U.S. patent application number 11/301055 was filed with the patent office on 2006-05-04 for hydrogels for orthopedic repair.
This patent application is currently assigned to GENZYME CORPORATION. Invention is credited to Luis Z. Avila, Arthur J. Coury, Stephen D. Goodrich, Peter K. Jarrett, Hildegard M. Kramer, John F. Traverse.
Application Number | 20060093648 11/301055 |
Document ID | / |
Family ID | 35966190 |
Filed Date | 2006-05-04 |
United States Patent
Application |
20060093648 |
Kind Code |
A1 |
Coury; Arthur J. ; et
al. |
May 4, 2006 |
Hydrogels for orthopedic repair
Abstract
Hydrogels intended for orthopedic applications, including repair
and regeneration of cartilage, bone, joint surfaces and related
tissues, must possess greater strength and toughness than hydrogels
used in soft tissue repair. A hydrogel formulation is provided
which has high strength, toughness, a suitable mechanical modulus
and low equilibrium hydration. It may also have controlled porosity
or degradation time. It can be made to polymerize in situ with high
("good" to "excellent") adherence to target tissue or surfaces. A
preferred formulation for forming such gels comprises 40 to 80% by
weight of a low-molecular weight polar monomer and 30 to 10% of a
hydrophilic macromeric crosslinker.
Inventors: |
Coury; Arthur J.; (Boston,
MA) ; Goodrich; Stephen D.; (Norcross, GA) ;
Kramer; Hildegard M.; (Westport, CT) ; Avila; Luis
Z.; (Arlington, MA) ; Traverse; John F.;
(Somerville, MA) ; Jarrett; Peter K.; (Sudbury,
MA) |
Correspondence
Address: |
FISH & RICHARDSON PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
GENZYME CORPORATION
|
Family ID: |
35966190 |
Appl. No.: |
11/301055 |
Filed: |
December 12, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09658390 |
Sep 8, 2000 |
7008635 |
|
|
11301055 |
Dec 12, 2005 |
|
|
|
60153190 |
Sep 10, 1999 |
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Current U.S.
Class: |
424/426 ;
525/54.1; 526/227; 560/155; 560/40; 560/41 |
Current CPC
Class: |
A61K 9/06 20130101 |
Class at
Publication: |
424/426 ;
525/054.1; 526/227; 560/040; 560/041; 560/155 |
International
Class: |
A61F 2/00 20060101
A61F002/00; A61K 47/48 20060101 A61K047/48; C08F 4/28 20060101
C08F004/28 |
Claims
1. A covalently polymerizable, water-absorbing, hydrogel-forming
material, wherein the material has both hydrophilic and hydrophobic
regions and is polymerized to form a hydrogel characterized as
having the following properties: a) absorbing water to less than
about 300% of its initial weight, on equilibration with water or
bodily liquids, b) having a solids content of at least about 20%
after equilibration in water or bodily liquids; c) having an
elongation to failure of at least about 25% hydration to
equilibrium; and d) being sufficiently biocompatible to permit the
treatment or repair of biological tissue, or used as an implant in
a patient.
2. The material of claim 1, having a molecular weight after
polymerization of at least 10 kDa.
3. The material of claim 1, which is covalently crosslinked.
4. The material of claim 1, which is non-covalently
crosslinked.
5. The material of claim 1, having a tensile modulus of at least
about 50 kPa after equilibrium hydration.
6. The material of claim 1, having an equilibrium water content of
at least about 2%.
7. The material of claim 1, being capable of being formed in situ
on body tissue or a medical implant by one or both of
polymerization and crosslinking.
8. The material of claim 1, adhering to tissue when polymerized
thereon.
9. The material of claim 1, being substantially elastic during a
10% elongation and release therefrom.
10. The material of claim 1, further characterized in being
lubricious.
11. The material of claim 1, further characterized in comprising,
before polymerization or crosslinking, a) at least one component
which is a macromer of molecular weight of about 1000 Da or more,
at least 20% of the macromer being a hydrophilic block or region
and comprising at least one chemical reactive group; and b) at
least one component bearing more than one chemically reactive
group.
12. The material of claim 1, further characterized in comprising,
before polymerization or crosslinking, at least 20% by weight of at
lest one amphiphilic water-soluble monomer of molecular weight less
than about 100 Da.
13. The material of claim 1, in which the water absorption at
equilibrium hydration is less than about 200%.
14. The material of claim 1, in which the solids content is at
least about 25% after equilibrium swelling.
15. The material of claim 1, in which the elongation to failure is
at least about 200%.
16. The material of claim 1, in which the tensile modulus is at
least 200 kPa.
17. The material of claim 1, further compromising a therapeutic,
prophylactic or diagnostic agent.
18. The material of claim 1 formed by polymerization of a mixture
comprising: a) about 40% to about 100% by weight of one or more
polymerizable monomers having a molecular weight of about 1000 Da
or less; wherein at lest about 40% by weight of the monomers
consists of amphiphilic monomers; wherein no more than about 50% by
weight of the monomers consists of functionally hydrophobic
monomers; b) 0% to about 40% by weight of a reactive macromer
having a molecular weight greater than about 500 Da, which
comprises on average more than one polymerizable group per
molecule, and which has hydrophilic groups comprising about 20% of
the macromer; and c) 0% to about 40% water.
19. The material of claim 1 in the form of a coating on an implant
device.
20. The material of claim 1 forming an implant or device.
21-37. (canceled)
Description
[0001] This application claims priority to U.S. Ser. No.
60/153,190, filed Sep. 10, 1999.
FIELD OF THE INVENTION
[0002] This invention is generally in the field of treatments of
disease, particularly disease of skeletal or orthopedic tissues
such as cartilage and bone, using polymeric materials having high
adherence to tissue, low degree of swelling, toughness and
biocompatibility.
BACKGROUND OF THE INVENTION
[0003] Hydrogel materials are useful in coating, sealing and
adhesion of soft tissues, for example as described in U.S. Pat. No.
5,410,016 to Hubbell et al., U.S. Pat. No. 5,800,373 to Melanson et
al., and U.S. Pat. Nos. 5,844,016, and 5,900,245 to Sawhney et al.
Important properties of these hydrogels are their biocompatibility,
their ability to adhere strongly to tissue, and good mechanical
compliance, which is appropriately matched to that of the tissue.
Biocompatibility is achieved by the use of materials that are
especially compatible with tissue, such as polyalkylene oxides, and
by a high water content, similar to that of the tissue being
coated.
[0004] However, these gels are less useful in situations in which
the gels are subject to high mechanical stress. An example of such
a situation is in the repair of bone and other skeletally related
tissues, such as cartilage, the tibial meniscus, tendons and
ligaments, spinal disks, and muscle (collectively, "orthopedic
tissues"), or in composite implants intended for such uses. Repair
of injuries, disease or defects of orthopedic tissues can be
difficult because the gel needs to offer protection to the
structures under mechanical stress. Tight adherence to the
substrate is often beneficial in achieving this purpose. Repair of
articular cartilage is especially difficult. A surface must be
provided which is resistant to abrasion and provides cushioning
during regeneration and maturation of the cartilage, for example,
following implants of tissues, cells or aggregates. On the other
hand, appropriate stress transmitted to the cells facilitates
appropriate alignment and generation of a normal intercellular
matrix. Similar considerations apply to bone regeneration,
especially at joints.
[0005] Traditional hydrogels are not strong enough to withstand the
applied stresses, particularly over the length of time required,
especially for long periods of time such as those required for
regeneration of bone or connective tissue. Such gels also tend to
swell extensively in aqueous environments, which can interfere with
mechanical properties of the injured joint or other site. Moreover,
hydrogels do not tend to adhere strongly to tissue, especially to
moist tissue, or when pre-formed before application to tissue. On
the other hand, traditional solid implants (which typically are
formed of hydrophobic materials) can be too rigid and brittle,
thereby impeding or preventing tissue repair or regeneration. They
may also lack lubricity, which can compromise performance in joints
as well as pose a risk of abrasion of the opposing surface.
[0006] A material that has the appropriate balance of strength and
compliance as well as the biocompatibility of a hydrogel, and that
has strong adherence to orthopedic tissues, is needed.
[0007] It is an object of the present invention to provide
biocompatible hydrogels which strongly adhere to orthopedic
tissues.
[0008] It is another object of the present invention to provide
hydrogels with strong mechanical properties.
[0009] It is another object of the present invention to provide
monomers from which hydrogels with strong mechanical properties can
be formed, and methods of use thereof.
SUMMARY OF THE INVENTION
[0010] Polymeric materials have been developed which can be
effective in treatment of orthopedic tissues, such as cartilage,
bone and accessory structures, and implants. In one embodiment, the
material includes a mixture of two components which copolymerize to
form a hydrogel that contains hydrophilic and hydrophobic regions.
The first component is covalently-crosslinkable, hydrophilic,
polymeric, of high biocompatibility, and optionally spontaneously
hydrolyzing ("biodegradable"). It is preferably sufficiently
hydrophilic to be water-soluble at a temperature between about 0
and 70.degree. C. The second component is more hydrophobic
(although it is preferably water-soluble under the same
conditions), is covalently polymerizable, provides structural
strength and limits the water absorption capacity of the formed
gel. Upon reaction in situ in the presence of polymerization
initiators bound to or adhered to the tissue ("priming systems"),
the resulting polymerized hydrogel adheres tightly to the tissues,
and has suitable mechanical properties, including toughness,
strength and resiliency to facilitate repair or regeneration of the
tissue. It also remains as a hydrogel, retaining the advantages of
biocompatibility and lubricity. The hydrogel is optionally
biodegradable.
[0011] In a second embodiment, the material is predominantly a
high-molecular weight, covalently-polymerizable macromer, which is
soluble or paste-like at high concentration (e.g., 40% or more by
weight) in the formulation, and which can be polymerized to form a
tough, adherent, biocompatible coating on tissue.
[0012] In a third embodiment, monomers of molecular weight less
than about 1 kDa, or mixtures of monomers, are the sole or
principal precursors of the material. A significant fraction of the
weight of the solution, for example 40% or more, is amphiphilic
monomers; functionally hydrophobic monomers form less than about
50% of the mixture; macromers comprise from zero to less than about
30% of the weight, and water is from zero to less than about 40% of
the weight.
[0013] The polymerized materials have a controlled, low degree of
swelling on continued exposure to water, combined with a tensile
modulus which may be in excess of 1 MPa and also having a
significant elongation to break (e.g., 10% or more). This
combination of properties makes the materials tough, resilient, and
able to withstand cyclic mechanical stress for extended periods.
The material can also be made porous, and thereby permissive of
cell or tissue ingrowth in the process of tissue repair. Porosity
formation may be intrinsic to the materials or may be provided by
pore-forming excipients or processes.
[0014] Methods of use of such materials in the treatment, repair or
regeneration of tissues are described.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a graph of the mechanical properties, tensile
strength and modulus, psi, and percent elongation. These are shown
for the material as initially formed, for the material after
hydration (swelling) for 1 day at 37.degree. C., and for the
material after accelerated incubation for 13 days at 57.degree.
C.
DETAILED DESCRIPTION OF THE INVENTION
I. HYDROGEL COMPOSITIONS
[0016] A. Required Hydrogel Properties
[0017] A range of materials can be used to obtain the desired
hydrogel. The key attributes of the formed hydrogel are low
swelling at high proportions of solids, high tensile modulus,
significant elongation to failure, biocompatibility, and adherence,
as defined below.
[0018] SWELLING and HYDRATION: Swelling results from the absorption
of water by a formed polymeric material, which can be initially dry
or already contain water. It is expressed herein as the percent
increase in weight of a material from its initial state to a state
in equilibrium with an aqueous solution, such as water or a bodily
fluid. For example, if a piece of material had a weight of 1 g when
formed, and 2 g after equilibration with water, it would exhibit a
swelling of 100%. Direct measurement of volume could also be used
to determine the degree of swelling. An appropriate time and
temperature for obtaining near-equilibrium hydration of a material,
in configurement relevant to implant application, is incubation for
about 24 hrs in water, ideally at 37.degree. C. to simulate body
temperature. However, a simple overnight incubation at room
temperature normally gives a hydration, or degree of swelling, that
is adequately close to true equilibrium. (It should be noted that
this may not be true for other materials--for example, conventional
hydrophobic thermoplastics, such as polyethylene).
[0019] Prior art gels containing similar materials, such as those
described in U.S. Pat. No. 5,410,016 to Hubbell, et al., composed
largely or entirely of crosslinked hydrophilic macromers, tend to
swell several hundred percent. These gels are highly "elastic"
(compliant) and correspondingly do not resist stress well.
Hydrogels with relatively little swelling can be made, for example,
from dilute crosslinked polyacrylamide, such as gels used for
electrophoresis. However, these gels are very brittle and weak and
are not suited for the purposes described herein. In these cases,
the lack of swelling is achieved in part by having a low percentage
of gel-forming solids in the composition. Prior art non-gel
materials, such as polylactide, do not swell significantly, but
have such a high modulus and hardness that they have a low elastic
limit and tend to deform irreversibly or fracture under stress.
[0020] Gels with a low degree of swelling are preferred. The most
preferred gels have an equilibrium swelling of about 150% or less.
Preferred gels have a swelling of about 200% or less. Gels with
swelling below about 300% are potentially of use. Low degrees of
swelling are achieved at high concentrations of gel-forming solids.
Suitable ranges of gel-forming solids at the time of gel formation
are at least about 30% by weight, preferably over 40%, more
preferably over 50%, and yet more preferably over 60%. The
preferred embodiments have over 70% solids at the time of
formation. Correspondingly, the concentration of solids after
equilibrium swelling is also high. The gel-forming materials should
comprise at least 20% by weight of the gel after swelling to
equilibrium in bodily fluids. Higher values are preferable, such as
30% or more. The preferred embodiments have 40% or higher solids
after equilibration with water.
[0021] MODULUS: A material's modulus is the ratio of stress
(applied force per unit area) over strain (ratio of compressed or
stretched length to original length). It is expressed in units of
force per unit area, such as Pascals or PSI, and is typically
measured quantitatively on a device such as an Instron.RTM.
mechanical tester. The gels described herein have a modulus that is
quite high for a hydrogel. The most preferred values of the tensile
or compressive modulus, at small strains and after swelling, are
over 1 megaPascal (MPa). Gels with a post-swelling modulus of 500
kiloPascals (kPa) or greater are preferred. Gels with a modulus of
100 kPa, preferably 200 kPa or more, are of use in the invention.
Gels with a modulus above about 50 kPa can be used in low-stress
situations.
[0022] ELONGATION TO FAILURE: For the purposes described herein,
elongation to failure is the strain (degree of deformation) at
which the material fails (breaks), expressed as a percent of the
material's original length. It is also measured on an Instron.RTM.
tester or similar device. A material with a 100% elongation
(strain) at failure is double its original length. Materials with a
significant elongation to failure are preferred. Preferred
materials have values above about 300%, and suitable materials can
have values in the range of about 25% to over 800% if other
properties are appropriate. In addition to the elongation to
failure value, having a measurable range in which the material is
elastic, i.e., returns to its original shape, is important for its
durability, particularly under the conditions found in joints and
other orthopedic tissues. As used herein the term "elastic"
includes "substantially elastic" and "predominantly elastic" and is
used to describe materials that have low modulus in tension or
compression and high elongation to break. Substantially elastic
materials include materials in which up to 25% of the deformation
can be irreversible (plastic) deformation. The deformation of
preferred materials is substantially elastic.
[0023] TOUGHNESS: The values of elongation and modulus can be
combined to give a quantitative measurement of toughness, which is
the area under the stress-strain curve to the failure point.
However, there are several potential complicating factors, such as
rate of elongation and shape of the test piece. For the purposes
described herein, the area under the curve should only be used as a
means of comparison of related samples. "Toughness" is used herein
only in a comparative sense unless otherwise specified. A
qualitative measure of toughness, for gels of a particular
thickness, is obtained by compressing a piece of gel between the
jaws of a locking surgical hemostat. A standard compressive load
can be achieved by specifying how many "clicks"--detents giving
progressively higher compressive force--on the locking mechanism
are used. Gels that do not fracture in this test are tougher than
those that do fracture.
[0024] BIOCOMPATIBILITY: A material is biocompatible if its
implantation does not provoke a severe local or systemic
inflammatory reaction. This is in distinction to the transient mild
inflammatory response that accompanies essentially all implants.
Biocompatibility may be determined by histological examination of
the implant site at various times after implantation. One sign of
poor biocompatibility can be a severe, chronic, unresolved
phagocytic response at the site. Another sign of poor
biocompatibility can be necrosis or regression of tissue at the
site.
[0025] ADHERENCE: Adherence of gels to tissue can be optimized by
techniques that employ functional primers, as described in U.S.
Pat. No. 5,800,373 to Melanson et al., U.S. Pat. Nos. 5,844,016, or
5,900,245 to Sawhney et al. for gels formed by polymerization of
ethylenically unsaturated precursors. Suitable gel compositions
form strong bonds to tissue. These techniques are also applicable
to creating strong adherence of the materials to tissue, including
tissue to which it is difficult to obtain adherence by conventional
methods, for example, cartilage.
[0026] A general procedure for applying materials to orthopedic
tissue involves brushing or dabbing primer over a larger area than
that over which the material is applied. Thereafter, material is
brushed or dabbed over the deposited primer. Then bulk material is
applied by dripping (if liquid) or spreading (if paste) over yet a
smaller area of the treated zone. Then light (at appropriate
wavelength, intensity, distance and for an appropriate time) is
applied at each zone, or other means of polymerizing the material
are used.
[0027] Adherence of the hydrogel to tissue may be determined by
passing a 20 gauge needle through the base of the hydrogel near the
tissue interface, then grasping the needle at both ends, and
finally lifting the needle parallel to the tissue while holding
down the test object. The needle eventually releases either via
adhesive failure of the hydrogel to the tissue, or by cohesive
failure of the hydrogel or tissue. The examples below show many
primed hydrogels that provided bonds strong enough to cause
cohesive failure.
[0028] Adherence may be qualitatively rated as follows. "Excellent
adherence" means that upon application of force to the needle,
cohesive failure of tissue or gel was observed. "Moderate
adherence" means that upon application of force to the needle
failure was partially cohesive and partially adhesive. "Fair
adherence" means that the mode of failure was adhesive failure.
"Poor adherence" means that a light force, as compared with the
force needed to cause cohesive failure, was needed to cause
adhesive failure. Preferred gels have moderate to excellent
adherence on this scale.
[0029] LUBRICITY is the quality of a surface that confers
relatively low frictional forces between that surface and an
opposing surface, often via a thin film of liquid material on the
surface that wets both surfaces. The fluid can be adsorbed to the
surface, or exuded by the surface, or both. Hydrogels tend to be
naturally lubricious. In addition, hydrogel surfaces have an innate
affinity for water. Natural cartilage has a similar property.
[0030] Gel or hydrogel, as used herein, includes the traditional
hydrogel, in which polymer and water each form continuous phases.
As used herein, these terms may also include materials absorbing at
least 5% of an aqueous phase, which is not necessarily continuous.
As used herein "functionally hydrophobic monomers" means monomers
including reactive groups and hydrophobic groups and having up to
one group that is no more hydrophilic than an alkyl ester or a
dialkyl amide. Examples of functionally hydrophobic monomers
include vinyl caprolactam (VC), methyl acrylate, methyl
methacrylate, styrene, N-vinyl pyrrolidone (VP), and N-vinyl
imidazole (VI). In contrast, examples of amphiphilic monomers
include diacetone acrylamide (DAA), vinyloxyethanol (VOE),
2-acrylamido-2-methylpropane (AMPS), and methyl acryloyl lactate
(ALM) and its relatives.
[0031] B. Gel-Forming Precursors
[0032] The gel-forming materials comprise reactive polymers
(macromers), with molecular weights ranging from about 500 Daltons
(Da) to about 200,000 Da, measured by any conventional technique.
These macromers contain hydrophobic and hydrophilic regions and are
combined, in most embodiments, with reactive low molecular weight
monomers, having molecular weights below about 1000 Da. The
combination is preferably characterized by being sufficiently
hydrophobic after polymerization to provide hydrogels with low
swelling and relatively high solids content after equilibration
with water. For example, the preferred polymeric solids
concentration after equilibration of the formed gel with water or
bodily fluids will be in the range of from about 15% wt/wt to above
70% wt/wt. This characteristic may involve phase separation or
coacervate formation during polymerization, leading to a
heterogeneous hydrogel. Some products may be porous.
1. Macromers
[0033] A variety of macromers that can be used to form the hydrogel
are described in the literature. A preferred family based on a PEG
(polyethylene glycol; poly(ethylene oxide)) backbone and acrylate
termination is described in U.S. Pat. No. 5,410,016 to Hubbell et
al., U.S. Pat. No. 5,573,934 to Hubbell et al., U.S. Pat. No.
5,800,373 to Melanson et al., U.S. Pat. No. 5,844,016 and U.S. Pat.
No. 5,900,245 to Swahney et al. and in International Patent
Publication No. WO 96/29370 by Board of Regents, University of
Texas, and WO 98/2243 and WO 99/07417 by Focal. Design, synthesis
and use of such molecules are described. These molecules can
readily be adapted for use in the system described herein with
little experimentation. Other suitable materials, or materials
readily modified to be suitable, are described in U.S. Pat. No.
4,938,763 to Dunn, et al., U.S. Pat. Nos. 5,100,992 and 4,826,945
to Cohn et al, U.S. Pat. Nos. 4,741,872 and 5,160,745 to De Luca et
al, U.S. Pat. No. 4,511,478 to Nowinski et al., U.S. Pat. No.
5,198,507 to Kohn et al., U.S. Pat. No. 5,219,564 to Zalipsky et
al.; WO 98/00170 by Hennink et al; WO 99/03454 by Hubbell et al.;
and U.S. Pat. No. 5,854,382 to Loomis et al.
[0034] Macromers which polymerize to form hydrogels via
condensation or electrophile/nucleophile chemistry are described in
numerous publications, including U.S. Pat. Nos. 5,744,545,
5,614,587, and 5,874,500 to Rhee et al; U.S. Pat. No. 5,514,379 to
Weissleder and Bogdanov; U.S. Pat. No. 5,173,301 to Itoh and
Matsuda; U.S. Pat. No. 5,583,114 to Barrows et al, and U.S. Pat.
No. 4,057,535 to Lipatova et al. Other examples include U.S. Pat.
No. 4,839,345 to Doi, et al.; U.S. Pat. Nos. 5,252,714, 5,739,208
and 5,672,662 to Harris, et al.; U.S. Pat. Nos. 4,740,534,
4,994.542, and 4,806,614 to Matsuda, et al.; U.S. Pat. No.
4,804,691 to English et al.; and WO 99/14259 by Harris.
[0035] Although poly(ethylene glycol) (PEG) is preferred for
forming the macromeric backbone because of its biocompatibility and
stability, other macromolecules are also useful. These include, as
illustrated below, PEG-PPO (copolymers of polyethylene glycol and
polypropylene oxide), hydrophilic segmented urethanes, and
multivalently-derivatizable surfactants, in each case derivatized
to carry reactive groups. A wide variety of other hydrophilic
natural and synthetic polymers are suitable for use in backbones
for forming macromers to make the bydrogels. These include
hydrophilic synthetic polymers, such as polyvinylpyrrolidone,
polyvinyl alcohol (including partially deacetylated
polyvinylacetate), poly[meth]acrylic acid and poly[meth]acrylamides
(where "[meth]" indicates optional methyl substitution of the
acrylate group), and mixed water-soluble copolymers such as
copolymers of maleic acid and ethylene. Natural, synthetic and
semi-synthetic saccharides and polysaccharides include hydroxyalkyl
celluloses, dextran, Ficoll.TM., bacterial fermentation products
such as xanthan or gellan, and food-grade materials such as
alginates, carrageenans, pectins, agars, glucomannans,
galactomannans, hyaluronic acid, heparin, chondroitin sulfate, and
other glycosaminoglycans, and starch. Proteins and nucleic acids
can be used. Multivalently-substitutable lipids, such as "dimer
fatty acid", monoacylglycerol, phosphatidyl inositol, cardiolipin,
and derivatives thereof, can also be used as components of a
backbone for forming a macromer.
[0036] In some cases, systems containing only macromeric components
can be used. It is important in this case that at least some of the
macromeric components have significant hydrophobic character, to
form hydrophobic domains on polymerization. Suitable backbones for
such a macromer, to which polymerizable groups can be grafted,
include water-soluble or water-dispersible copolymers of ethylene
oxide with propylene oxide and/or butylene oxide, and
polyurethanes, polyesters and polyamides containing hydrophilic
segments.
2. Monomers
[0037] Low molecular weight monomers that are useful in the
hydrogel materials share several key properties. The first property
is that the monomers should react appropriately in the presence of
the other components of the system, in particular a macromeric
component or water, when either or both are present. To obtain this
property, it is preferable, but not required, that the monomers be
miscible with other components of the material. One key material is
water at room or elevated temperature, up to about 100.degree. C.,
with which the monomer is preferably soluble or miscible to a
significant extent, such as 30% wt/vol., preferably 40% wt/vol.,
and most preferably 50% wt/vol. or higher. Alternatively, the
monomer can dissolve in or be a solvent for a macromer under
similar conditions, in the presence or the absence of water.
However, compositions formed of partially immiscible macromers and
monomers can be suitable if the polymerization reaction gives the
required properties for the final polymerized materials.
[0038] The second property is that the monomer should impart the
characteristic of low swelling in aqueous solution to the hydrogel
upon polymerization. One mechanism for providing decreased swelling
is a significant decrease in water absorption of a polymer formed
predominantly from the monomer by polymerization. At the high
concentration of solids in the hydrogels, a distinctly
heterogeneous hydrogel may form upon polymerization, or during
subsequent swelling in aqueous solutions.
[0039] Thirdly, the product formed from the polymerization of the
monomer and the macromer must contain water, or must be capable of
absorbing water. This can be as little as 2% to 5% by weight at
equilibrium, but preferably is at least 10% and more preferably is
20% or more. This water is important for providing lubricity to the
polymerized composition. The material does not need to be a
hydrogel at the conclusion of polymerization, if it can absorb or
adsorb sufficient water to become lubricious when in contact with
bodily fluids.
[0040] Unsaturated monomers which have been found experimentally to
be preferable for this function include diacetone acrylamide
("DAA"; CAS 2873-97-4). The minimum effective concentration for DAA
is about 30% as sole monomer, but may be less in blends with other
monomers. These include vinylcaprolactan (VC), vinyloxyethanol
(VOE), or up to about 10% of 2-acrylamido 2-methyl propanesulfonic
acid (AMPS). It is believed that other low molecular weight
monomers are suitable when blended with DAA; suitability and
limiting concentrations are readily determined by experimentation.
The useful range of monomers increases substantially when the
macromer has significant hydrophobic segments or domains.
[0041] It is believed that the effectiveness of the preferred low
molecular weight monomers is due to a balance of hydrophobic and
hydrophilic domains or segments, in the composition after
polymerization. The hydrophobic domains serve to control and limit
water uptake, and reinforce the polymerized composition which
functions as a water-swollen matrix. This is why it is important
that at least some of the macromer, or a segment of the macromer,
is hydrophilic, and remains hydrophilic after the polymerization;
and that a segment of the macromer, or of the monomer after
polymerization, be hydrophobic.
[0042] A representative class of preferred monomers are
acryloyllactic acid-methyl esters (ALM). Methyl acryloyl lactate;
the acrylic ester of lactic acid methyl ester;
CH.sub.2.dbd.CH--C(.dbd.O)OCH(CH.sub.3)C(.dbd.O)OCH.sub.3) is
prepared as described in Example 30. The ALM monomer can be viewed
as being composed of three parts, generally designated "AHK". "A"
designates a reactive group, which in ALM is the residue of acrylic
acid after esterification to the hydroxy group of lactic acid. "H"
designates a hydroxy carboxylic acid, which is lactic acid in ALM.
Finally, "K" designates an alkyl group, or another relatively inert
group, containing an alcohol group before esterification to the H
carboxyl group. In ALM, the K group is the residue of methanol.
[0043] It will be appreciated by those of skill in the art that
variants of the ALM structure can readily be manufactured, and will
allow the tailoring of the properties of the monomer to a
particular tissue situation. For example, each of these groups can
be replaced with analogous groups of the same class, resulting in
variations in the hydrophobicity, crystallinity, and hydrolysis
stability of the materials resulting from the polymerization of
these monomers. Thus, A can be selected from acrylic acid and
methacrylic acid, or from other acids carrying unsaturation. These
include crotonic, isocrotonic, tiglic, angelic, and cinnamic acids,
and unsaturated diacids including maleic, fumaric, citraconic,
mesaconic, itaconic, citric and isocitric acids, as well as
monoesters or monoamides of the dicarboxylic acids.
[0044] H can be any of a large number of hydroxy carboxylic acids.
These are the residues widely used to create degradability in
polymers, so that they will degrade to small, metabolizable or
excretable units, in a reasonably predictable way in the body. The
most commonly used of these are the lower alkyl hydroxy acids,
including glycolic acid, lactic acid, 3-hydroxy-propanoic acid, 2-,
3-, or 4-hydroxybutyric acid, the various isomers of
hydroxypentanoic acid (including valeric acid), and the
hydroxyhexanoic acid isomers, including 2-caproic acid and
6-caproic acid (epsilon-caproic acid). Many of these hydroxy acids
are available in "lactide" or lactone forms, which can simplify
synthesis. Other commonly used hydroxy acids include the lactone
and hydrolyzed forms of dioxanone (1,4-dioxan-2-one) and other
cyclic dioxanones, and of similar 1-oxan-2-one ethers with 5 and 7
membered rings.
[0045] In general, when H is formed from the 2-hydroxy acids, the
monomers and the corresponding polymers and copolymers tend to
degrade by hydrolysis most rapidly, followed by the 3-, 4-, 5-, and
6-hydroxyacids. This is due mainly to the hydrophobicity of the
higher hydroxy acids. Hydrophobicity tends to exclude water from
the labile ester bond between the H and the K group, which slows
degradation. Hydrophobicity can also be affected by increasing the
hydrocarbon content of the hydroxy acid by incorporation of side
chains, such as the methyl group in lactic acid. Likewise,
increased hydrophobicity of the K group also slows hydrolysis.
Steric protection of the ester linkage from water would also slow
hydrolysis. Degradation time is also affected by the crystallinity
of the polymer or copolymer. Increases in crystallinity tend to
exclude water from the labile ester bond between the H and the K
group, which slows degradation. Crystallinity of the polymer or
copolymer can be affected by typical factors such as tacticity,
molecular weight, etc.
[0046] In an alternative structure, H can be the residue of an
amino acid, especially of an alpha-amino acid. The linkage between
the A and the H group is then an amide linkage. This increases the
difference in hydrolysis rates between the A-H linkage and the H-K
linkage when K is being removed. For example, glycine ethyl ester
hydrochloride is commercially available, and could be acrylated
under essentially the same conditions as methyl glycolate (above),
particularly after conversion to the free amine. It is expected
that it would preferentially de-esterify to form the derivatized
lactic acid under the same conditions as ALM (see Example 33).
[0047] K is an esterified group, which is methyl in ALM. The lower
alcohols are preferred as sources of K groups, as they will become
innocuous alcohols upon hydrolysis of the ester bond to the H
group's carboxyl. These include methanol, ethanol, propanol,
isopropanol, isomers of butanol, isomers of pentanol, and isomers
of hexanol. More generally, larger alkyls are also suitable, such
as those formed from fatty acids (containing up to about 30 carbon
atoms), or from sterols (e.g., cholesterol, cholestanol) or other
lipid materials with hydroxy groups (e.g., sphingosine). As is
known, increase in the size of the K component will tend to
increase the hydrophobicity of the material, which will change both
its mechanical properties and its degradation time.
[0048] Other K groups containing alcohol groups (to provide a
readily hydrolyzable linkage) are possible. These may include
biologically active molecules, polymers, and other large molecules.
Steric considerations will generally require that such monomers be
polymerized together with small monomers--for example, AHK
molecules with K derived from lower alcohols; or suitable non-AHK
polymerizable monomers.
[0049] Some of the starting "HK" materials for the synthesis in
which an activated "A" group (here, acryloyl chloride) is added to
a preformed HK group (here, methyl lactate) are commercially
available. These include ethyl and/or methyl esters of lactic,
glycolic, 2-hydroxybutyric, 2-hydroxycaproic, and 6-hydroxycaproic
acid. However, propyl and higher substituents are not readily
available. The amine equivalents (e.g., glycine ethyl ester
hydrochloride) have similar availability. A synthetic method for
making monomers containing any of a wide range of K groups is
described in the examples. The principal requirement of the "K"
group is that it contain at least one hydroxyl group.
[0050] C. Excipients
[0051] Compositions can also include ancillary reagents, such as
catalysts or initiators of polymerization; excipients, including
buffers; stabilizers; and dye. The compositions will be tailored to
accommodate the chemistry or chemistries that are used to
polymerize and crosslink the materials.
[0052] It should be noted that while reinforcing materials such as
fibers and particulates can be added to the hydrogel materials to
improve their toughness under load and shear, it is preferable if
the hydrogel materials spontaneously form segregated microstructure
during polymerization or subsequent hydration. Such materials are
thereby "self-reinforcing". This unusual property, when it can be
obtained while satisfying other requirements, is a preferred but
not required feature.
[0053] The hydrogel materials may contain other therapeutic,
prophylactic or diagnostic materials which interact with or on the
tissues to which the material has been applied. These materials
include drugs and other therapeutically active materials, such as
proteins, small molecule drugs, nucleic acid molecules, sugars and
polysaccharides, lipids, natural extracts, glycosaminoglycans and
inorganic compounds. As noted above, excipients such as
plasticizers, emollients, fillers, lubricants, buffers, and
stabilizers, may also be added. Any of these may be admixed into
the material before or during polymerization or crosslinking, and
optionally may be encased in liposomes, microparticles, or other
delivery forms, for local or systemic delivery.
II. METHODS FOR POLYMERIZATION
[0054] Any reaction chemistry that is compatible with application
in an aqueous environment, and that can be conducted safely on
living tissue, is potentially suitable to polymerize the gels. A
preferred chemistry involves the use of ethylenically-unsaturated
materials, including but not limited to vinyl, acrylic, and alkyl
groups ("unsaturated group"). At least some of the macromer or the
monomer is preferably substituted (,as terminal or side groups,) so
as to be at least difunctional to allow crosslinking in addition to
linear polymerization. Reactions with ethylenically unsaturated
materials commonly are free-radical chain-growth reactions, and
typically are initiated with the use of a chemical initiator or a
photoinitiator. Free-radical polymerizable linkages are preferred
for forming the hydrogels. The preferred monomers, DAA and ALM,
react by this mechanism, and it is convenient to use the same
method for crosslinking. However, polymerization and/or
crosslinking can be provided by other chemistries, such as those
noted above. Any crosslinking or polymerization method that can be
used in situ in the body is potentially of use.
[0055] An alternative chemistry involves step-growth (condensation)
polymerization, and similar heterolytic reactions. For example, a
leaving group, such as an N-hydroxy succinimide ester, is easily
displaced by a nucleophilic group, such as an amine. To create
linear polymers, the preponderance of reactive molecules must have
a functionality of two. To create a crosslinked gel, the
composition must contain reactive molecules with functionality
greater than two. Because polymerization of at least one component
to form a low-solubility material is thought to be involved in
obtaining the preferred gel compositions, there may be several
types of reactive materials in the composition.
[0056] Systems of polymerization and crosslinking using both types
of chemistry are possible. For example, one component, or a
fraction of a component, could carry an electrophilic center with a
good leaving group as well as an unsaturated group, while another
reactive component could carry nucleophilic groups. Then the first
component could polymerize by free radicals, while also becoming
crosslinked by the second component. Moreover, certain reactive
groups are inherently capable of undergoing several types of
crosslinking. For example, a maleimide group can undergo
Michael-type addition with a nucleophile such as an amine or thiol,
but can also polymerize by free radical polymerization of its
double bond. It can also react by hydrolysis of its strained ring,
for example by reaction with an amine to form an amide.
[0057] Hydrogels can be homo-polymers or hetero-polymers (or
co-polymers), interpenetrating networks or semi-interpenetrating
networks.
[0058] The polymerized materials can be covalently or
non-covalently crosslinked. Non-covalently crosslinked materials
have a molecular weight after polymerization of less than 200
kDa.
III. MEDICAL APPLICATIONS
[0059] The hydrogels described herein are useful in the treatment
of what may be termed "orthopedic tissues". The medical specialty
of orthopedics is concerned with the preservation, restoration and
development of the form and function of the musculoskeletal system,
extremities, spine and associated structures by medical, surgical
and physical methods." (Stedman's Medical Dictionary, 25.sup.th
ed., Williams & Wilkins, 1996). Orthopedic tissues include
bone, cartilage, and related structures, for example, meniscus,
bursa, synovial membranes, and other structures of the joints, as
well as tendons, ligaments, muscles and the annulus and nucleus of
the vertebral disks. Tissues with similar mechanical properties
such as teeth, gums, and gingival ligaments can also be treated
effectively with the hydrogel materials.
[0060] The properties of the hydrogel forming reagents have been
tailored to enable the creation of materials that are hydrogels (as
herein defined), and that also adhere well to orthopedic tissues.
Such strong adherence can be difficult to achieve with polymeric
materials in current uses. For example, fasteners and sculpting of
undercuts and hollows in bone and cartilage can be required to
obtain good attachment of available polymeric implants. The
hydrogel materials described herein are characterized by their
strong adherence. When polymerized in the presence of the tissue
with the use of appropriate priming techniques, the hydrogels can
adhere to tissue with sufficient tenacity that either the gel or
the tissue will fail before the adhesive bond between the tissue
and the implant is broken ("excellent" adherence, as defined
above). "Good" adherence is also acceptable in these materials.
[0061] Moreover, these materials have the appropriate mechanical
strength and other mechanical properties, such as resilience and
stiffness, to withstand the forces applied in these anatomical
situations. In addition, the same physical properties make the
hydrogels suitable for coating of implants applied to the joints
and similar structures. Among the therapeutic benefits provided by
these hydrogels is the provision of lubricity to a treated surface.
The hydrogel coating can simulate the natural lubricity of an
orthopedic surface, such as cartilage, thereby allowing favorable
joint articulation while preventing damage as the underlying tissue
heals.
[0062] Another benefit is the ability to remodel a joint surface by
shaping the polymerized deposit with a mold to create or re-create
a surface profile of a tissue, such as a condyle. For example, a
desired profile can be present in a transparent or highly
translucent molding member. The tissue surface is primed with
reactive materials as described herein, and the cavity of the mold
is filled with materials to form the hydrogel. The filled mold is
placed, or is subsequently applied to the tissue surface, so that
the unpolymerized materials are in contact with the primed surface.
Then the material is polymerized by application of light, or by
waiting for polymerization of pre-mixed reactive materials (in
which latter case, the mold need not be transparent or
translucent). After polymerization, the mold is removed, leaving a
dense, lubricious, tightly-adhering hydrogel-forming material
having the appropriate profile. Alternatively, if the material is
applied as a paste, or physically gels on contact with tissue (for
example, because of a temperature change), then it can be shaped to
a profile using a scalpel or other instrument before or after
polymerization.
[0063] Likewise, the hydrogel materials and techniques described
herein can be used to resurface damaged sites. For example, the
site from which cartilage grafts is taken can be irregular, and be
susceptible to damage, or can damage opposing surfaces. Coating or
filling the void with the hydrogel materials will prevent ancillary
damage while the tissue heals. The material may optionally be
designed to be removed by spontaneous degradation, or by controlled
abrasion, during this process. A particular advantage of the
hydrogel materials, in this and other uses, is that the improved
materials can be applied by minimally invasive techniques, for
example through a needle or narrow cannula, and polymerized in
situ. This makes resurfacing and other operations simpler, and thus
less traumatic and less costly, while improving the chances of
success. Because the application procedure is simple and minimally
invasive, it can be repeated as required to maintain the usefulness
of a tissue--for example, a knee joint--and thereby postpone the
requirement for a joint replacement or other invasive repair
procedure. In such procedures, it is acceptable for the
hydrogel-forming implant or surface coating to gradually abrade, as
long as the resulting particles are of a size which is appropriate
to cause no excessive tissue response. The material can
concurrently degrade by simple or enzymatically-catalyzed
hydrolysis.
[0064] In another use, a torn area of a meniscus can be initially
repaired by standard methods, which use pinning and suturing to
re-appose the torn segments. A layer of the hydrogel is then
applied. The firmly-adherent gel material redistributes the applied
load on the meniscus during healing. Similar uses can be found in
other locations in the body, such as in the spine, and in non-limb
joints, such as the jaw.
[0065] While the hydrogel materials have been described in terms of
coatings on tissue or on implants, it is also possible to use these
materials as extremely strong yet biocompatible medical adhesives,
by coating both surfaces to be adhered with a primer and
polymerizing the materials while the materials are in contact with
both primed surfaces. Allowance should be made for the predictable
expansion of the adhesive during its hydration to equilibrium.
IV. EXAMPLES
[0066] The present invention will be further understood by
reference to the following non-limiting examples.
[0067] The examples demonstrate that it is possible to make
extremely strong, resilient, low-swelling hydrogels which are
biocompatible and which adhere well to orthopedic tissue. The
examples also show that the more successful formulations, in terms
of having the desired end properties as polymerized gels, have an
initial water content before polymerization ranging from 0% up to
about 40% (wt/wt). The range giving the best gels was broad:
successful formulations were found at 0% and at 33%, and at several
concentrations in between.
[0068] The remainder of the formulations contained polymerizable
materials. Macromers having molecular weights above 500 Da
(typically over 1000 Da, and as high as about 100 kDa,) constituted
from 0% to about 50% of the weight The range of about 10% to about
20% was most often successful.
[0069] The macromers used were also crosslinking agents. It is
believed that the macromers serve two functions, as the crosslinker
and as the hydrophilic region, and that these functions could be
placed in separate molecules if required. However, the combination
of the two functions in one molecule is convenient.
[0070] Monomers, with molecular weights below 1000 Da, and more
typically below about 500 Da, constituted from about 45% up to 100%
of the formulation, typically in the range of about 50% to 90%, and
most frequently in the range of about 60 to 80%. The most
successful monomers, DAA and ALM, each have hydrophobic groups and
more than one hydrophilic group. ALM has two ester bonds, while DAA
has an amide and a ketone. The poorly water-soluble ALM could form
gels at 100% concentration, which absorbed over 2% of water, and
formed better gels when containing a hydrophilic crosslinker. In
contrast, the water-soluble DAA, VC or combinations of the two,
without a crosslinker, were not suitable as the sole polymerizable
component.
[0071] In general, polyacrylamide and polyacrylic acid are not
suitable as major components of the gel since they are known to
swell and form weak gels. It is significant that DAA is
amphiphilic, having both hydrophilic and hydrophobic regions, and
it is believed that a substantial proportion of the materials in
the hydrogel should be amphiphilic. On the other hand, very
hydrophobic monomers, such as methyl methacrylate or styrene, form
rigid, non-swelling polymers. It is clear from the examples
concerning pure ALM that using ALM as the sole monomer produces
materials near the low end of the range for water absorption.
However, addition of more hydrophilic monomers, particularly
crosslinking macromers, imparts an improved degree of hydration as
well as improved resiliance. Because the degree of hydrophobicity
that is useful is limited, those "AHK" analogs of ALM that have
relatively small hydroxy or amino acids, and relatively small ester
groups, are preferred. In summary, a preferred composition includes
at least about 5%, preferably about 10%, and most preferably about
20% to at least about 50%, of a monomer or macromer having
substantial water solubility. Alternatively, the hydrophilicity can
be provided by an amphiphilic macromer, even one of low solubility
(e.g., certain poloxamers, such as Pluroric-type polymers) having a
substantially water-soluble block comprising at least about 20% of
the weight of the polymer.
[0072] The compositions that are most suitable for these
applications form gels that have a maximum equilibrium swelling in
water of about 300%, and preferably less than 200%. Values of about
100%, or less, are more preferred. To maintain adequate toughness
and tensile properties, the percent of solids in the swollen state
should be at least about 20%, preferably 30%, and most preferably
40% or more. To obtain favorable combinations of these properties,
a pre-swelling solids content of 40% or more of polymerizable
materials is preferred, but this value is secondary to obtaining
the required post-swelling values.
[0073] The gels both before and after swelling must be resilient,
for durability under dynamic conditions of use. A value of the
percent elongation to failure of 100% or more is preferred, but
smaller elongations, such as 25% to 50%, can be suitable,
especially at high solids contents. There is no upper limit on the
desirable elastic (reversible) elongation at failure. Some
irreversible deformation may also occur. Tensile strength and
modulus are clearly important. It is straightforward to obtain a
measurement of tensile values, but not as easy to prescribe a
limiting value, in part because of the non-criticality of the exact
form of the stress-strain curve, in this application. In general,
the preferred materials have tensile values of well over 1 MPa
before hydration, and of over 0.4 MPa after hydration.
Post-hydration values can clearly be lower, especially when the
implant or coating is subject to compressive loading with little
shear. Post-hydration values of 100-200 kPa are suitable. In some
uses, tensile strengths of 20 to 50 kPA can be used.
Example 1
Preparation of PEGTMC-diacrylate/DAA Hydrogel
[0074] A macromer consisting of a 35 kiloDalton (kDa) core
(manufacturer-specified molecular weight; MW about 27 kDa by GPC)
of polyethylene glycol (PEG) is reacted with trimethylene
carbonate, giving hydroxy-terminated molecules with an average of
about two PEG segments and about 15 TMC groups per molecule. This
molecule is then end-capped with acryloyl chloride to make it
crosslinkable. The molecule is called 35KTA2. Details of synthesis
are described in WO 98/12243 by Focal.
[0075] A solution was prepared in water which contained by weight
about 68% DAA, 15% 35KTA2, about 17% water, and materials for
redox-assisted photopolymerization, including Irgacure.RTM. 651
(2,2-dimethoxy 2-phenyl acetophenone; DMAP), t-butyl hydroperoxide,
and tiethylamine as electron carrier and buffer. This was
accomplished by adding 3.0 g of 35kTA2 and 13.6 g of DAA to 3.4 g
of water, and heating to 70.degree. C. with stirring to complete
dissolution. Then 83 microliters of 6% t-butylhydroperoxide (in
water) and 30 microliters of molten DMAP were added, with stirring
and heating as required for dissolution. The mixture was treated by
centrifugation or standing to remove bubbles. It was either stored
at minus 40.degree. C. (dark), or used warm (45-50.degree. C.) or
at room temperature to form a hydrogel.
[0076] This gel-forming material was polymerized by illumination
with near-UV light, 350-400 nm band from a xenon source, for about
40 seconds at about 50 to 100 mW per square centimeter, to form
bulk gels for testing of mechanical and other properties. When
applied to tissue to test adherence, the tissue was primed with a
solution prepared as follows. Ferrous gluconate (0.71 g) and 1.42 g
D-fructose were dissolved in 100 mL of water. In 7.0 g of this
solution, 3.0 g of a low-molecular weight macromer, 3.3 KLA2 (made
from nominal 3.3 kDa PEG with an average of five lactate residues
per PEG, acrylate end-capped) was dissolved. The primer was applied
to the tissue surface with a brush. Priming technology is described
in more detail in U.S. Pat. Nos. 5,800,373 and 5,844,016 to
Hubbell, et al.; synthesis of the 35KTA2 macromers is described in
WO 98/12243 by Focal; and synthesis of the 3.3KLA2 macromer is
described in U.S. Pat. No. 5,410,016 to Hubbell et al., along with
techniques for photopolymerization.
[0077] The bulk properties of the "68 DAA/15 35KTA2" gels are
presented in FIG. 1 as formed, after incubation in water for 1 day
at 37.degree. C., and after 7 days at 57.degree. C. (accelerated
aging).
[0078] In Table 1, the preferred material is compared to cartilage
and meniscus in mechanical properties: tensile modulus, tensile
strength and elongation. TABLE-US-00001 TABLE 1 Material Properties
of Bovine Cartilage and Meniscus and Hydrogel Tensile Tensile
Strength Elongation Modulus (MPa) (MPa) (%) Articular Cartilage
3-10 -- -- Meniscus 50-70 5-30 15-20 68 DAA/15 35KTA.sub.2/ 8.9 8
800 17 H.sub.2O (as formed) 1.1 2 500 (swollen .about.90%)
[0079] "Elongation (%)" is length at failure less original length,
divided by original length. Tensile strength is secant modulus at
maximum stress before failure. The final percent solids was about
40%. The gels scored "Excellent" on tissue adhesion, and passed the
clamp (hemostat) test. The gels were turbid (white, nearly opaque)
before swelling, and were opaque after swelling. Microscopic
examination suggested the presence of heterogeneity in the
structure, and possibly the presence of porosity.
Examples 2-27
Synthesis and Comparison of DAA and Other Vinyl-Based Hydrogel
Materials
[0080] Additional samples of potentially suitable materials were
prepared and subjected to a limited set of tests. These samples are
shown in Table 2. TABLE-US-00002 TABLE 2 DAA and Other Vinyl-Based
Hydrogels % Vinyl Physical Physical % Solids Example Monomers.sup.2
Macromer(s) %.sup.1 Characteristics Characteristics H.sub.2O at
Clamp.sup.5 No. (%).sup.1 (%).sup.1 H.sub.2O As Formed.sup.4 After
Hydration Uptake Equil. test Adherence.sup.6, Notes 2 DAA (4.4)
35KTA.sub.2 60.6 Soft, elastic Very soft, elastic 362 6.36 Pass
Cohesive (20.0) (swollen) Failure 20KTA.sub.2 (5.0) Artic Cartil 3
DAA (60.0) None 40.0 Rigid, opaque, Rigid, opaque, .about.0
.about.60.0 -- -- plastic (yielded) plastic 4 DAA (49.1)
35KTA.sub.2 32.7 Tough, opaque, Flexible, opaque, 139 28.1 Cohes.
Fail (18.2) resilient resilient Patella 5 DAA (54.0) 3.3KL5 (10.0)
36.0 Strong, brittle Brittle 93 33.2 6 DAA (41.0) 35KTA.sub.2 27.2
-- -- 176 26.3 -- -- VOE (21.6) (10.0) 7 DAA (51.0) 35KTA.sub.2
34.0 Tough, notch Tough, opaque, 135 -- -- -- (1.50) resistant
flexible 8 DAA (68.0) 35KTA.sub.2 17.0 Stiff, opaque, Somewhat
tough, 101 -- -- -- (15.0) notch resistant opaque, flexible 9 DAA
(49) 35KTA.sub.2 (18) 33 Very tough, -- -- -- -- Cohesive opaque
Failure Vertebral disk annulus 10 DAA (30) HDI.sup.7-BDO.sup.7, 40
Tough, opaque, Softened after 149 24 Pass 2 -- 3.3 KA.sub.2 (30)
good tear swell click resistance Fail 3 click 11 DAA (60)
HDI.sup.7-BDO.sup.7, 20 Stiff, tough Stiffer than Ex 90 42 --
promising 3.3KA.sub.2 (20) 10 polyurethane macromer 12 DAA (60)
Tween A.sub.3.sup.7 20 -- -- 184 31 -- -- AMPS (2) (5) 13 DAA (68)
35KTA.sub.2 (15) 17 Tough, opaque 87 44 -- Soln. and Paste
formulation soln. - Cohes Fail Paste mixed cohes/adhes Fail to
cart, lig, bone 14 DAA (68) 35 KTA.sub.2 (15) 17 -- -- -- -- --
Disk annulus, knee cartilage of pig, Cohes. Fail 15 DAA (68)
35KTA.sub.2 (15) 17 Tough, opaque -- -- -- -- 7 day sub Q implants
- Gel formed in situ-benign tissue response 16 NIPAM (68)
35KTA.sub.2 (15) 19.4 Tough, opaque Low Mod., Clear 1018 6.6 Pass
Extreme range of toughness. Loss on hydration 17 VC (69)
35KTA.sub.2 (26) 15 Clear, soft, Slightly hazy, 669 11.0 Fail Low
exotherm elastic weakened 18 VC (26) 35KTA.sub.2 (13) (18) Very
tough, Softened 184 28.9 -- DAA (43) opaque 19 VI (84) 35KTA.sub.2
(16) 0 Did not solidify -- -- -- -- No water; melted at 82 deg. and
cured 20 MVA (84) 35KTA.sub.2 (16) 0 Soft, elastic, Softened clear
325 19.8 -- -- same as last clear 21 DAA (59) 35KTA.sub.2 (11) 0
Rigid, Soft, opaque 145 40.8 Same; Cured as VC (30) translucent
liquid or paste to tough product 22 DAA (70) F-88A.sub.2 (13) 17
Very rigid, Softened 51 54.8 translucent 23 DAA (70) F-127 A.sub.2
(13) 17 Clear, hard, Softened, 47 56.2 Pass tough translucent 24 VC
(33) F-127 A.sub.2 (67) 0 Rubbery, clear, Softened, brittle 219
31.3 Fail Melted to mix tough 25 DAA (50) F-127 A.sub.2 (50) 0
Clear, tough Softened, clear, 155 39.2 Equivocal Melted to mix
tough Pass 26 DAA (44) F-127 A.sub.2 (44) 12 Clear, tough Softened,
clear, 131 38.3 Pass Tore cleanly from tough defect 27 VC (100) --
-- Yellow, tacky, Soft, weak, tacky -- -- -- Very slow cure, rigid
inhibited Notes to Table 2: .sup.1Percent of total formulation
.sup.2DAA = Diacetone acrylamide; VC = Vinyl caprolactam; VOE =
Vinyloxyethanol; MVA = Methyl vinyl acrylamide; AMPS = 2,
Acrylamido-2-methylpropane sulfonic acid; VP = N-vinyl pyrrolidone
.sup.3t-BHP, t-Butyl Hydroperoxide (.about.250 ppm) for redox with
primer .sup.4UV cured (40 sec, ca. 100 mW/cm.sup.2; 350-400 nm),
Irgacure .RTM. 651 Photoinitiator, sometimes added as solution in
where the weight of. VC is twice the weight of Irgacure .RTM..
.sup.5Hemostat (2 clicks) applied to specimen, cast and cured as
"disk" on Petri dish (see details elsewhere) - swollen unless
indicated. Pass means resisted breakthough for more than 5 sec.
(preferably for at least 30 sec). .sup.6Using 30% 3.3 KL5A2, 500
ppm ferrous gluconate; 1% fructose in water as primer. Adherence
test involves inserting 20 gauge needle at base of gel and pulling
up parallel to base. The ratings "E", "M", "F", and "P" correspond
with "excellent adherence", "moderate adherence", "fair adherence",
and "poor adherence", respectively. .sup.7BDO = 1.4-Butanediol; HDI
= Hexamethylene diisocyanate; F-127 = Pluronic' F-127 copolymer,
Tween A.sub.3 = Tween' surfactant, triacrylate; P-65 = Pluronic
P-65 copolymer .sup.8NIPAM = N-Isopropylacrylamide; VC = N-vinyl
caprolactam; DAA = Diacetone acrylamide, VI = N-vinyl imidazole
.sup.9"Plu" = Pluronic F-88 or Pluronic F-127 copolymer
[0081] Examples 2-27 demonstrate certain formulations that
polymerize to produce hydrogels acceptable for orthopedic
applications, as well as selected control materials.
[0082] Example 2 shows a "classic" hydrogel which, although it
contains some (4.4%) DAA, and although it adheres well to tissue,
has a high swelling and low final solids concentration. It is too
soft for use in a load-bearing application, because its final
polymer concentration (6.36% solids) is too low.
[0083] Example 3 shows that DAA without a crosslinker forms a
plastic with a yield point, rather than a highly resilient
material.
[0084] Examples 4, 5, 7, and 9 show variations of the preferred
formula, which is depicted in example 8. Like example 8, these
examples also yield hydrogel materials useful for orthopedic
applications.
[0085] Example 6 shows partial substitution of DAA with a charged
monomer.
[0086] Examples 10 and 11 show the use of a polyether urethane
backbone, the synthesis of which is described below in Example
28.
[0087] Example 12 shows use of a surfactant, polyoxyethylene
sorbitan monolaurate (Tween.RTM. 20), which has been derivatized to
contain about three acrylic groups per molecule, as a hydrophilic
crosslinking macromer.
[0088] Examples 13 and 14 show adherence of the preferred formula
of Examples 1 or 8 to various tissues. Example 13 also compares the
preferred formulation as a solution (after heating) versus as a
paste, as obtained without heating, or on thawing from the frozen
state without heating. The paste is less adherent, giving
"Moderate" rather than "Excellent" adhesion.
[0089] Example 15 summarizes a subcutaneous implantation experiment
(in rats) with the preferred formulation. Good biocompatibility
(minimal tissue response) was found.
[0090] Examples 16 and 17 show that complete substitution of
N-isopropyl acrylamide (NIPAM) and vinylcaprolactam (VC) for DAA
gives gels that swell extensively and thereby lose toughness.
However, Example 18 shows that VC can partially substitute for DAA
with retention of desirable properties. Since DAA is more
hydrophobic than VC, this effect may demonstrate desirability for
hydrophobicity in the material.
[0091] Examples 19-21 show non-water-containing formulations, made
by co-dissolving the macromers and the monomers with heating.
Example 19 is unsuitable; Example 20 is marginal but acceptable;
and Example 21 is essentially the same as Example 18, which
contained water during
[0092] Examples 4, 5, 7, and 9 show variations of the preferred
formula, which is depicted in example 8. Like example 8, these
examples also yield hydrogel materials useful for orthopedic
applications.
[0093] Example 6 shows partial substitution of DAA with a charged
monomer.
[0094] Examples 10 and 11 show the use of a polyether urethane
backbone, the synthesis of which is described below in Example
28.
[0095] Example 12 shows use of a surfactant, polyoxyethylene
sorbitan monolaurate (Tween.RTM. 20), which has been derivatized to
contain about three acrylic groups per molecule, as a hydrophilic
crosslinking macromer.
[0096] Examples 13 and 14 show adherence of the preferred formula
of Examples 1 or 8 to various tissues. Example 13 also compares the
preferred formulation as a solution (after heating) versus as a
paste, as obtained without heating, or on thawing from the frozen
state without heating. The paste is less adherent, giving
"Moderate" rather than "Excellent" adhesion.
[0097] Example 15 summarizes a subcutaneous implantation experiment
(in rats) with the preferred formulation. Good biocompatibility
(minimal tissue response) was found.
[0098] Examples 16 and 17 show that complete substitution of
N-isopropyl acrylamide (NIPAM) and vinylcaprolactam (VC) for DAA
gives gels that swell extensively and thereby lose toughness.
However, Example 18 shows that VC can partially substitute for DAA
with retention of desirable properties. Since DAA is more
hydrophobic than VC, this effect may demonstrate desirability for
hydrophobicity in the material.
[0099] Examples 19-21 show non-water-containing formulations, made
by co-dissolving the macromers and the monomers with heating.
Example 19 is unsuitable; Example 20 is marginal but acceptable;
and Example 21 is essentially the same as Example 18, which
contained water during polymerization. Note that Example 20 uses
methyl vinylacrylamide (MVA) as monomer, and does not contain
DAA.
[0100] Examples 22-26 show various formulations in which the
macromer is an acrylated poloxamer (i.e., PEG-PPO block copolymer),
made by simple acrylation of commercial materials, such as the
Pluronic.RTM. surfactants by BASF. These macromers, which have
hydrophobic segments, can also form hydrogel materials for
orthopedic use. However, the formulation with VC is relatively
brittle, while the DAA-containing formulae are acceptable.
[0101] Example 27 shows that VC alone is not satisfactory, as
expected from the absence of crosslinking.
Example 28
Hydrogels Based on Polyurethane-Based Macromers
[0102] The reaction of PEG or poloxamer diols and, optionally
short-chain diols with diisocyanates, produces macromeric diols
which can be reacted with acryloyl chloride, optionally after
reaction to provide degradable linkages, to provide
acrylic-functional macromonomers with a wide range of properties
from soft and weak to quite tough. These versatile compositions
allow control of solubility and hydrophobicity.
[0103] A macromer with a polyurethane backbone, used in Examples 10
and 11 above, was prepared by reacting 1,4-butanediol (1.27 g,
0.0147 m), PET, MW 3,400 (50.00 g, 0.0147 m) and
1,6-diisocyanatohexane (4.66 g, 0.0277 m) in toluene with
dibutyltin dilaurate catalyst (80.degree. C., 4 hr.). The resulting
macrodiol was acrylated with acryloyl chloride and isolated by
precipitation with hexane. This material was used in an
adhesive/sealant fonnulation, shown in Example 10, by mixing it
(3.0 g) into a solution of DAA (3.0 g) in water (4.0 g). This
solution was warmed and 6% aqueous t-butyl hydroperoxide (42 mL)
along with molten Irgacure.RTM. 651 (15 .mu.L) were mixed in. The
resulting formulation was treated to remove bubbles by
centrifugation or allowing it to stand at ambient and stored at
-40.degree. or used to prepare hydrogel.
[0104] A similar preparation was used in Example 11 by mixing 2 g
of the acrylated polyurethane with a solution containing 6 g of DAA
and 2 g of water; the other ingredients were the same.
Example 29
In vivo Testing of Orthopedic Hydrogel
[0105] An acute implant study was performed with the preferred
composition DAA (68%)/35KTA2 (15%)/H.sub.2O (17%), on a rabbit
medial femoral condyle in which a 3 mm.times.1 mm defect had been
created. A strong bond was formed between the hydrogel implant and
the cartilage and bone to which it had been applied.
[0106] A 10 day study showed that the hydrogel remained in place
with no apparent damage. Surrounding tissue was found to be
comparable to untreated, injured controls, demonstrating short-term
biocompatibility. In particular, histological sections showed no
apparent damage or injury to adjacent cartilage, either in the
chondrocytes or in the matrix. The materials used in this study had
previously passed cytocompatibility tests and were sterile and
non-pyrogenic. The results indicated that the hydrogel replaced
cartilage tissue, caused no damage, and allowed function of the
joint for the duration of the study.
Example 30
Synthesis, Polymerization, and Testing of polyALM
[0107] Acryloyllactic acid-methyl ester was designed for the
formation of orthopedic materials. Acryloyllactic acid-methyl ester
(ALM; methyl acryloyl lactate; the acrylic ester of lactic acid
methyl ester;
CH.sub.2.circleincircle.CH--C(.dbd.O)OCH(CH.sub.3)C(.dbd.O)OCH.sub.3)
was prepared as follows.
[0108] A 15.61 g amount of methyl lactate (isomer S(-)) in 81 mL
toluene was reacted with 13.79 g acryloyl chloride in the presence
of 15.79 g triethylamine at less than 20.degree. C. The acryloyl
chloride was added drop-wise with cooling to the reaction mixture
containing the TEA, to control the exotherm. The resultant TEA.HCl
salt was filtered off; and the ALM/toluene solution was purified by
passing it through a column containing 15 g alumina, and stabilized
with 6.5 mg hydroquinone. The ALM product was isolated by removal
of toluene under vacuum using a rotary evaporator.
[0109] The ALM yield ranged from 72% to 75%. Based on analysis by
Proton-Nuclear Magnetic Resonance Spectroscopy (H-NMR), the amber
product typically contains: 94.4% ALM, 1.0% acryloyllactic acid
ethyl ester (ALE), 0.0% TEA.HCl, 1.43% methyl lactate, 0.72%
acrylic acid, and 1.45% toluene.
[0110] Then the ALM was distilled under vacuum at 60-62 C and
0.8-0.95 mTorr, yielding a clear, colorless fluid. Based on
analysis by H-NMR, the ALM typically contains: 98.01% ALM, 0.74%
ALE, 0.0% TEA.HCl, 1.43% methyl lactate, 0.22% acrylic acid, and
0.02% toluene.
[0111] Polymer A: A neat solution of 150 g ALM was auto-polymerized
under vacuum at 60-70.degree. C. for about 20 minutes (exotherm to
120.degree. C.). The very elastic, ultra high molecular weight (MW)
polymer required breaking of the reaction vessel for removal. The
polymer swelled and or showed partial solubility in most organic
solvents, including chloroform, methylene chloride, dimethyl
sulfoxide, tetrahydrofuran, hexafluorisopropanol, but was not
soluble in water. This material hydrated 2.7% over a period of 3
days at 37.degree. C. and had a modulus of 338.64 kPa after vacuum
drying.
[0112] Polymer B: A neat solution of 1.95 g ALM was polymerized
under N.sub.2 with 10.0 mg benzoyl peroxide as initiator by heating
at 60-70.degree. C. for about 5 minutes. The elastic, high MW
polymer required breaking of the reaction vessel for removal. This
polymer had a modulus of 29.55 kPa.
[0113] Polymer C: A low MW equivalent was prepared by
polymerization of 2.45 g ALM with 30.2 mg benzoyl peroxide as
initiator by heating at 60-70.degree. C. for about 5 minutes. This
polymer had a modulus of 16.2 kPa. Both Polymers B and C were very
flexible and soluble in most organic solvents, including
chloroform, methylene chloride, dimethyl sulfoxide,
tetrahydrofuran, but were not soluble in water.
[0114] A 0.2261 g piece of the high MW polyALM (Polymer B) was
incubated with about 30 mL of phosphate buffer pH 7.4 at 37.degree.
C. The sample weight was 0.2272 g after 3 days. The material was
dried for 24 hrs under vacuum at room temperature. The weight
decreased to 0.2212 g, indicating an equilibrium hydration of about
2.2%. This demonstrates that although the high MW polyALM was
insoluble in water, it absorbed water to at least 2.2% by weight.
The hydrated polyALM was lubricious rather than tacky. The modulus
of this incubated polymer was 44.18 kPa.
[0115] A 0.3163 g amount of the low MW polyALM (Polymer C) was
incubated with about 30 mL of phosphate buffer pH 7.4 at 37.degree.
C. The sample weight was 0.3131 g after 3 days. The material was
dried for 4 hrs under vacuum at room temperature. The weight
decreased to 0.2967 g, indicating an equilibrium hydration of about
5.2%. This demonstrates that although the low MW polyALM was
insoluble in water, it absorbed water to at least 5.2% by weight.
The hydrated polyALM was lubricious rather than tacky. The modulus
of this polymer was 26.95 kPa
[0116] Polymers A, B, and C were incubated at 85.degree. C. in
water at pH 11.8-12.5. After 8 days, Polymer A had substantially
dissolved. The aqueous solution was viscous. Polymers B and C
substantially dissolved over 6 days at 85.degree. C. The aqueous
solutions were somewhat viscous.
[0117] Mechanical properties of the swollen (24 hrs) and unswollen
poly ALM, Polymers A, B, and C, include:
[0118] a) all three materials passed the forceps test for
toughness; and
[0119] b) all three materials had an extension to break of at least
100%.
A sensory test (manipulation) indicated that the materials were
both deformable, but would probably be sufficiently tough to
protect cartilage.
[0120] Thus, polymers of ALM can be prepared to have moduli,
toughness and hydration appropriate for application to orthopedic
tissues, and further are degradable in an accelerated test.
Example 31
ALM-Containing Copolymers
[0121] ALM was copolymerized with other materials. Combinations
tested included:
[0122] a) 17% 35KTA2 macromer (see description in Table 2), 18%
water and 65% ALM, mixed in that order by heating to about
70.degree. C. This mixture was polymerized with UV light in the
presence of 0.3% Irgacure.RTM. photoinitiator. The resulting
material was opaque, and felt somewhat porous. After incubation
with water, the material was lubricious and had apparently swelled,
but it failed the forceps test.
[0123] b) 60% ALM, 30% vinyl caprolactam (VC), and 10% 35KTA2 were
mixed by heating to about 70.degree. C. This mixture was
polymerized with UV light in the presence of 0.3% ppm Irgacure.RTM.
photoinitiator. The as-polymerized material was clear, but turned
opaque on brief incubation with water. The material was rigid and
slightly brittle before hydration, but swelled about 40% and became
resilient and plastic after overnight hydration. Elongation to
break was over 50%, and the material passed the forceps test for
toughness. The compressive modulus of the hydrated material was 151
kPa.
[0124] c) 75% ALM,15% VC, and 10% 35KTA2 were mixed by heating to
about 70.degree. C. This mixture was polymerized with UV light in
the presence of 0.3% ppm Irgacure.RTM. photoinitiator. The
as-polymerized material was clear, but turned opaque on brief
incubation with water. This material was less rigid and less
brittle than the material described in example b) before hydration,
but this material swelled about 40% and became resilient and
plastic after overnight hydration. Elongation to break was over
50%, and the material passed the forceps test for toughness. A
folded hydrated disc sprang back to its original shape in less than
5 seconds, whereas an equivalent disc from material described in
example b, above, required about 30 seconds to spring back.
[0125] d) 90% ALM and 10% 35KTA2 were mixed by heating to about 70
C. This mixture did not polymerize within 5 minutes with UV light
in the presence of 0.3% ppm Irgacure.RTM. photoinitiator.
[0126] Examples 30 and 31 demonstrate that a material useful as an
orthopedic repair material, as defined herein, can be made from a
degradable material. Based on these examples, one of skill in the
art can make a new material, which has the desired properties of
low swelling at high proportions of solids, high tensile modulus,
significant elongation to failure, biocompatibility, and
adherence.
Example 32
AHC Monomers
[0127] Step 1. Synthesis of ALA (Acryloyl lactic acid). The ALM
material described above is a convenient starting material for this
synthesis, because methyl lactate is commercially available.
Acryloyl chloride can be substituted with other active
ethylenically unsaturated compounds, for example acryl imidazole or
methacryl bromide or cinnamoyl succinimide, depending on the active
group desired in the AHK material.
[0128] ALM is hydrolyzed to ALA by selective de-esterification in
basic aqueous solution. The reaction takes advantage of the more
rapid hydrolysis of the methyl lactate ester (the H to K bond)
compared to the acryloyl-lactyl ester (the A to H bond). in a
typical procedure, 10.03 g of ALM (92.92% pure) is dispersed in 90
mL of water and hydrolyzed with 5.45 mL of 10 N sodium hydroxide to
the Na-acryloyllactic acid salt. The base is added dropwise at
20-25.degree. C. The Na-acryloyllactic acid salt is converted to
acryloyllactic acid (ALA) with 6N HCl at pH 1.0. The ALA is
extracted from the aqueous phase with 112 mL toluene overnight
using a liquid-liquid extractor. Residual moisture is removed with
6 g of magnesium sulfate. After filtration of the magnesium
sulfate, the toluene is removed under vacuum using a rotary
evaporator. The concentrated ALA is a yellow colored oil. Typical
analysis of ALA by .sup.1H-NMR: TABLE-US-00003 % ALA % Toluene %
Lactic Acid % Acrylic Acid 95.78 2.53 0.16 1.53
It was determined experimentally that the above conditions
optimized the yield of acryloyllactic acid (ALA), in that most of
the ALM had hydrolyzed but significant hydrolysis of the
acryloyl-lactyl ester bond had not begun.
[0129] Step 2. Synthesis of ALC (acryloyl lactoyl chloride,
CH.sub.2.dbd.CH--CO--OCH--O--CH(CH.sub.3)--CO--Cl). This step is a
straightforward activation reaction for a carboxylic acid, and many
procedures are known for such activation.
[0130] In a typical procedure, crude ALA (free acid) was taken up
in tetrahydrofuran (THF), and an excess of oxaloyl chloride and a
catalytic amount of dimethylformamide (DMF) were added. After
incubation for about 20 minutes at 0.degree. C., the reaction was
essentially complete. The crude reaction mixture was used directly
for the next step.
[0131] Step 3. Synthesis of AHK esters. This is simply a reaction
of an active carboxyl, such as an acyl chloride, with an alcohol.
Many such procedures are known in the literature. The following
hypothetical experiment illustrates the general method.
[0132] Rather than purifying the ALC, it is most convenient and
efficient to add this ALC containing solution directly to a desired
alcohol in a suitable solvent along with a suitable amine (e.g.
pyridine or triethylamine) to scavenge generated acid. For example,
the above THF solution containing ALC can be added to a solution of
0.9% equivalent of cholesterol in toluene, based on the calculated
ALA content and triethylamine. After completion of the reaction,
the cholesterol ester of ALA is obtained after removal of the amine
salt and concentration on a rotary evaporator under reduced
pressure.
[0133] The activation of the free acid (e.g. ALA) to the activated
ester (e.g., ALC) and subsequent synthesis of an AHK ester can also
be accomplished as a single or stepwise "one-pot" activation, using
suitable acylating agents--for example, dicyclohexylcarbodiimide
(DCC) with a catalytic amount of dimethylaninopyridine. A variety
of groups can be used as leaving groups C. These include a halogen,
a residue of a succinimidyl group, a residue of imidazole, a
residue of a thioester, nitrophenols, pyridines, and o-acyl ureas.
The key requirement is that the leaving group be readily
displacable by an nucleophilic reagent, such as a hydroxyl group,
an amine, or a thiol.
Example 33
Acryl-lactate Ester of a Polymer
[0134] Polyvinyl alcohol (PVA) was reacted with ALC to form the
monomer acryloyl-lactyl-PVA. ALC was prepared essentially as
described above. PVA from Aldrich had a stated molecular weight of
10 kDa (however the actual weight was from 9 kDa to 10 kDa) and was
stated to be about 80% hydrolyzed. Ten grams of PVA were placed in
a 3-neck 250 mL flask and pyridine was added to about 200 mL final
volume. The mixture was stirred under nitrogen to dissolve the PVA.
The flask was heated to about 95.degree. C. and distillation of
pyridine began. The PVA began to precipitate at about 120.degree.
C.; addition of about 200 mL of dimethylacetamide (DMAC) produced a
homogenous solution and reduced the temperature to about 70.degree.
C. After reduction in volume by distillation to about 200 mL, the
mixture was allowed to cool to 60.degree. C. and ALC (450 .mu.L;
approximately 97% purity and activity) was added.
[0135] The mixture was maintained at 60.degree. C. under stirring
and nitrogen for 20 minutes. Then it was precipitated by pouring it
into 1800 mL of toluene with vigorous stirring. The gelatinous
precipitate was vacuum filtered. The precipitate was mixed with 200
mL hexanes, and filtered; this was repeated twice. A fine damp
powder was obtained and was vacuum dried at 40.degree. C.
overnight.
[0136] The resulting yield contained 9.18 g. .sup.1H-NMR analysis
indicated about 0.77 acrylate-lactate substitution per PVA
molecule. Free radical polymerization of this monomer failed to
yield a gel, as expected from the low degree of substitution and
the likelihood of steric hindrance.
[0137] Another experiment, in which DMAC was the solvent and 300
.mu.L of pyridine was added along with 450 .mu.L of ALC for a 60
minute reaction time, produced a polymer at 9.2% yield. At 10%
polymer in buffered water, this polymer gave a loose gel when
copolymerized with about an equal weight of vinyl caprolactone. The
copolymerization was carried out using eosin Y as photoinitiator
and triethanolamine as electron transfer reagent under visible
light.
[0138] This study demonstrates that the monomer can include a
polymer as the "K" group, and its properties can be tailored by
variable degrees of derivatization.
[0139] Modifications and variations of the hydrogels and methods
for manufacture and use thereof will be obvious to those skilled in
the art. Such modifications and uses thereof will be obvious to
those skilled in the art.
* * * * *