FAA chains
that hinders crystallization of PVA chains nearby can compromise
the mechanical strength of the PVA hydrogels. However, the presence
of PAA increases the equilibrium water content and provides high
surface lubricity in annealed PVA hydrogels. Therefore, if PAA
chains are separated from PVA chains in the immiscible blends of
PVA and PAA, PVA chains in the separated PVA domains can further
crystallize without disturbance from PAA through thermal annealing
process, while PAA chains still can maintain high water
retainability which imparts surface lubricity upon rehydration. The
carboxylic acid groups in PAA chains are almost 100% protonated at
lower pH values than pH 1.5. Carboxylic acids in PAA actively form
hydrogen-bonds with hydroxyl groups in PVA chains to promote
miscibility among PVA and PAA chains at the acidic regime with low
pH. However, when PAA molecules are partially ionized with
increasing pH, the hydrogen bonds between PAA and PVA chains start
to break, lowering the miscibility of PVA and PAA, finally leading
to an immiscible solution of PVA-PAA mixture.
[0217] With further increase of solution pH above a certain pH
value (which is the "miscibility transition inducing" pH
(pH.sub.mt)), at which the intermolecular interaction between PVA
and PAA no longer favors PVA-PAA complex configuration, PVA-PAA
mixture finally becomes an immiscible solution. For example, for
making FAA-containing PVA hydrogel with 25% total polymer of 19:1
PVA:PAA ratio, the native pH of an aqueous PAA (1.654 w/w %)
solution prior to dissolving PVA powder is about 3.0 at room
temperature. Such composition without any additional pH-adjustment
forms a completely clear miscible PVA-PAA solution with added PVA
at 90.degree. C. On the other hand, when the pH of 1.654 w/w % PAA
solution is increased to a value of pH 5.5 prior to addition of PVA
powder, the final PVA-PAA mixture turns into a slightly opaque
immiscible blend. Therefore, the pH.sub.mt at which PVA-PAA
solutions with 25% total polymer having a PVA:PAA ratio of 19:1
turn from miscible to immiscible blends can be a value between
about 3.0 and about 5.5. The pH.sub.int can vary depending on
several factors such as the total polymer concentration, molecular
weight of each polymer, PVA:PAA ratio, salt concentration or ionic
strength of the solution and the like. By adjusting the pH values
of the PVA-PAA solutions below or above the pH.sub.mt, the
miscibility of PVA-PAA solutions can be manipulated prior to
gelation. Hence the molecular interaction among PVA and PAA chains
during the gelation and the post-gelation process can be controlled
by pH of the solution. Once the PAA-rich and PVA-rich domains are
phase-separated in the immiscible PVA-PAA solution above the
pH.sub.mt, crystallization of PVA chains are less likely to be
affected by the hindrance of FAA chains, thereby ultimately
improving the creep resistance of the PAA containing PVA hydrogels
through achieving high degree of PVA crystallinity.
[0218] According to another aspect of the invention, above
described processes also can be carried under high pressure
environment. The thermal treatment method described herein also can
be carried out at an elevated pressure than the ambient
atmosphere.
[0219] According to another aspect of the invention, cross-linking
of PAA in PVA gels with or without PEG can be done by gamma or
e-beam irradiation. Cross-linking of PAA in PVA gels with or
without PEG can be done by chemical cross-liking method using
cross-linking agents such as ethyleneglycol dimethacrylate (EGDMA).
Cross-linking density of PAA in PVA gels can be controlled through
pH-adjustment prior to cross-linking by altering the number of
protonated carboxylates in PAA chains.
[0220] According to another aspect of the invention, "vertical"
gradient properties of the final gel can be formed by composition
control, for example, a) Layer-by-layer buildup of PVA-PAA gels
with varying composition ratio of PVA to PAA in each layer by
adding one layer at a time in repeated freeze-thawing process; b)
Layer-by-layer buildup of PVA-PAA-PEG gels with varying composition
ratio of PVA to PAA or PVA to PEG in each layer by adding one layer
at a time in repeated freeze-thawing process or theta-gelling
process; and c) co-extrusion to form layers of PVA/PAA and/or
PV/PEG/PAA of different concentrations.
[0221] According to another aspect of the invention, the "vertical"
gradient properties of the final gel can be also formed by heating
condition control by a) having one of the surfaces of the
dehydrated gel in contact with higher temperature than the opposite
surface of the said gel; and b) having only one of the surfaces of
the non-PEG containing dehydrated gel in contact with PEG during
heating; and c) having one of the surfaces of the non-PEG
containing, dehydrated gel in contact with PEG and higher
temperature than the opposite surfaces of the said gel.
[0222] In one embodiment of the invention, PEG is used as a
non-volatile non-solvent for PVA hydrogels. DMSO is used instead of
water in preparing the aqueous PVA-PAA-solution, the precursor to
the hydrogel.
[0223] In one embodiment of the invention, PEG solution is a
solution of PEG in a solvent (preferably water, ethanol, ethylene
glycol, DMSO, or others). The solution concentration can be
anywhere between 0.1% (wt) PEG and 99.9% (wt) PEG. The PEG in the
solution can be of different molecular weights (preferably 300,
400, or 500 g/mol, more than 300 g/mol, 1000 g/mol, 5000 g/mol or
higher). The PEG in the solution can be a blend of different
average molecular weight PEGs.
[0224] In another embodiment, PEG containing PVA-PAA-hydrogel is
prepared using the freeze-thaw method starting with an aqueous PVA
solution (at least about 10% (wt) PVA, about 15% (wt) PVA, about
20% (wt) PVA, about 25% (wt) PVA, about 27% (wt) PVA, about 30%
(wt) PVA, about 35% (wt) PVA, about 40% (wt) PVA, about 45% (wt)
PVA, about above 50% (wt) PVA) and subjecting it to freeze-thaw
cycles (at least 1 cycle, more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10
or more cycles). At this step the PVA-PAA-hydrogel can be
optionally placed in saline to reach full hydration. Subsequently,
the gel is placed in a low molecular weight PEG solution. This is
to dope the hydrogel with the non-solvent PEG. The duration of PEG
solution soak can be varied to either reach a uniform equilibrium
PEG content throughout the hydrogel or to reach a non-uniform PEG
distribution (by shortening the soak duration). The latter results
in PEG-rich skin and a gradient of PEG concentration within the
PVA-PAA-hydrogel.
[0225] In another embodiment, PEG containing PVA hydrogel is
prepared by starting with an aqueous PVA solution (at least about
10% (wt) PVA, above about 15% (wt) PVA, about 20% (wt) PVA, about
25% (wt) PVA, about 27% (wt) PVA, about 30% (wt) PVA, about 35%
(wt) PVA, about 40% (wt) PVA, about 45% (wt) PVA, about above 50%
(wt) PVA) and mixing it with a low molecular weight PEG solution at
an elevated temperature (above room temperature or above 50.degree.
C.). Upon cooling down to room temperature, the mixture forms a
PVA-PAA-hydrogel containing water and the non-solvent PEG. In
another embodiment, the hot PVA-PAA/PEG mixture is not cooled to
room temperature but instead is subjected to freeze-thaw
cycles.
[0226] In another embodiment, PVA-PAA-hydrogel is heat dehydrated.
The PVA-PAA-hydrogel contains PEG during heat dehydration (or
heating). The heat dehydration is carried out at about 40.degree.
C., at above about 40.degree. C., at about 80.degree. C., at above
80.degree. C., at 90.degree. C., at about 100.degree. C., at above
100.degree. C., at about 150.degree. C., at about 160.degree. C.,
at above 160.degree. C., at about 180.degree. C., at above
180.degree. C., at about 200.degree. C., or at above 200.degree. C.
In another embodiment, the dehydration is carried out at about
40.degree. C., about 80.degree. C., about 90.degree. C., about
100.degree. C., about 150.degree. C., about 160.degree. C., about
180.degree. C., about 200.degree. C., or above 200.degree. C. The
duration and the temperature of the thermal treatment depends on
the size and hydration level of the hydrogel, for example, the
duration can be for about an hour or less, about 5 hours, about 10
hours, about 24 hours, several days, or a few weeks. The heat
dehydration can be carried out in any environment, preferably in an
inert gas like nitrogen or argon or in vacuum. The heat dehydration
also can be carried out in air or acetylene gas or mixture of a
number of gases. The heat dehydration can be carried out either by
placing the hydrogel in an already heated environment to achieve a
higher rate of heat dehydration or by heating the hydrogel slowly
to achieve a slower rate of heat dehydration. The rate of heat
dehydration can be such that the hydrogel loses weight from removal
of water at a rate of 1% weight loss per day, 10% weight loss per
day, 50% weight loss per day, 1% weight loss per hour, 10% weight
loss per hour, 50% weight loss per hour, 1% weight loss per minute,
5% weight loss per minute, 10% weight loss per minute, 50% weight
loss per minute or any amount thereabout or therebetween. The rate
of heat dehydration depends on the rate at which the temperature is
raised and the size of the hydrogel. Prior to heat dehydration, the
hydration level of the hydrogel can be reduced by vacuum
dehydration. Subsequent to the heat dehydration the hydrogel is
placed in saline solution for re-hydration. This results in good
levels of re-hydration in the PVA hydrogel resulting in high
mechanical strength and good lubrication when articulating against
human cartilage or other hydrophilic surfaces. This hydrogel is
expected to maintain its hydrogen bonded structure, thus is not be
subject to dissolution over long-term in water, saline or bodily
fluid.
[0227] Although the description and examples are given for a
PVA-hydrogel systems, but can be applied to any hydrogel system of
a polymeric structure, that is, with long-chain molecules.
Therefore, the invention provides hydrogel systems that includes,
but not limited to, PVA as the base material.
[0228] According to one aspect of the invention, polyvinyl alcohol
(PVA) can be used as the base hydrogel. The base PVA-hydrogel can
be prepared by the well-known freeze-thaw method by subjecting a
PVA solution (PVA can be dissolved in solvents such as water or
DMSO) to one or multiple cycles of freeze-thaw. PVA solution used
in the freeze-thaw method can contain another ingredient like PEG.
The base PVA-hydrogel also can be prepared by radiation
cross-linking of a PVA solution. Another method of preparing the
PVA-hydrogel can be used to blend a PVA solution with a gellant
such as (PEG) at an elevated temperature and cooling down to room
temperature.
[0229] In one embodiment, the hydrogel can be of any shape, such a
cubical shape, cylindrical shape, rectangular prism shape, or
implant shape.
[0230] In another embodiment, NIPAAm can be used as the base
hydrogel. The base NIPAAm hydrogel can be prepared by radiation
cross-linking of a NIPAAm solution. Alternatively, the methods
described by Lowman et al. can be used.
[0231] In another embodiment, a topological gel (TP) can be used as
the base hydrogel. The base TP hydrogel can be prepared by methods
described by Tanaka et al. (see Progress in Polymer Science, 2005,
30:1-9). The polymer chains in TP gels are flexibly bound by
cross-linkers that are sliding along the individual chain.
[0232] In the following embodiments, a nanocomposite (NC) gel
structure can be used as the base hydrogel. The base NC hydrogel
can be prepared by methods described by Tanaka et al. (see Prog.
Polym. Sci. 2005, 30:1-9).
[0233] In some of the embodiments a dehydrated hydrogel can be used
as the base hydrogel. The level of dehydration can be controlled
such that the base hydrogel contains between 99% and 1% water, more
preferably between 99% and 5% water, more preferably between 99%
and 25% water, more preferably between 99% and 50% water, more
preferably between 99% and 75% hydrogel, more preferably about 70%
(wt) water, or 80% (wt) water.
[0234] The water content of the hydrogel can be determined by
measuring the weight change of between its equilibrium hydration
level and its dehydrated level.
[0235] In some embodiments, a hot solution of PVA/PAA/PEG in water
is cooled down to room temperature and is used in its "as-gelled"
form.
[0236] According to one aspect of the invention, the
PVA-PAA-PEG-hydrogel is immersed in water, deionized water, saline
solution, phosphate buffered saline solution, Ringer's solution or
salinated water to remove the PEG. The process is called the
dePEGing process. During dePEGing the hydrogel also absorbs water
approaching equilibrium water content. Therefore, dePEGing also can
be a re-hydration process.
[0237] In another embodiment, the dehydrated hydrogel is
re-hydrated. In some of the embodiments, the re-hydrated hydrogel
contains less water than the hydrogel did before the dehydration
step.
[0238] In some embodiments, the hydrogel dimensions are large
enough so as to allow the machining of a medical device.
[0239] Dehydration of the hydrogel can be achieved by a variety of
methods. For instance, the hydrogel can be placed in vacuum at room
temperature or at elevated temperatures to drive out the water and
cause dehydration. The amount of vacuum can be reduced by adding
air or inert gas to the vacuum chamber where the hydrogel is placed
during dehydration. Dehydration of the hydrogel also can be
achieved by keeping it in air or inert gas at room temperature or
at an elevated temperature. Dehydration in air or inert gas also
can be carried out at temperatures lower than room temperature. In
many embodiments, if the dehydration is carried out at elevated
temperatures, it is necessary to keep the temperature below the
melting point of the hydrogel. However, the melting point of the
hydrogel can increase during the dehydration step and make it
possible to go to higher temperatures as the dehydration evolves.
Dehydration of the hydrogel also can be carried out by placing the
hydrogel in a solvent. In this case the solvent drives the water
out of the hydrogel. For example, placing of PVA-PAA-hydrogel in a
low molecular weight PEG (higher than 100 g/mol, about 300-400
g/mol, about 500 g/mol) can cause dehydration of the
PVA-PAA-hydrogel. In this case the PEG can be used as pure or in a
solution. The higher the PEG concentration the higher the extent of
dehydration. The solvent dehydration also can be carried out at
elevated temperatures. These dehydration methods can be used in
combination with each other.
[0240] Re-hydration of the hydrogel can be done in water containing
solutions such as, saline, water, deionized water, salinated water,
or an aqueous solution or DMSO.
[0241] In some embodiments, the hydrogel is shaped into a medical
device and subsequently dehydrated. The dehydrated implant is then
re-hydrated. The initial size and shape of the medical implant is
tailored such that the shrinkage caused by the dehydration and the
swelling caused by the subsequent re-hydration (in most embodiments
the dehydration shrinkage is larger than the re-hydration swelling)
result in the desired implant size and shape that can be used in a
human joint.
[0242] In certain embodiments, the PVA-PAA-hydrogel can be machined
into a desired shape to act as medical device, such as a kidney
shaped interpositional device for the knee, a cup shaped
interpositional device for the hip, a glenoid shaped
interpositional device for the shoulder, other shapes for
interpositional devices for any human joint. Also the machining of
the PVA-PAA-hydrogel can result in a cylindrical, cuboid, or other
shapes to fill cartilage defects either present in the joint or
prepared by the surgeon during the operation.
[0243] The PVA-PAA-hydrogel medical device can be an
interpositional device such as a unispacer, to act as a free
floating articular implant in a human joint, such as the knee
joint, the hip joint, the shoulder joint, the elbow joint, and the
upper and lower extremity joints.
[0244] In some of the embodiments, the PVA-PAA-hydrogel is placed
in 100% PEG to dehydrate the hydrogel. Subsequently the dehydrated
gel is placed in saline solution for re-hydration. This process
decreases the equilibrium water content in the gel, and hence
further improves the mechanical properties of the hydrogel.
[0245] In other embodiments, the PVA-PAA-hydrogel is placed in a
PEG-water solution for controlled dehydration followed by
re-hydration in saline. The concentration of the PEG-water solution
can be tailored to achieve desired level of dehydration of the
hydrogel. Higher dehydrations provide more improvements in
mechanical properties and at lower dehydrations the improvement is
less. In some applications, it is desirable to achieve a lower
stiffness; therefore a lower PEG and/or water concentration
solution can be used for the dehydration process.
[0246] In some embodiments the PVA-PAA-hydrogel is dehydrated in
vacuum at room temperature or at an elevated temperature. The
vacuum dehydration can be carried out at about 10.degree. C., above
about 10.degree. C., about 20.degree. C., about 30, 40, 50, 60, 75,
80, 90.degree. C., about 100.degree. C. or above 100.degree. C., or
at 130.degree. C. or any temperature thereabout or
therebetween.
[0247] In some embodiments the vacuum dehydration of the
PVA-PAA-hydrogel is first carried out at room temperature until a
desired level of dehydration is reached; thereafter the temperature
is increased to further dehydrate the hydrogel. The temperature is
increased, preferably to above about 100.degree. C., to above or
below 160.degree. C., for example, above about 80.degree. C. to
about 260.degree. C.
[0248] In some embodiments, the PVA-PAA-hydrogel is heated in air
or inert gas or partial vacuum of inert gas for dehydration.
[0249] In some of these embodiments, the PVA-PAA-hydrogel is vacuum
dehydrated before heating in air or inert gas.
[0250] In some embodiments, the heating of the PVA-PAA-hydrogel is
carried out slowly; for example at less than about 1.degree.
C./min, at more than about 1.degree. C./min, at 2, 5, 10.degree.
C./min or faster. Slower heating rates results in stronger gels
than higher heating rates with some of the PVA-hydrogel
formulations.
[0251] In most embodiments the finished medical device is packaged
and sterilized.
[0252] In some of the embodiments the hydrogel is subjected to
dehydration steps. The dehydration is carried out in air or in
vacuum or at an elevated temperature (for instance heating at above
or below 160.degree. C., for example, above about 80.degree. C. to
about 260.degree. C.). The dehydration causes loss of water hence a
reduction in volume accompanied by a reduction in weight. The
weight loss is due to loss of water. The reduction in volume on the
other hand could be due to the loss of water or further
crystallization of the hydrogel. In some embodiments the
dehydration is carried out by placing the hydrogel in a low
molecular weight polymer (for instance placing a PVA-PAA-hydrogel
in a PEG solution). In some cases the dehydration is caused by loss
of water, but in most cases, there is also uptake of the
non-solvent by the hydrogel. Therefore, the weight change of the
hydrogel is the sum of loss of water and uptake of the non-solvent.
The change in volume in this case is due to loss of water, uptake
of the non-solvent, further crystallization of the hydrogel, or
partial collapse of the porous structure of the non-solvent that is
not occupying the space that water was filling in the pores.
[0253] In some of the embodiments, the hydrogel is attached to a
metal piece. The metal piece is a porous backside surface that is
used for bone-in-growth in the body to fix the hydrogel implant in
place. The metal piece attachment to the hydrogel can be achieved
by having a porous surface on the substrate where it makes contact
with the hydrogel; the porous surface can be infiltrated by the
gelling hydrogel solution (for instance a hot PVA-PAA and/or PEG
mixture in water); when the solution forms a hydrogel, the hydrogel
can be interconnected with the metal piece by filling the porous
space.
[0254] In some embodiments, there can be more than one metal piece
attached to the hydrogel for fixation with the hydrogel in the body
to multiple locations.
[0255] In some embodiments, the hydrogel/metal piece construct can
be used during the processing steps described above, such as
solvent dehydration, non-solvent dehydration, irradiation,
packaging, sterilization, and the like.
[0256] In some of the embodiments the hydrogel contains hyaluronic
acid (HA), either by having HA present in the solutions used to
make the hydrogel and/or by diffusing HA into the hydrogel. In some
of the embodiments the HA-containing hydrogel is irradiated. The
irradiation can be carried out before, after, or during the
processing steps such as vacuum dehydration, non-solvent
dehydration, re-hydration, and/or heating. The irradiation
cross-links the hydrogel matrix and in some embodiments also forms
covalent bonds with the HA. Addition HA to some of the hydrogels
increases the lubricity of the hydrogel implant. It can be
beneficial for the PVA-PAA-hydrogels to contain substantially
reduced water content.
[0257] In some embodiments, the hydrated hydrogel implants are
slightly heated at the surface to partially melt the hydrogel and
allow it to reform with more uptake and lubricity.
[0258] In some embodiments, a microwave oven can be used to prepare
the PVA solution. The PVA powder is place in water and the mixture
is heated in a microwave oven to form a solution.
[0259] In some of the embodiments the heat dehydration or heating
of the hydrogel is carried out in a microwave oven.
[0260] According to one embodiment of the invention, PVA-PAA-gel is
prepared by a process comprising the steps of: providing polymeric
material such as PVA powder; mixing with water at temperature above
the room temperature (such as at about 50.degree. C.-60.degree.
C.), thereby forming a solution; subjecting the solution to at
least one freeze-thaw cycle or heating to a temperature below the
melting temperature such as about 80.degree. C.; cooling the heated
solution to an ambient temperature such as room temperature,
thereby forming a hydrogel (which is generally uniform, may also
contain hydrogel particles); and/or dehydrating the hydrogel,
thereby forming the PVA-PAA-hydrogel.
[0261] Embodiments and aspects of the invention also include:
[0262] 1. PVA-hydrogels that are capable of re-hydration following
dehydration, wherein the PVA-hydrogel is capable of re-hydration
following dehydration, wherein a) the dehydration reduces the
weight of the hydrogel, for example, by more than about 34%; and b)
the re-hydration results increase in equilibrium water content in
the re-hydrated hydrogel, for example, at least about 46%.
[0263] 2. PVA-hydrogels with biaxial orientation.
[0264] 3. PVA-hydrogels with uniaxial orientation.
[0265] 4. PVA-hydrogels with a high ultimate tensile strength.
[0266] 5. Dehydration of a PVA-hydrogel containing water and/or one
or more other ingredients (for example, PEG or Salt), wherein
[0267] a. the ingredient is non-volatile such as PEG; [0268] b. the
ingredient is at least partially miscible with water; [0269] c. at
least 0.1% of the hydrogel's weight constitutes one or more
non-volatile ingredients, such as PEG, hydrocarbons, and the like;
[0270] d. the ingredients are water miscible polymer such as PEO,
Pluronic, amino acids, proteoglycans, polyvinylpyrrolidone,
polysaccharides, dermatin sulfate, keratin sulfate, chondroitin
sulfate, dextran suflate, and the like; [0271] e. the ingredient is
selected from the group of PEG, salt, NaCl, KCl, CaCl.sub.2,
vitamins, carboxylic acids, hydrocarbons, esters, amino acids, and
the like; [0272] f. the ingredient is PEG, wherein [0273] i. PEG of
different molecular weights, or [0274] ii. blends of PEGs, [0275]
g. the dehydration is carried out by placing in a non-solvent,
wherein [0276] i. the non-solvent is selected from PEG, alcohols
(such as isopropyl alcohol), acetones, saturated salinated water,
aqueous solution of a salt of an alkali metal, vitamins, carboxylic
acids, and the like, or [0277] ii. the non-solvent contains more
than one ingredients such as water, PEG, vitamins, polymers,
proteoglycans, carboxylic acids, esters, and the like. [0278] h.
the dehydration is carried out by leaving the hydrogel in air;
[0279] i. the dehydration is carried out by placing the hydrogel in
vacuum; [0280] j. the dehydration is carried out by placing the
hydrogel in vacuum at room temperature; [0281] k. the dehydration
is carried out by placing the hydrogel in vacuum at an elevated
temperature; [0282] l. the dehydration is carried out by heating
the hydrogel in air or inert gas to elevated temperature, wherein
[0283] i. the heating rate is slow, [0284] ii. the heating rate is
fast, or [0285] iii. the heating follows the vacuum or air
dehydration; and [0286] m. the dehydrated hydrogel is re-hydrated
[0287] i. by placing in water, saline solution, Ringer's solution,
salinated water, buffer solution, and the like, [0288] ii. by
placing in a relative humidity chamber, or [0289] iii. by placing
at room temperature or at an elevated temperature.
[0290] Each composition and attendant aspects, and each method and
attendant aspects, which are described above can be combined with
another in a manner consistent with the teachings contained herein.
According to the embodiments of the inventions, all methods and the
steps in each method can be applied in any order and repeated as
many times in a manner consistent with the teachings contained
herein.
DEFINITIONS
[0291] The term "supercritical fluid" refers to what is known in
the art, for example, supercritical propane, acetylene, carbon
dioxide (CO.sub.2). In this connection the critical temperature is
that temperature above which a gas cannot be liquefied by pressure
alone. The pressure under which a substance may exist as a gas in
equilibrium with the liquid at the critical temperature is the
critical pressure. Supercritical fluid condition generally means
that the fluid is subjected to such a temperature and such a
pressure that a supercritical fluid and thereby a supercritical
fluid mixture is obtained, the temperature being above the
supercritical temperature, which for CO.sub.2 is 31.3.degree. C.,
and the pressure being above the supercritical pressure, which for
CO.sub.2 is 73.8 bar.
[0292] The term "heating" refers to thermal treatment of the
polymer at or to a desired heating temperature. In one aspect,
heating can be carried out at a rate of about 10.degree. C. per
minute to the desired heating temperature. In another aspect, the
heating can be carried out at the desired heating temperature for
desired period of time. In other words, heated polymers can be
annealed or continued to heat at the desired temperature for a
desired period of time. Heating time at or to a desired heating
temperature can be at least 1 minute to 48 hours to several weeks
long. In one aspect the heating time is about 1 hour to about 24
hours. Heating temperature refers to the thermal condition for
heating in accordance with the invention.
[0293] The term "annealing" refers to heating the hydrogels below
its peak melting point. Annealing time can be at least 1 minute to
several days long. In one aspect the annealing time is about 4
hours to about 48 hours, preferably 24 to 48 hours and more
preferably about 24 hours. "Annealing temperature" refers to the
thermal condition for annealing in accordance with the invention.
In certain embodiments, the term "annealing" refer as a type of
thermal treatment.
[0294] At any step of manufacture, the hydrogel can be irradiated
by e-beam or gamma to cross-link. The irradiation can be carried
out in air, in inert gas, in sensitizing gas, or in a fluid medium
such as water, saline solution, polyethylene-glycol solution, and
the like. The radiation dose level is between one kGy and 10,000
kGy, preferably 25 kGy, 40 kGy, 50 kGy, 200 kGy, 250 kGy, or
above.
[0295] The terms "about" or "approximately" in the context of
numerical values and ranges refers to values or ranges that
approximate or are close to the recited values or ranges such that
the invention can perform as intended, such as having a desired
degree of cross-linking, creep resistance, lubricity and/or
toughness, as is apparent to the skilled person from the teachings
contained herein. This is due, at least in part, to the varying
properties of polymer compositions. Thus these terms encompass
values beyond those resulting from systematic error. These terms
make explicit what is implicit.
[0296] "Irradiation", in one aspect of the invention, the type of
radiation, preferably ionizing, is used. According to another
aspect of the invention, a dose of ionizing radiation ranging from
about 25 kGy to about 1000 kGy is used. The radiation dose can be
about 25 kGy, about 50 kGy, about 65 kGy, about 75 kGy, about 100
kGy, about 150, kGy, about 200 kGy, about 300 kGy, about 400 kGy,
about 500 kGy, about 600 kGy, about 700 kGy, about 800 kGy, about
900 kGy, or about 1000 kGy, or above 1000 kGy, or any value
thereabout or therebetween. Preferably, the radiation dose can be
between about 25 kGy and about 150 kGy or between about 50 kGy and
about 100 kGy. These types of radiation, including gamma and/or
electron beam, kills or inactivates bacteria, viruses, or other
microbial agents potentially contaminating medical implants,
including the interfaces, thereby achieving product sterility. The
irradiation, which may be electron or gamma irradiation, in
accordance with the present invention can be carried out in air
atmosphere containing oxygen, wherein the oxygen concentration in
the atmosphere is at least 1%, 2%, 4%, or up to about 22%, or any
value thereabout or therebetween. In another aspect, the
irradiation can be carried out in an inert atmosphere, wherein the
atmosphere contains gas selected from the group consisting of
nitrogen, argon, helium, neon, or the like, or a combination
thereof. The irradiation also can be carried out in a sensitizing
gas such as acetylene or mixture or a sensitizing gas with an inert
gas or inert gases. The irradiation also can be carried out in a
vacuum. The irradiation can also be carried out at room
temperature, or at between room temperature and the melting point
of the polymeric material, or at above the melting point of the
polymeric material. Subsequent to the irradiation step the hydrogel
can be melted or heated to a temperature below its melting point
for annealing. These post-irradiation thermal treatments can be
carried out in air, PEG, solvents, non-solvents, inert gas and/or
in vacuum. Also the irradiation can be carried out in small
increments of radiation dose and in some embodiments these
sequences of incremental irradiation can be interrupted with a
thermal treatment. The sequential irradiation can be carried out
with about 1, 10, 20, 30, 40, 50, 100 kGy, or higher radiation dose
increments. Between each or some of the increments the hydrogel can
be thermally treated by melting and/or annealing steps. The thermal
treatment after irradiation is mostly to reduce or to eliminate the
residual free radicals in the hydrogels created by irradiation,
and/or eliminate the crystalline matter, and/or help in the removal
of any extractables that may be present in the hydrogel.
[0297] In accordance with another aspect of this invention, the
irradiation may be carried out in a sensitizing atmosphere. This
may comprise a gaseous substance which is of sufficiently small
molecular size to diffuse into the polymer and which, on
irradiation, acts as a polyfunctional grafting moiety. Examples
include substituted or unsubstituted polyunsaturated hydrocarbons;
for example, acetylenic hydrocarbons such as acetylene; conjugated
or unconjugated olefinic hydrocarbons such as butadiene and
(meth)acrylate monomers; sulphur monochloride, with
chloro-tri-fluoroethylene (CTFE) or acetylene being particularly
preferred. By "gaseous" is meant herein that the sensitizing
atmosphere is in the gas phase, either above or below its critical
temperature, at the irradiation temperature.
[0298] "Metal Piece", in accordance with the invention, the piece
forming an interface with polymeric material is, for example, a
metal. The metal piece in functional relation with polymeric
material, according to the present invention, can be made of a
cobalt chrome alloy, stainless steel, titanium, titanium alloy or
nickel cobalt alloy, for example.
[0299] "Non-metallic Piece", in accordance with the invention, the
piece forming an interface with polymeric material is, for example,
a non-metal. The non-metal piece in functional relation with
polymeric material, according to the present invention, can be made
of ceramic material, for example.
[0300] An atmosphere or an environment that refers to or includes
"air" will have a mixture of reactive and inert gases. Air contains
nitrogen, oxygen, CO.sub.2, traces of other gases, including other
inert gases (for example, noble gases), water vapor, etc.
[0301] An inert atmosphere refers to an environment that contains
one or more inert gases (for example, nitrogen, argon, helium, or
neon) of sufficient purity that the atmosphere is inert and gases
of such purity are commercially available. An "inert atmosphere" or
"inert environment" typically has no more than about 1% oxygen and
more preferably, provides a condition that allows free radicals in
polymeric materials to form cross links without problematic
oxidation during sterilization. An inert atmosphere is used to
avoid some deleterious effects of O.sub.2, which could, depending
on conditions, cause problematic oxidation of the device. Inert
gasses, such as nitrogen, argon, helium, or neon, can be used when
sterilizing polymeric medical implants with ionizing radiation.
[0302] Inert atmospheric conditions such as nitrogen, argon,
helium, neon, or vacuum are also used for sterilizing interfaces of
in medical implants by ionizing radiation.
[0303] Inert conditions also can refer to use of an inert fluid,
inert gas, or inert liquid medium, such as silicon oil.
[0304] The term "vacuum" refers to an environment having no
appreciable amount of gas. A vacuum is used to avoid O.sub.2. A
vacuum condition can be used for sterilizing implants by ionizing
radiation. A vacuum condition can be created using a commercially
available vacuum pump. A vacuum condition also can be used when
sterilizing interfaces in medical implants by ionizing
radiation.
[0305] "Sterilization", one aspect of the present invention
discloses a process of sterilization of medical implants containing
PVA-hydrogels, such as PVA-PAA-hydrogels. The process comprises
sterilizing the medical implants by ionizing sterilization with
gamma or electron beam radiation, for example, at a dose level
ranging from about 25-70 kGy, or by gas sterilization with ethylene
oxide or gas plasma.
[0306] Another aspect of the present invention discloses a process
of sterilization of medical implants containing PVA-hydrogels, such
as PVA-PAA-hydrogels. The process comprises sterilizing the medical
implants by ionizing sterilization with gamma or electron beam
radiation, for example, at a dose level ranging from 25-200 kGy.
The dose level of sterilization is higher than standard levels used
in irradiation. This is to allow cross-linking or further
cross-linking of the medical implants during sterilization.
[0307] The term "contact" includes physical proximity with or
touching, mixing or blending of one ingredient with another. For
example, a PVA solution in contacted with a PAA solution.
[0308] The term "hydrogel" or the term "PVA-hydrogels", as
described herein, encompasses all PVA-based hydrogels,
"PVA-PAA-hydrogels", "PVA-PAA-PEG-hydrogels",
"PVA-PEG-PAA-hydrogels" and all other hydrogel compositions
disclosed herein, including de-hydrated hydrogels. PVA-hydrogels
are networks of hydrophilic polymers containing absorbed water that
can absorb a large amounts of energy, such as mechanical energy,
before failure.
[0309] The term "creep resistance" (adj. creep resistant) generally
refers to the resistance to continued extension or deformation,
which results from the viscoelastic flow of the polymer chains
under continuous load.
[0310] The term "lubricity" (adj. lubricious) generally refers to a
physical properties of a hydrogel, for example, it is a measure of
the slipperiness of a hydrogel surface, which also relates to the
hydrophilicity of the same surface.
[0311] Each composition and attendant aspects, and each method and
attendant aspects, which are described above can be combined with
another in a manner consistent with the teachings contained herein.
According to the embodiments of the inventions, all methods and the
steps in each method can be applied in any order and repeated as
many times in a manner consistent with the teachings contained
herein.
[0312] The invention is further described by the following
examples, which do not limit the invention in any manner.
EXAMPLES
[0313] Determination of the Equilibrium Water Content (EWC) in a
Hydrogel:
[0314] Following method was used to determine the equilibrium water
content (EWC) in a hydrogel. The specimens were first immersed in
saline solution with agitation for removal of any unbound molecules
and for equilibrium hydration. To determine when the gels reached
equilibrium hydration, their weight changes were recorded daily and
the saline solution was replaced with fresh saline solution. After
the equilibrium hydration level was reached, the equilibrium
hydration weights of the specimens were recorded. Subsequently, the
gel specimens were dried in an air convection oven at 90.degree. C.
until no significant changes in weight were detected. The EWC in a
gel was then calculated by the ratio of the difference between the
hydrated and dehydrated weights to the weight at equilibrated
hydration state.
Example 1
15% Total Polymer of 7:3 PVA:PAA Ratio with 15% PEG; 3 Freeze-Thaw
Cycles
[0315] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 15 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was placed in a -17.degree. C. freezer for 16 hours,
and subsequently thawed at room temperature for 8 hours. This
process completed one cycle of freeze-thaw procedure. Upon
completion of 3 freeze-thaw cycles, the resulting hydrogel sheet
was removed from the mold and immersed in saline until equilibrium
re-hydration. The equilibrium water content of the final gel was
89.63.+-.0.17%.
Example 2
15% Total Polymer of 7:3 PVA:PAA Ratio with 15% PEG; 3 Freeze-Thaw
Cycles; Vacuum-Dehydrated
[0316] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 15 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was placed in a -17.degree. C. freezer for 16 hours,
and subsequently thawed at room temperature for 8 hours. This
process completed one cycle of freeze-thaw procedure. Upon
completion of 3 freeze-thaw cycles, the resulting hydrogel sheet
was removed from the mold and dehydrated under vacuum at room
temperature until the weight changes of the hydrogel due to
dehydration reached equilibrium. The vacuum-dehydrated gel was then
immersed in saline until equilibrium re-hydration. The equilibrium
water content of the final gel was 89.17.+-.0.11%.
Example 3
15% Total Polymer of 7:3 PVA:PAA Ratio with 15% PEG; 3 Freeze-Thaw
Cycles; Vacuum-Dehydrated; Heated
[0317] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 15 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was placed in a -17.degree. C. freezer for 16 hours,
and subsequently thawed at room temperature for 8 hours. This
process completed one cycle of freeze-thaw procedure. Upon
completion of 3 freeze-thaw cycles, the resulting hydrogel sheet
was removed from the mold and dehydrated under vacuum at room
temperature until the weight changes of the hydrogel due to
dehydration reached equilibrium. After vacuum dehydration, the
hydrogel specimen was heated at 160.degree. C. in an argon-filled
closed chamber already heated to 160.degree. C. for one hour. The
heated gel was then immersed in saline until equilibrium
re-hydration. The equilibrium water content of the final gel was
72.93.+-.1.04%.
[0318] The PVA-PAA hydrogels formed from 15% solid PVA-PAA-PEG
blends with 15% PEG by 3 cycle freeze-thawing after various
processing described in Examples 1-3 are shown in FIG. 1, as FIG. 1
(A) After re-hydration in saline (Example 1), FIG. 1 (B) After
vacuum dehydration followed by re-hydration in saline (Example 2),
and FIG. 1 (C) After vacuum dehydration and subsequent heating
followed by re-hydration in saline (Example 3).
Example 4
15% Total Polymer of 7:3 PVA:PAA Ratio with 15% PEG; 3 Freeze-Thaw
Cycles; dePEGed; Vacuum-Dehydrated; Heated
[0319] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW-400) (PEG400) of 15 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was placed in a -17.degree. C. freezer for 16 hours,
and subsequently thawed at room temperature for 8 hours. This
process completed one cycle of freeze-thaw procedure. Upon
completion of 3 freeze-thaw cycles, the hydrogel was removed from
the mold and placed in a saline solution for "dePEGing" process,
which removes the residual PEG in the gel by exchanging with water
during re-hydration in saline. The dePEGed PVA-PAA gel was then
dehydrated under vacuum at room temperature until the weight
changes of the hydrogel due to dehydration reached equilibrium.
After vacuum dehydration, the hydrogel specimen was heated at
160.degree. C. in an argon-filled closed chamber already heated to
160.degree. C. for one hour. The heated gel was then immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 42.40.+-.0.48%.
[0320] Table 1 shows the weight changes and equilibrium water
content (EWC) of PVA-PAA hydrogels formed from 15% solid
PVA-PAA-PEG blends with 15% PEG by 3 cycle freeze-thawing at each
stage of processing from Examples 1-4.
TABLE-US-00001 TABLE 1 Weight changes and equilibrium water content
(EWC) of PVA-PAA-hydrogels. Weight Changes with respect to the
as-gelled Measurements made state (%) EWC (%) As-gelled 0.0 Not
measured After re-hydration in saline (Example 13.93 89.63 .+-.
0.17 1) After vacuum dehydration -72.73 Not measured After vacuum
dehydration followed 14.93 89.17 .+-. 0.11 by re-hydration in
saline (Example 2) After vacuum dehydration and -72.72 Not measured
subsequent heating After vacuum dehydration and -49.03 72.93 .+-.
1.04 subsequent heating followed by re- hydration in saline
(Example 3) After dePEGing in saline and -86.79 Not measured
subsequent vacuum dehydration After dePEGing in saline and -87.36
Not measured subsequent vacuum dehydration and heating After
dePEGing in saline and -80.66 42.20 .+-. 0.48 subsequent vacuum
dehydration and heating followed by re-hydration in saline (Example
4)
[0321] Table 1 also shows that in the presence of PEG, heating only
reduced the EWC to 73%, whereas in the absence of PEG, the
reduction was much higher (EWC=42%). PEG protected the pores from
collapsing during the thermal treatment.
Example 5
15% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles
[0322] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MVV=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and immersed in saline until equilibrium re-hydration. The
equilibrium water content of the final processed gel was
84.11.+-.6.77%.
Example 6
15% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles; Vacuum-Dehydrated
[0323] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and dehydrated under vacuum at room temperature until the
weight changes of the hydrogel due to dehydration reached
equilibrium. After vacuum dehydration, the gel was immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 73.98.+-.0.14%.
Example 7
15% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles; Vacuum-Dehydrated; Heated
[0324] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and dehydrated under vacuum at room temperature until the
weight changes of the hydrogel due to dehydration reached
equilibrium. After vacuum dehydration, the hydrogel specimen was
heated at 160.degree. C. in an argon-filled closed chamber already
heated to 160.degree. C. for one hour. The heated gel was then
immersed in saline until equilibrium re-hydration. The equilibrium
water content of the final processed gel was 36.50.+-.0.37%.
Example 8
15% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles; PEG400-Immersed
[0325] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and immersed in 100% PEG400 with agitation until the
weight changes of the hydrogel due to PEG immersion reached
equilibrium. Subsequenlty, the PEG-dehydrated PVA-PAA gel was
immersed in saline until equilibrium re-hydration. The equilibrium
water content of the final processed gel was 85.54.+-.0.11%.
[0326] The PVA-PAA hydrogels formed from 15% solid PVA-PAA blends
by 3 cycle freeze-thawing after various processing described in
Examples 5-8 are shown in FIG. 2, as FIG. 2 (A) After re-hydration
in saline (Example 5), FIG. 2 (B) After vacuum dehydration followed
by re-hydration in saline (Example 6), FIG. 2 (C) After vacuum
dehydration and subsequent heating followed by re-hydration in
saline (Example 7), and FIG. 2 (D) After immersing in 100% PEG400
followed by re-hydration in saline (Example 8).
Example 9
15% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles; PEG400-Immersed; Vacuum-Dehydrated
[0327] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and immersed in 100% PEG400 with agitation until the
weight changes of the hydrogel reached equilibrium. Subsequently,
the PEG-doped PVA-PAA gel was dehydrated under vacuum at room
temperature. After vacuum dehydration, the gel was immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 83.81%.
Example 10
15% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles; PEG400-Immersed; Vacuum-Dehydrated; Heated
[0328] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 15 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and immersed in 100% PEG400 with agitation until the
weight changes of the hydrogel reached equilibrium. Subsequently,
the PEG-doped PVA-PAA gel was dehydrated under vacuum at room
temperature. After vacuum dehydration, the gel was heated at
160.degree. C. in an argon-filled closed chamber already heated to
160.degree. C. for one hour. The heated gel was then immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 69.34.+-.1.28%.
[0329] Table 2 shows the weight changes and equilibrium water
content (EWC) of PVA-PAA hydrogels formed from 15% solid PVA-PAA
blends by 3 cycle freeze-thawing at each stage of processing from
Examples 5-10.
TABLE-US-00002 TABLE 2 Weight changes and equilibrium water content
(EWC) of PVA-PAA-hydrogels. Weight Measurements made Changes (%)
EWC (%) As-gelled 0.0 Not measured After re-hydration in saline
(Example 5) 5.25 84.11 .+-. 6.77 After vacuum dehydration -83.61
Not measured After vacuum dehydration followed by re- -45.36 73.98
.+-. 0.14 hydration in saline (Example 6) After vacuum dehydration
and subsequent -83.49 Not measured heating After vacuum dehydration
and subsequent -76.63 36.50 .+-. 0.37 heating followed by
re-hydration in saline (Example 7) After immersing in 100% PEG400
-61.23 Not measured After immersing in 100% PEG400 -13.13 85.54
.+-. 0.11 followed by re-hydration in saline (Example 8) After
immersing in 100% PEG400 and -62.61 Not measured subsequent vacuum
dehydration After immersing in 100% PEG400 and -16.40 83.81
subsequent vacuum dehydration followed by re-hydration in saline
(Example 9) After immersing in 100% PEG400 and -65.57 Not measured
subsequent vacuum dehydration and heating After immersing in 100%
PEG400 and -48.51 69.34 .+-. 1.04 subsequent vacuum dehydration and
heating followed by re-hydration in saline (Example 10)
[0330] As observed in Examples 1-4, when present, PEG protected the
pores from collapsing during the thermal treatment.
Example 11
30% Total Polymer of 7:3 PVA:PAA Ratio with 15% PEG; Room Temp
Gelling; Vacuum-Dehydrated
[0331] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=50,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 30 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW-400) (PEG400) of 15 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. The resulting clear
solution was degassed to remove air bubbles and poured into a hot
glass mold and sealed with a glass cover. This mold was kept
between two stainless steel blocks that were previously heated to
90.degree. C. The mold then was slowly cooled down to room
temperature for 24 hours. Upon gelling, the resulting hydrogel
sheet was removed from the mold and dehydrated under vacuum at room
temperature. After vacuum dehydration, the gel was immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 74.57.+-.0.32%.
Example 12
30% Total Polymer of 7:3 PVA:PAA Ratio with 15% PEG; Room
Temperature Gelling; Vacuum-Dehydrated; Heated
[0332] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=50,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 30 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 15 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was slowly cooled down to room temperature for 24
hours. Upon gelling, the resulting hydrogel sheet was removed from
the mold and dehydrated under vacuum at room temperature. After
vacuum dehydration, the gel was heated at 160.degree. C. in an
argon-filled closed chamber already heated to 160.degree. C. for
one hour. The heated gel was then immersed in saline until
equilibrium re-hydration. The equilibrium water content of the
final processed gel was 57.66.+-.1.40%.
Example 13
27% Total Polymer of 7:3 PVA:PAA Ratio with 15% PEG; Room Temp
Gelling; Vacuum-Dehydrated
[0333] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 15 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was slowly cooled down to room temperature for 24
hours. Upon gelling, the resulting hydrogel sheet was removed from
the mold and dehydrated under vacuum at room temperature. After
vacuum dehydration, the gel was immersed in saline until
equilibrium re-hydration. The equilibrium water content of the
final processed gel was 77.17.+-.0.05%.
Example 14
27% Total Polymer of 7:3 PVA:PAA Ratio with 15% PEG; Room Temp
Gelling; Vacuum-Dehydrated; Heated
[0334] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 15 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was slowly cooled down to room temperature for 24
hours. Upon gelling, the resulting hydrogel sheet was removed from
the mold and dehydrated under vacuum at room temperature. After
vacuum dehydration, the gel was heated at 160.degree. C. in an
argon-filled closed chamber already heated to 160.degree. C. for
one hour. The heated gel was then immersed in saline until
equilibrium re-hydration. The equilibrium water content of the
final processed gel was 57.58.+-.0.92%.
[0335] Table 3 shows the weight changes and equilibrium water
content (EWC) of PVA-PAA hydrogels formed from 27% solid
PVA-PAA-PEG blends with 15% PEG by 1 day room temperature gelling
at each stage of processing from Examples 11-13.
Example 15
27% Total Polymer of 7:3 PVA:PAA Ratio with 20% PEG; 3 Freeze-Thaw
Cycles
[0336] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polyscienees) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 20 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was placed in a -17.degree. C. freezer for 16 hours,
and subsequently thawed at room temperature for 8 hours. This
process completed one cycle of freeze-thaw procedure. Upon
completion of 3 freeze-thaw cycles, the resulting hydrogel sheet
was removed from the mold and immersed in saline until equilibrium
re-hydration. The equilibrium water content of the final processed
gel was 83.33.+-.0.09%.
TABLE-US-00003 TABLE 3 Weight changes and equilibrium water content
(EWC) of PVA-PAA-hydrogels. Weight Measurements made Changes (%)
EWC (%) As-gelled 0.00 Not measured After vacuum dehydration -59.22
Not measured After vacuum dehydration followed by 2.49 77.17 .+-.
0.05 re-hydrationin saline (Example 13) After vacuum dehydration
and -60.04 subsequent heating After vacuum dehydration and -38.00
57.58 .+-. 0.92 subsequent heating followed by re-hydration in
saline (Example 14)
Example 16
27% Total Polymer of 7:3 PVA:PAA Ratio with 20% PEG; 3 Freeze-Thaw
Cycles; Vacuum-Dehydrated
[0337] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 20 w/w %.degree. of PEG
with respect to the total PEG and water amount in the mixture was
added to the solution with vigorous mechanical stirring at
90.degree. C. to form a homogenous PVA-PAA-PEG solution. Resulting
clear solution was degassed to remove air bubbles and poured into a
hot glass mold and sealed with a glass cover. This mold was kept
between two stainless steel blocks that were previously heated to
90.degree. C. The mold then was placed in a -17.degree. C. freezer
for 16 hours, and subsequently thawed at room temperature for 8
hours. This process completed one cycle of freeze-thaw procedure.
Upon completion of 3 freeze-thaw cycles, the resulting hydrogel
sheet was removed from the mold and dehydrated under vacuum at room
temperature. After vacuum dehydration, the gel was immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 83.25.+-.0.27%.
Example 17
27% Total Polymer of 7:3 PVA:PAA Ratio with 20% PEG; 3 Freeze-Thaw
Cycles; Vacuum-Dehydrated; Heated
[0338] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 20 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was placed in a -17.degree. C. freezer for 16 hours,
and subsequently thawed at room temperature for 8 hours. This
process completed one cycle of freeze-thaw procedure. Upon
completion of 3 freeze-thaw cycles, the resulting hydrogel sheet
was removed from the mold and dehydrated under vacuum at room
temperature. After vacuum dehydration, the gel was heated at
160.degree. C. in an argon-filled closed chamber already heated to
160.degree. C. for one hour. The heated gel was then immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 66.72.+-.0.19%.
[0339] Table 4 shows the weight changes and equilibrium water
content (EWC) of PVA-PAA hydrogels formed from 27% solid
PVA-PAA-PEG blends with 20% PEG by 3 cycle freeze-thawing at each
stage of processing from Examples 15-17.
Example 18
27% Total Polymer of 7:3 PVA:PAA Ratio with 20% PEG; Room Temp
Gelling
[0340] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 20 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was slowly cooled down to room temperature for 24
hours. Upon gelling, the resulting hydrogel sheet was removed from
the mold and immersed in saline until equilibrium re-hydration. The
equilibrium water content of the final processed gel was
91.61.+-.0.06%.
TABLE-US-00004 TABLE 4 Weight changes and equilibrium water content
(EWC) of PVA-PAA-hydrogels. Weight Measurements made Changes (%)
EWC (%) As-gelled 0.00 Not Measured After re-hydration in saline
31.33 83.33 .+-. 0.09 (Example 15) After vacuum dehydration -58.38
Not Measured After vacuum dehydration followed by 30.08 83.25 .+-.
0.27 re-hydration in saline (Example 16) After vacuum dehydration
and -59.19 Not Measured subsequent heating After vacuum dehydration
and -23.77 66.72 .+-. 0.19 subsequent heating followed by
re-hydration in saline (Example 17)
Example 19
27% Total Polymer of 7:3 PVA:PAA Ratio with 20% PEG; Room Temp
Gelling, Vacuum-Dehydrated
[0341] PVA 115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 20 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was slowly cooled down to room temperature for 24
hours. Upon gelling, the resulting hydrogel sheet was removed from
the mold and dehydrated under vacuum at room temperature. After
vacuum dehydration, the gel was immersed in saline until
equilibrium re-hydration. The equilibrium water content of the
final processed gel was 82.12.+-.0.10%.
Example 20
27% Total Polymer of 7:3 PVA:PAA Ratio with 20% PEG; Room Temp
Gelling; Vacuum-Dehydrated; Heated
[0342] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Subsequently, pre-heated
polyethylene glycol (MW=400) (PEG400) of 20 w/w % of PEG with
respect to the total PEG and water amount in the mixture was added
to the solution with vigorous mechanical stirring at 90.degree. C.
to form a homogenous PVA-PAA-PEG solution. Resulting clear solution
was degassed to remove air bubbles and poured into a hot glass mold
and sealed with a glass cover. This mold was kept between two
stainless steel blocks that were previously heated to 90.degree. C.
The mold then was slowly cooled down to room temperature for 24
hours. Upon gelling, the resulting hydrogel sheet was removed from
the mold and dehydrated under vacuum at room temperature. After
vacuum dehydration, the gel was heated at 160.degree. C. in an
argon-filled closed chamber already heated to 160.degree. C. for
one hour. The heated gel immersed in saline until equilibrium
re-hydration. The equilibrium water content of the final processed
gel was 63.71.+-.0.42%.
TABLE-US-00005 TABLE 5 Weight changes and equilibrium water content
(EWC) of PVA-PAA-hydrogels. Weight Measurements made Changes (%)
EWC (%) As-gelled 0.00 Not Measured After re-hydration in saline
127.33 91.61 .+-. 0.06 (Example 18) After vacuum dehydration -58.70
Not Measured After vacuum dehydration followed by 21.44 82.12 .+-.
0.10 re-hydration in saline (Example 19) After vacuum dehydration
and -60.06 Not Measured subsequent heating After vacuum dehydration
and -29.54 63.71 .+-. 0.42 subsequent heating followed by
re-hydration in saline (Example 20)
[0343] Table 5 shows the weight changes and equilibrium water
content (EWC) of PVA-PAA hydrogels formed from 27% solid
PVA-PAA-PEG blends with 20% PEG by 1 day room temperature gelling
at each stage of processing from Examples 18-20.
Example 21
27% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles; Vacuum-Dehydrated
[0344] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and dehydrated under vacuum at room temperature until the
weight changes of the hydrogel due to dehydration reached
equilibrium. After vacuum dehydration, the gel was immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 71.67.+-.1.00%.
Example 22
27% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles; PEG400-Immersed
[0345] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and immersed in 100% PEG400 with agitation until the
weight changes of the hydrogel due to PEG immersion reached
equilibrium. Subsequently, the PEG-dehydrated PVA-PAA gel was
immersed in saline until equilibrium re-hydration. The equilibrium
water content of the final processed gel was 76.21.+-.0.10%.
Example 23
7:3 27% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3
Freeze-Thaw Cycles; PEG400-Immersed; Vacuum-Dehydrated
[0346] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and immersed in 100% PEG400 with agitation until the
weight changes of the hydrogel reached equilibrium. Subsequently,
the PEG-doped PVA-PAA gel was dehydrated under vacuum at room
temperature. After vacuum dehydration, the gel was immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 74.64.+-.0.19%.
Example 24
27% Total Polymer of 7:3 PVA:PAA Ratio with No PEG; 3 Freeze-Thaw
Cycles; PEG400-Immersed; Vacuum-Dehydrated; Heated
[0347] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products, Ontario, N.Y.) was mixed into an aqueous solution of PAA
(MW=200,000 g/mol, Polysciences) at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA ratio was 7:3 with 27 w/w
% total polymer content in the blend. Resulting clear solution was
degassed to remove air bubbles and poured into a hot glass mold and
sealed with a glass cover. This mold was kept between two stainless
steel blocks that were previously heated to 90.degree. C. The mold
then was placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 3
freeze-thaw cycles, the resulting hydrogel sheet was removed from
the mold and immersed in 100% PEG400 with agitation until the
weight changes of the hydrogel reached equilibrium. Subsequently,
the PEG-doped PVA-PAA gel was dehydrated under vacuum at room
temperature. After vacuum dehydration, the gel was heated at
160.degree. C. in an argon-filled closed chamber already heated to
160.degree. C. for one hour. The heated gel was then immersed in
saline until equilibrium re-hydration. The equilibrium water
content of the final processed gel was 55.68.+-.1.52%.
TABLE-US-00006 TABLE 6 Weight changes and equilibrium water content
(EWC) of PVA-PAA-hydrogels. Weight Measurements made Changes (%)
EWC (%) After Freeze-thaw process 0.0 Not measured After vacuum
dehydration -67.32 Not measured After vacuum dehydration followed
-2.65 71.67 .+-. 1.00 by re-hydration in saline After immersing in
100% PEG400 -53.38 Not measured After immersing in 100% PEG400
18.54 76.21 .+-. 0.10 followed by re-hydration in saline After
immersing in 100% PEG400 and -56.09 Not measured subsequent vacuum
dehydration After immersing in 100% PEG400 and 12.39 74.64 .+-.
0.19 subsequent vacuum dehydration followed by re-hydration in
saline After immersing in 100% PEG400 and -57.29 Not measured
subsequent vacuum dehydration and heating After immersing in 100%
PEG400 and -30.92 55.68 .+-. 1.52 subsequent vacuum dehydration and
heating followed by re-hydration in saline
[0348] Table 6 shows the weight changes and equilibrium water
content (EWC) of PVA-PAA hydrogels formed from 27% solid PVA-PAA
blends by 3 cycle freeze-thawing at each stage of processing from
Examples 21-24.
Example 25
Creep Test of PVA Gels Produced by Examples 1-24
[0349] Hydrogel sheet samples from above examples were machined
with a 17 mm diameter trephine and were allowed to equilibrate in
saline solution at 40.degree. C. for at least 24 hours prior to the
start of the creep test.
[0350] The hydrogel creep test was done on a MTS (Eden Prairie,
Minn.) 858 Mini Bionix servohydraulic machine. Cylindrical hydrogel
specimens, approximately 17 mm in diameter and between 5-10 mm in
height, were placed between stainless steel compression plates for
testing. Prior to the start of the test, the top and bottom
compression plates were brought together and the LVDT displacement
was zeroed at this position. After placing the specimen on the
bottom plate, the top plate was lowered until it made contact with
the top surface of the creep specimen. The displacement reading
from the LVDT on the MTS was recorded as the height of the
specimen. The compressive load was initially ramped at a rate of 50
Newton/minute (N/min) to a creep load of 100 Newton (N). This load
was maintained constant for 10 hours. The load was subsequently
reduced at a rate of 50 N/min to a recovery load of 10 N. This load
was also held constant for 10 hours. Time, displacement and load
values were recorded once every 2 seconds during the loading and
unloading cycles. The data was plotted as compressive strain vs.
time to compare the creep behavior of different hydrogel
formulations described above (see FIG. 3).
[0351] Creep strain was calculated as (1) the strain at the
completion of ramp-up to 100 N load, (2) the total strain after 10
hours of loading, (3) the viscoelastic strain after 10 hours of
loading, (4) the elastic recovery upon unloading from 100 to 10 N,
(5) the viscoelastic strain recovery after 10 hours of unloading
under 10 N, (6) the total strain recovery after 10 hours of
unloading under 10 N, and (7) the total strain after 10 hours of
loading followed by 10 hours of unloading under 10 N (see FIG. 3).
FIG. 3 shows creep behavior is characterized in the Strain vs. Time
plots for the 10 hour loading and 10 hour unloading cycles
respectively. Table 7 shows the elastic and viscoelastic strains
achieved during the loading and unloading stages of the creep
experiments with the hydrogel samples used in example 25.
TABLE-US-00007 TABLE 7 Elastic and viscoplastic strains observed
during the loading and unloading stages of the creep experiments.
Total Viscoelastic Total Strain after Total Viscoelastic Strain
Strain 10 hours of Strain Strain Strain Elastic Recovery Recovery
Loading Sample (all samples were hydrated in saline at on after
after Recovery after after 10 followed by room temperature to
achieve equilibrium Initial 10 hours of 10 hours of on 10 hours of
hours of 10 hours of Sample hydration levels and then conditioned
in 40.degree. C. Loading Loading Loading Unloading Unloading
Unloading Unloading Number saline for at least 24 hours prior to
testing) (%) (%) (%) (%) (%) (%) (%) 1 15% 7:3 PVA:PAA(200K); 15%
PEG; 3FT; vac- 10.9 25.5 14.5 7.5 6.8 14.3 11.1 deh (Example 2) 2
15% 7:3 PVA:PAA(200K); 15% PEG; 3FT; vac- 18.4 36.2 17.8 14.3 9.1
23.4 12.8 deh; heated (Example 3) 3 15% 7:3 PVA:PAA(200K); 15% PEG;
3FT; 8.9 12.0 3.1 4.3 3.6 7.9 4.1 dePEGed; vac-deh; heated (Example
4) 4 15% 7:3 PVA:PAA(200K); No PEG; 3FT; vac- 34.1 42.3 8.2 20.6
6.0 26.5 15.8 deh (Example 6) 5 15% 7:3 PVA:PAA(200K); No PEG; 3FT;
PEG- 57.1 71.9 14.8 15.5 2.0 17.5 54.4 imm (Example 8) 6 15% 7:3
PVA:PAA(200K); No PEG; 3FT; PEG- 10.9 25.5 14.5 7.5 6.8 14.3 11.1
imm; vac-deh; heated (Example 10) 7 30% 7:3 PVA:PAA(50K); 15% PEG;
RT 1 day; 11.4 15.7 4.3 7.3 3.9 11.2 4.5 vac-deh: heated (Example
12) 8 27% 7:3 PVA:PAA(200K); 20% PEG; 3FT; vac- 27.2 40.8 13.6 17.3
9.7 27.0 13.9 deh; heated (Example 17) 9 27% 7:3 PVA:PAA(200K); 20%
PEG; RT 1 day; 22.7 32.6 9.9 14.9 9.6 24.5 8.1 vac-deh; heated
(Example 19) 10 27% 7:3 PVA:PAA(200K); No PEG; 3FT; PEG- 9.8 14.3
4.5 8.9 4.3 13.2 1.1 imm; vac-deh; heated (Example 24)
[0352] FIGS. 4-6 further illustrates creep behavior is
characterized in the Strain vs. Time plots for the 10 hour loading
and unloading cycles, respectively, for the samples numbers 1-10 as
shown in Table 7. FIG. 7 shows total creep strain of PVA hydrogels
obtained from creep test as described in Example 24 and is plotted
as a function of equilibrium water content.
Example 26
Coefficient of Friction Measurements of PVA Gels Produced by
Examples 1-24
[0353] Coefficient of friction is measured on hydrogel samples
formed by above methods in DI water at 40.degree. C. against CoCr.
An aluminum bath is mounted onto the Peltier plate and the hydrogel
sample is placed in the bath. In this test, a CoCr ring is mounted
into the upper fixture of a shear rheometer (AR-1000, TA
Instruments Inc.). The CoCr runs against the hydrogel sample at a
constant shear rate of 0.11/s. The torsional load is recorded under
normal loads of approximately 1, 2, 4, 6, and 8 N. Using the method
of Kavehpour and McKinley (see Kavehpour, H. P. and McKinley, G.
H., Tribology Letters, 17(2), pp. 327-335, 2004), the coefficient
of friction between the hydrogel and the CoCr counter face can be
calculated.
Example 27
Comparison of PVA Gels Having the Same Composition by Different
Methods of Making (PEG Presence During PVA PAA Gelling Vs PEG
Sequentially Incorporated after PVA-PAA Gelling)
[0354] The PVA hydrogels made by the methods described in Example 1
(where PEG is present during PVA-PAA gelling; denoted as
"PVA-PAA-PEG gel") and in Example 8 (where PEG is sequentially
incorporated after PVA-PAA gelling; denoted as "PVA-PAA gel with
PEG incorporated") essentially contain all three components of PVA,
PAA, and PEG before they are further processed, for example,
rehydrated in saline or dehydrated by thermal treatment. However,
whether PEG is present during the time of PVA gelling or it is
incorporated into the already-formed PVA gels result in slightly
different PVA microstructures as seen in FIGS. 8 and 9.
[0355] FIG. 8 illustrates a confocal micrograph of rehydrated PVA
hydrogel made by a method (Example 1) where PEG was present in the
PVA and FAA solution during the time of gelling process (scale
bar=20 .mu.m). FIG. 9 illustrates a confocal micrograph of
rehydrated PVA hydrogel made by a method (Example 8) where PEG was
sequentially incorporated in pre-made PVA-PAA gels (scale bar=20
.mu.m). Both gels, as depicted in FIGS. 8 and 9, contain the same
composition ratio of PVA and PAA (7:3).
[0356] The PVA-PAA-PEG gel in FIG. 1 shows more uniformly sized
pores surrounded by finer PVA struts than the PVA-PAA gel with PEG
incorporated in FIG. 2, which shows much thicker and web-like
polymer matrix with various shaped and sized pores. Presence of PEG
during the PVA-PAA gelling tend to increase the final water content
in the further processed gel, which closely affects creep
resistance. FIG. 3 shows a comparison of creep resistance in such
PVA hydrogels that were thermally treated by methods described in
Examples 3 and 9, respectively. The PVA-PAA-PEG gel results in a
slightly higher total creep resistance with greater elastic
response and the same final creep strain compared to the PVA-PAA
gel with PEG incorporated.
[0357] FIG. 10 shows creep resistance of the PVA-PAA-PEG gel where
PEG was present during PVA gelling and PVA-PAA gel with PEG
incorporated where PEG was incorporated after PVA gelling. Both
gels were thermally treated and rehydrated in saline prior to creep
deformation test.
Example 28
Diffusion of FAA into PVA Hydrogels
[0358] This example shows another method of including PAA into PVA
gels by immersing formed PVA gels into PAA solutions. PEG can be
mixed in PAA solutions simultaneously or PAA-absorbed PVA gels can
be sequentially immersed in PEG 100% or other PEG containing
solvents.
[0359] Thirty grams of poly (vinyl alcohol) (PVA, MW=115,000) were
added to 170 grams of cold deionized water and stirred while
heating for about 2 hours to prepare a fully dissolved 15% (wt) PVA
solution. The dissolved PVA solution was kept for in an air
convection oven at 90.degree. C. for degassing. PEG was heated to
90.degree. C. in an air convection oven. 66 grams of hot poly
(ethylene glycol) (PEG, MW=400) (at approximately 90.degree. C.)
was slowly mixed to the hot PVA solution by mechanical stirring
while heating. The gelling solution of PVA-PEG was poured into
different size molds kept at 90.degree. C. The molds were covered
with an insulating blanket and left to cool down to room
temperature. The solution formed a hydrogel upon cooling down to
room temperature. The hydrogel was removed from the mold and placed
in a saline solution for "dePEGing" process, which removes the
residual PEG in the gel by exchanging with water during rehydration
in saline. Such dePEGed gels are then used as basal PVA gels for
diffusion of MA.
[0360] PVA cryogels can be used as basal PVA gels. A hot 15% PVA
aqueous solution was poured into pre-heated molds (for example, the
mold can be pre-heated to a temperature between about 1 and about
200.degree. C., preferably between about 25.degree. C. and about
150.degree. C., more preferably about 90.degree. C.) and the molds
were placed in a -17.degree. C. freezer for 16 hours, and
subsequently thawed at room temperature for 8 hours. This process
completed one cycle of freeze-thaw procedure. Upon completion of 1
or more freeze-thaw cycles, the hydrogel was removed from the mold
and was subject to PAA diffusion.
[0361] Two different molecular weight PAA were (MW=200,000 g/mol
(99.7% hydrolyzed), 25 w/w % in water, polysciences; MW=5,000
g/mol, 49.24 w/w % in water) dissolved in deionized water at room
temperature to prepare 5% and 25% aqueous solutions of each
molecular weight PAA. 49.24 w/w % PAA (MW=5,000 g/mol) was used
with no dilution as .about.50% concentration. DePEGed gels were cut
into six pieces of 20 mm.times.20 mm.times.14 mm dimension to
ensure uniform surface to volume ratio in each specimen. Each
specimen was immersed in six different solutions and mechanically
agitated (see FIG. 11). The weight change of each specimen was
monitored until the diffusion process reached equilibrium. FIG. 11
depicts DePEGed PVA hydrogels after PAA diffusion by immersion in
six different FAA aqueous solutions, as FIG. 11(A) 25% PAA
(MW=200K) solution, FIG. 11(B) 5% PAA (MW=200K), FIG. 11(C) 5% FAA
(MW=5K), FIG. 11(D) 25% PAA (MW=5K), FIG. 11(E) deionized water
with no PAA (control), and FIG. 11 (F) .about.50% PAA (MW=5K).
[0362] Initially opaque dePEGed gel (see FIG. 11E) became
translucent and distorted in shape (see FIG. 11A and FIG. 11F), and
slightly opaque (see FIG. 11D), which indicates that PAA has been
diffused into the gels and water has been extracted out of the
gels. The effects of PAA diffusion can be controlled by PAA
concentration and PAA molecular weight during the PAA immersion.
PAA diffused PVA gels are then subsequently subject to further
processing to stabilize the PAA within the PVA-matrix by
crosslinking methods such as heating, radiation, chemical reaction,
and the like.
[0363] Table 8 shows the weight changes of each dePEGed PVA
hydrogels after PAA diffusion by immersion in six different PAA
aqueous solutions.
TABLE-US-00008 TABLE 8 Weight changes of each dePEGed PVA hydrogels
after PAA diffusion by immersion in six different PAA aqueous
solutions. Condition of PAA aqueous solutions used for immersion
Weight sam- PAA concentration PAA molecular changes ples (w/w %)
weight (g/mol) (%) A 25 200,000 -85.36 B 5 200,000 -0.79 C 5 5,000
4.08 D 25 5,000 6.04 E 0 -- 0.35 F ~50 (49.24) 5,000 -55.77
Example 29
25% Total Polymer of Various PVA:PAA Ratios, PEG-Doped or
PEG-Blended, Followed by Post-Gelation Treatments
[0364] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products) was mixed into an aqueous solution of PAA (MW=200,000
g/mol, Polysciences) at 90.degree. C. to form a homogenous PVA-PAA
solution. The PVA:PAA weight ratio was varied from "PVA only"
(i.e., contains no PAA), 9:1, 8:2 to 7:3 with 25 w/w % total
polymer content in each blend. Two types of gels, for example,
PEG-doped (Type 1) and PEG-blended (Type 2) with different blending
ratios of PVA:PAA were used.
[0365] Type 1--PEG-Doped Gels:
[0366] PVA-PAA solution was poured into pre-heated glass sheet
molds and subjected to three freeze-thaw cycles (16 hour-freezing
at -17.degree. C. and 8 hour-thawing at room temperature).
Subsequently, the molded gels were immersed in 100% PEG (PEG-doping
by immersion) followed by vacuum dehydration and annealing at
160.degree. C. in argon in a self-pressurized vessel for an hour.
For argon gas atmosphere, the vessel containing the gels was purged
with argon gas for at least 5 minutes prior to annealing. It is
believed that there were incidents where the argon-purged vessels
were not completely sealed during the annealing process.
Consequently, the samples were not annealed in 100% inert argon
gas, i.e., the samples were exposed to residual air in argon gas
during annealing.
[0367] Type 2--PEG-Blended Gels:
[0368] About 15 w/w % PEG (with respect to the total PEG and the
amount of water in the PVA-PAA mixture) was pre-heated at
90.degree. C. and added to a hot PVA-PAA mixture to form a
homogeneous solution/blend of PVA-PAA-PEG. The resulting
homogeneous polymer blend was poured into a pre-heated glass molds.
Subsequently, the molded gels were subjected to three freeze-thaw
cycles followed by vacuum dehydration and annealing at about
160.degree. C. under argon in a self-pressurized vessel for an
hour. Each gel sheet was immersed in deionized (DI) water to remove
residual PEG and to reach an equilibrated rehydration.
[0369] The non-annealed "PVA only" (that is, PVA with no PAA) gels
in both Types 1 and 2 were made by rehydrating the gels in DI water
immediately upon removal from the molds after completion of the
freeze-thaw cycles.
[0370] Creep Test:
[0371] Cylindrical disks were cut from each hydrated hydrogel sheet
with a 17 mm diameter trephine. After equilibration in DI water at
40.degree. C. for 24 hours, creep tests were performed in a DI
water bath at 40.degree. C. on a multi-station mechanical tester
(Cambridge Polymer Group, Boston, Mass.). Gel disks were compressed
between polycarbonate plates at a ramping rate of 50 N/min while
immersed in DI water at 40.degree. C., to a creep load of 100
Newton (N). The load was maintained constant for 10 hours and
subsequently reduced at a rate of 50 N/min to a recovery load of 10
N. This load also was held constant for 10 hours. Time,
displacement and load values were recorded during the loading. The
total creep strain was taken as a representative characteristic of
the results.
[0372] Equilibrium Water Content (EWC):
[0373] The hydrogel samples were equilibrium hydrated in deionized
(DI) water either at 25.degree. C. or at 40.degree. C. at least for
24 hours and dried in vacuum oven for 1 day, subsequently dried in
an air convection oven at 90.degree. C. until no significant weight
changes were detected. The EWC in a gel was then calculated by the
ratio of the difference between the hydrated and dehydrated weights
to the weight at the equilibrated hydration state.
[0374] Coefficient of Friction:
[0375] The COF testing was performed on a AR2000ex rheometer (TA
Instruments, Newark, Del.) in DI water at 40.degree. C. using a
custom-designed annular CoCr ring (outer diameter 31.2, inner
diameter 28.8 mm, and surface roughness, R.sub.a=0.08 .mu.m)
against flat hydrogels in a custom-designed aluminum bath. The
samples were equilibrated in DI water at 40.degree. C. for 1 day
prior to the test. Torque, normal force, and velocity data were
recorded for 90 seconds at 1, 3, 5 and 7 N with 2 minutes
equilibration at the given load in between the runs from low to
high loading at a constant shear rate of 0.1 1/s and analyzed for
the coefficient of friction calculation.
[0376] Results:
[0377] Overall, adding PAA in PVA gels significantly increased the
EWC after annealing for both type 1 and type 2 gels (see FIGS. 12A
and 12B, also see Table 9 for detailed data). FIGS. 12A and 12B
illustrates the EWC of the PAA-containing PVA hydrogels ("PVA only;
NA" indicates the non-annealed hydrogel made with only PVA without
PAA). Such effects were more pronounced for the PVA hydrogels that
were equilibrated in DI at 40.degree. C. (FIG. 12B) prior to EWC
measurement than the ones equilibrated in DI at 25.degree. C. (FIG.
12A). The presence of PAA increased the EWC of annealed PVA
hydrogels up to comparable values to that of the non-annealed PVA
hydrogels.
TABLE-US-00009 TABLE 9 Equilibrium water content of the
PAA-containing PVA hydrogels as illustrated in FIGS. 12A and 12B.
PVA:PAA Weight Ratio EWC(%) at 25.degree. C. DI EWC(%) at
40.degree. C. DI (25% polymer content) Type 1 Type 2 Type 1 Type 2
PVA only 42.7 .+-. 0.9 52.3 .+-. 0.4 44.5 .+-. 0.9 53.3 .+-. 0.3
9:1 66.6 .+-. 8.1 74.6 .+-. 2.9 69.8 .+-. 7.2 81.2 .+-. 2.5 8:2
68.6 .+-. 1.9 75.2 .+-. 3.1 76.3 .+-. 2.0 82.9 .+-. 3.1 7:3 79.6
.+-. 7.0 74.5 .+-. 0.3 83.8 .+-. 4.3 79.6 .+-. 1.3 PVA only; NA
76.5 .+-. 0.1 78.7 .+-. 0.2 76.5 .+-. 0.2 79.1 .+-. 0.1
(Non-annealed)
[0378] Creep resistance of the annealed gels was reduced with the
presence of PAA due to increased EWC. (See FIGS. 13 and 14 for
typical creep behaviors of the PAA-containing PVA hydrogels made by
Type 1 and Type 2 methods, respectively) Nevertheless, except for
Type 1 gel with PVA:PAA ratio of 7:3, all of PAA-containing
annealed PVA gels showed superior creep resistance to that of the
non-annealed PVA gels with no PAA (PVA only; NA) (see FIG. 15 for
total creep strain comparison of the PAA-containing PVA
hydrogels).
[0379] The lubricity of the annealed PVA gels was significantly
improved in the presence of PAA for both type 1 and type 2 gels
(see FIGS. 16 and 17), as indicated by their COF values being lower
than those of 10:0 gels. FIGS. 16 and 17 illustrate Coefficient of
Friction (COF) of the PAA-containing PVA gels made by Type 1 and
Type 2 methods, respectively. The 7:3 (PVA:PAA) gels that had the
highest amounts of PAA present in the gel seemed slightly less
lubricious than 8:2 or 9:1 in both gel types, although the
differences were not statistically significant. Note that the
presence of PAA resulted in significantly lower COF values than the
values that could be obtained by Type 1 PVA only gels whether or
not the gels were annealed. Type 1 gel with PVA:PAA ratio of 9:1 is
the optimum formulation among the gels described in this example,
in terms of minimizing the changes in the COF and creep resistance
during annealing.
Example 30
Effects of PEG 400-Doping Step Prior to Annealing in 25% Total
Polymer of 7:3 PVA:PAA Ratio with No PEG, 3 Freeze-Thaw Cycles;
Vacuum-Dehydrated; and Heated
[0380] The effects of PEG 400 presence in the PAA-containing PVA
hydrogels during heating were quantified in terms of EWC, creep
resistance, and coefficient of friction. PVA (MW=115,000 g/mol
(99.7% hydrolyzed), Scientific Polymer Products) was mixed into an
aqueous solution of PAA (MW=200,000 g/mol, Polysciences) at
90.degree. C. to form a homogenous PVA-PAA solution. 25% total
polymer of 7:3 PVA:PAA gels were made by subjecting PVA-PAA
solution poured into pre-heated glass sheet molds to three
freeze-thaw cycles (16 hour-freezing at -17.degree. C. and 8
hour-thawing at room temperature). Subsequently, the "PEG-doped"
group (according to Example 29) was immersed in PEG400 (for
PEG-doping), followed by vacuum dehydration and annealing at
160.degree. C. under argon in a self-pressurized vessel for one
hour. For argon gas atmosphere, the vessel containing the gels was
purged with argon gas for at least 5 minutes prior to annealing. It
is believed that there were incidents where the argon-purged
vessels were not completely sealed during the annealing process.
Consequently, the samples were not annealed in 100% inert argon
gas, i.e., the samples were exposed to residual air in argon gas
during annealing.
[0381] The gels in control group (non PEG-doped) were vacuum
dehydrated immediately after removal of gels from molds, omitting
the PEG-doping step, followed by the same annealing procedure under
argon gas.
[0382] Total creep strain, EWC, and COF were measured as described
in Example 29. The hydrogels were equilibrated 40.degree. C. prior
to drying for EWC measurement.
[0383] Results:
[0384] The PEG doping step prior to thermal annealing significantly
increased EWC (see FIG. 18) in Type 1 gels with 7:3 PVA:PAA ratio.
The creep resistance of the PEG doped gels were largely inferior to
that of non PEG-doped gel, due to higher EWC. See FIGS. 18 and 19
for the total creep strain and typical creep behaviors of the
hydrogels, respectively. However, the presence of PEG during
thermal annealing in the PAA-containing Type 1 gel highly improved
the surface lubricity as evidenced by the markedly lower COF values
of the PEG-doped hydrogels as opposed to that of non PEG-doped
hydrogels (see FIG. 20). FIG. 20 shows Coefficient of Friction
(COF) of 25% total polymer hydrogels of 7:3 PVA:PAA ratio made with
or without the PEG doping step as described in this Example.
Example 31
25% Total Polymer of 19:1 PVA:PAA Ratio with No PEG, pH 3.0, 3
Freeze-Thaw Cycles; PEG-Doped, Vacuum-Dehydration; and Heating
[0385] 22.5 g of PAA (MW=200,000 g/mol, 25% solid in water,
Polysciences) containing 5.625 g of pure PAA is diluted in 317.625
g of deionized water with stirring with no heating to make a 1.654
w/w % PAA solution. The pH value of 1.654% PAA solution is
.about.3.0 at room temperature. 106.875 g of PVA powder (MW=115,000
g/mol (99.7% hydrolyzed), Scientific Polymer Products) is mixed
into the above PAA solution at 90.degree. C. to form a homogenous
PVA-PAA solution. The PVA:PAA weight ratio in the final PVA-PAA
solution is 19:1 with 25 w/w % total polymer content. The final
PVA-PAA solution is a completely clear miscible solution. The
PVA-PAA solution is poured into pre-heated glass sheet molds and
subjected to three freeze-thaw cycles (16 hour-freezing at
-17.degree. C. and 8 hour-thawing at room temperature).
Subsequently, the molded gel is immersed in 100% PEG400 followed by
vacuum dehydration and annealing at 160.degree. C. under argon in a
self-pressurized vessel for one hour. Gel sheets are immersed in
deionized (DI) water to remove residual PEG and to reach
equilibrated rehydration.
[0386] Total creep strain, EWC, and COF can be measured as
described in Example 29.
Example 32
25% Total Polymer of 99:1 PVA:PAA Ratio with No PEG, pH 1.5, 3
Freeze-Thaw Cycles; PEG-Doped, Vacuum-Dehydration; and Heating
[0387] 4.5 g of PAA (MW=200,000 g/mol, 25% solid in water,
Polysciences) containing 1.125 g of pure PAA is mixed in 334.125 g
of deionized water at room temperature to make a 0.332 wt % PAA
solution. The pH of 0.332% PAA solution is initially 3.3 at room
temperature and adjusted to pH 1.5 by adding a small amount of
hydrochloric acid (HCl) aqueous solution. 111.375 g of PVA powder
(MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer Products)
is mixed into the above PAA solution at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA weight ratio in the final
PVA-PAA solution is 99:1 with 25 w/w % total polymer content. The
final PVA-PAA solution is a completely clear miscible solution. The
PVA-PAA solution is poured into pre-heated glass sheet molds and
subjected to three freeze-thaw cycles (16 hour-freezing at
-17.degree. C. and 8 hour-thawing at room temperature).
Subsequently, the molded gel is immersed in 100% PEG400 followed by
vacuum dehydration and annealing at 160.degree. C. under argon in a
self-pressurized vessel for one hour. Gel sheets are immersed in
deionized (DI) water to remove residual PEG and to reach
equilibrated rehydration.
[0388] In making 99:1 PVA:PAA blends, pH adjustment toward acidic
condition is critically important in forming a homogenous miscible
solution of PVA and PAA prior to gelation through freeze-thawing
cycles. When pH of 0.332% PAA solutions is higher than 1.5, for
example, pH 2.674 or pH 3.315 before mixing PVA, cloudy and
immiscible solution is obtained in 99:1 PVA:PAA ratio mixtures at
90.degree. C.
[0389] Total creep strain, EWC, and COF can be measured as
described in Example 29.
Example 33
25% Total Polymer of 19:1 PVA:PAA Ratio with no PEG, pH 5.5, 3
Freeze-Thaw Cycles; PEG-Doped, Vacuum-Dehydration; and Heating
[0390] 22.5 g of PAA (MW=200,000 g/mol, 25% solid in water,
Polysciences) containing 5.625 g of pure PAA is diluted in 317.625
g of deionized water with stirring with no heating to make a 1.654
w/w % PAA solution. The pH value of 1.654% PAA solution is 2.998 at
room temperature and adjusted to pH 5.5 by adding a small amount of
sodium hydroxide (NaOH) aqueous solution. 106.875 g of PVA powder
(MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer Products)
is mixed into the above PAA solution at 90.degree. C. to form a
homogenous PVA-PAA solution. The PVA:PAA weight ratio in the final
PVA-PAA solution is 19:1 with 25 w/w % total polymer content. The
final PVA-PAA solution is homogenous but immiscible with slight
opacity. The PVA-PAA solution is poured into pre-heated glass sheet
molds and subjected to three freeze-thaw cycles (16 hour-freezing
at -17.degree. C. and 8 hour-thawing at room temperature).
Subsequently, the molded gel is immersed in 100% PEG400 followed by
vacuum dehydration and annealing at 160.degree. C. under argon in a
self-pressurized vessel for one hour. Gel sheets are immersed in
deionized (DI) water to remove residual PEG and to reach
equilibrated rehydration.
[0391] Total creep strain, EWC, and COF can be measured as
described in Example 29.
Example 34
25% Total Polymer of 99:1 PVA:PAA Ratio with No PEG, pH3.3,
Freeze-Thaw Cycles; PEG-Doped, Vacuum-Dehydration; and Heating
[0392] 4.5 g of PAA 200,000 g/mol, 25% solid in water,
Polysciences) containing 1.125 g of pure PAA is mixed in 334.125 g
of deionized water at room temperature to make a 0.332 wt % PAA
solution. The pH of 0.332% PAA solution is initially 3.315 at room
temperature and the PAA solution is used without any pH-adjustment.
111.375 g of PVA powder (MW=115,000 g/mol (99.7% hydrolyzed),
Scientific Polymer Products) is mixed into the above PAA solution
at 90.degree. C. to form a homogenous PVA-PAA solution.
[0393] The final PVA-PAA solution is homogenous but immiscible with
slight opacity. The PVA:PAA weight ratio in the final PVA-PAA
solution is 99:1 with 25 w/w % total polymer content. The PVA-PAA
solution is poured into pre-heated glass sheet molds and subjected
to three freeze-thaw cycles (16 hour-freezing at -17.degree. C. and
8 hour-thawing at room temperature). Subsequently, the molded gel
is immersed in 100% PEG400 followed by vacuum dehydration and
annealing at 160.degree. C. under argon in a self-pressurized
vessel for one hour. Gel sheets are immersed in deionized (DI)
water to remove residual PEG and to reach equilibrated
rehydration.
[0394] Total creep strain, EWC, and COF can be measured as
described in Example 29.
Example 35
Equilibrium Water Content (EWC) and Coefficient of Friction (COF)
Results in 25% Total Polymer of 99:1 or 19:1 PVA:PAA Ratio with No
PEG, 3 Freeze-Thaw Cycles; PEG-Immersion; Vacuum-Dehydrated; and
Heated
[0395] The type 1 PVA gels made with 99:1 or 19:1 PVA:PAA ratio
were made as Examples 31-34. Prior to gelling, during PVA-PAA
solution preparation, each solution was pH-adjusted to form either
a miscible blend or an immiscible blend prior to gelling. Upon
gelation, all gels were immersed in PEG, followed by vacuum
dehydration and subsequent annealing under argon gas for 1 hour at
160.degree. C.
[0396] As compared to the PVA-only gels, EWC remained unchanged
with 1% PAA content in the 99:1 PVA:PAA gels. In the 19:1 PVA:PAA
ratio gels, EWC increased significantly as opposed to PVA only
gels. As low as 1% PAA content showed a detectable decrease in COF
values in the PVA gels as opposed to PVA only gels. Miscibility of
the gelling solution did not seem to affect the surface lubricity,
which implies that the effects of chemical composition of the
functional groups can be more substantial than the surface
morphology of the PVA gels.
Example 36
Effects of Heating Conditions in 25% Total Polymer of 9:1 PVA:PAA
Ratio with No PEG, 3 Freeze-Thaw Cycles; PEG400-Immersed;
Vacuum-Dehydrated; and Heated
[0397] The effects of various heating conditions in the
PAA-containing PVA hydrogels with 9:1 PVA:PAA ratio were quantified
in terms of EWC, creep resistance, and coefficient of friction. PVA
(MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer Products)
was mixed into an aqueous solution of PAA (MW=200,000 g/mol,
Polysciences) at 90.degree. C. to form a homogenous PVA-PAA
solution. 25% total polymer of 9:1 PVA:PAA gels were made by
subjecting PVA-PAA solution poured into pre-heated glass sheet
molds to three freeze-thaw cycles (16 hour-freezing at -17.degree.
C. and 8 hour-thawing at room temperature). Subsequently, the gels
were immersed in PEG400 (for PEG-doping), followed by vacuum
dehydration and heating in a self-pressurized vessel. 1 hour
heating at 160.degree. C. under argon gas was used as the reference
condition and each parameter such as heating time, temperature, and
gas type was varied individually, one at a time, while other
parameters were kept unchanged. Four different annealing conditions
tested were: (A) 1 hour heating at 160.degree. C. under argon gas,
(B) 1 hour heating at 160.degree. C. in air (without argon gas
purging), (C) 16 hour heating at 160.degree. C. under argon gas,
and (D) 1 hour heating at 200.degree. C. under argon gas. For argon
gas atmosphere, the vessel containing the gels was purged with
argon gas for five minutes prior to annealing. After annealing, the
samples were rehydrated in deionized water until equilibrium
hydration was reached. Total creep strain, EWC, and COF were
measured as described in Example 29.
[0398] Results:
[0399] Various heating conditions resulted in changes in the EWC of
the gels (see FIG. 21) compared to the EWC value of 80% in the
reference annealing condition of 1 hour heating at 160.degree. C.
under argon gas. Presence of oxygen in the residual air inside the
annealing chamber during annealing slightly reduced EWC by 10% as
compared to the inert argon gas environment. Extended annealing
time from 1 hour to 16 hour and an increase in heating temperature
from 160.degree. C. to 200.degree. C. significantly reduced the EWC
to 38% and 45%, respectively.
[0400] Creep response of each gel was also affected by the various
annealing conditions (see FIG. 22). Total creep strain (TCS), which
is a representative value of creep behavior, was reduced when
heated in air instead of argon gas, at the longer annealing
duration, or at the higher temperature. The decrease in TCS due to
time or temperature changes was more significant than the presence
of air during annealing.
[0401] The surface lubricity of the gels was most significantly
improved by the presence of air during annealing as evidenced by
dramatically low COF values as opposed to the all of the other gels
heated under argon gas environment (see FIGS. 23 and 24). Extended
heating time and increased heating temperature seemed to adversely
affect the surface lubricity of the gels.
Example 37
Effects of the Presence of Air During Annealing in 25% Total
Polymer of Various PVA:PAA Ratios with No PEG, 3 Freeze-Thaw
Cycles; PEG400-Immersed; Vacuum-Dehydrated; and Heated
[0402] It was later found that in some of the previous experiments
some of the annealing vessels that were purged with argon gas to
anneal hydrogels in the absence of air were not completely sealed
to maintain inert state during the annealing process. Consequently,
some of the type 1 gels described in Examples 29 and 30 were
exposed to air during annealing and the COF, EWC, and creep data
presented in Examples 29 and 30 were generated from the samples
possibly annealed in the presence of residual air instead of solely
inert argon gas. In fact, the COF values reported above in Examples
29 and 30 are the average of four samples annealed individually.
Some of them showed unusually high variance in COF values. For
instance, the COF values under 7N normal force of the 7:3 PVA:PAA
gels made by the type 1 gel method were 0.109, 0.128, 0.075, and
0.056 for four samples. Therefore, to ascertain if the presence of
air was responsible for this variation, the effects of presence of
air during annealing in the PAA-containing PVA hydrogels with
various PVA:PAA ratios were quantified in terms of EWC and
coefficient of friction in this example. As described below, the
presence of air during annealing significantly improved the surface
lubricity of PAA-containing PVA gels as opposed to the absence of
air during annealing. Thus, the COF values presented in Examples 29
and 30 possibly show lower values than the actual COF values of the
gels that were annealed in the absence of air.
[0403] PVA (MW=115,000 g/mol (99.7% hydrolyzed), Scientific Polymer
Products) was mixed into an aqueous solution of PAA (MW=200,000
g/mol, Polysciences) at 90.degree. C. to form a homogenous PVA-PAA
solution. The PVA:PAA weight ratio was varied from "PVA only"
(i.e., contains no PAA), 9:1, 8:2 to 7:3 with 25 w/w % total
polymer content in each blend. Each PVA-PAA solution was poured
into pre-heated glass sheet molds to three freeze-thaw cycles (16
hour-freezing at -17.degree. C. and 8 hour-thawing at room
temperature). Subsequently, the gels were immersed in PEG400 for
PEG-doping (according to Example 29), followed by vacuum
dehydration and annealing at 160.degree. C. in a self-pressurized
vessel for one hour. For "argon" group (control), the vessel
containing the gels was purged with argon gas for at least 5
minutes prior to annealing. For "air" group, the argon gas purging
prior to annealing was omitted and the gels were annealed in a
self-pressurizing vessel containing ambient air that were already
present prior to placing the gels. After heating, the samples were
rehydrated in deionized water until equilibrium hydration was
reached. EWC, TCS and COF were measured as described in Example
29.
[0404] Results:
[0405] Thermal annealing adversely affected the surface lubricity
of PVA only gels (containing no PAA) as evidenced by increased COF
values after annealing. The increase in COF was more significant
when annealing was carried out under argon gas than in air (see
FIGS. 26 and 27). Presence of PAA in the PVA gels made by type 1
method completely eliminated such adverse effects on COF due to
annealing and further improved the surface lubricity beyond that of
non-annealed PVA only gels. Decrease in COF values due to PAA
presence in the annealed gel were amplified more significantly for
the gels annealed in the presence of air than in inert gas (for
example, COF of the 9:1 PVA:PAA ratio gel annealed in the presence
of air can be as low as 0.02, as opposed to the COF value of 0.18
in the same composition gel annealed under argon gas in the absence
of air), which signifies that residual oxygen from air inside the
annealing vessel might cause oxidation and/or other chemical
changes on the surface or in the bulk of the gel.
[0406] The EWC of PVA gels was increased by the presence of PAA in
the gels annealed both under argon gas and in air (FIG. 28). The
EWC showed a negligible or slight decrease (less than about 10%) in
the gels annealed in the presence of air as opposed to in the
absence of air. The total creep strain of the FAA-containing PVA
gels showed a slight (less than about 10%) or negligible decrease
in the presence of air (i.e., the ambient air containing nitrogen,
oxygen, CO.sub.2, traces of other gases, water vapor, etc., that
were already present in the self-pressurizing vessel prior to
placing the gels) during annealing as opposed to in the absence of
air (FIG. 29).
[0407] In conclusion, the FAA-containing PVA gels that were
annealed in the presence of air as opposed to the same PVA:PAA
composition gels that were annealed under argon gas in the absence
of air showed superior surface lubricity while maintaining the same
or slightly improved creep resistance.
[0408] It is to be understood that the description, specific
examples and data, while indicating exemplary embodiments, are
given by way of illustration and are not intended to limit the
present invention. Various changes and modifications within the
present invention will become apparent to the skilled artisan from
the discussion, disclosure and data contained herein, and thus are
considered part of the invention.
* * * * *