U.S. patent application number 09/550372 was filed with the patent office on 2002-02-21 for poly(propylene fumarate) cross linked with poly(ethylene glycol).
Invention is credited to He, Shulin, Mikos, Antonios G., Yaszemski, Michael J..
Application Number | 20020022676 09/550372 |
Document ID | / |
Family ID | 27494811 |
Filed Date | 2002-02-21 |
United States Patent
Application |
20020022676 |
Kind Code |
A1 |
He, Shulin ; et al. |
February 21, 2002 |
Poly(Propylene Fumarate) cross linked with Poly(Ethylene
Glycol)
Abstract
New injectable, in situ crosslinkable biodegradable polymer
composites comprise poly(propylene fumarate) (PPF), poly(ethylene
glycol)-dimethacrylate (PEG-DMA), an, optionally, .beta.-tricalcium
phosphate (.beta.-TCP). A method for controlling the crosslinking
characteristics of the composites, including the maximum
crosslinking temperature and the gel point, as well as the
properties of the cross linked composites such as the compressive
strength and modulus and the water holding capacity, is
disclosed.
Inventors: |
He, Shulin; (Houston,
TX) ; Yaszemski, Michael J.; (Rochester, MN) ;
Mikos, Antonios G.; (Houston, TX) |
Correspondence
Address: |
CONLEY ROSE & TAYON, P.C.
P. O. BOX 3267
HOUSTON
TX
77253-3267
US
|
Family ID: |
27494811 |
Appl. No.: |
09/550372 |
Filed: |
April 14, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
60129577 |
Apr 16, 1999 |
|
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|
60146991 |
Aug 3, 1999 |
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60167328 |
Nov 24, 1999 |
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60167388 |
Nov 24, 1999 |
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Current U.S.
Class: |
523/113 ;
523/115; 523/447; 528/301 |
Current CPC
Class: |
C08G 63/918 20130101;
C08G 81/025 20130101; A61L 27/18 20130101; C08L 67/07 20130101;
A61L 27/50 20130101; Y10S 530/815 20130101; Y10S 530/812 20130101;
C08G 63/676 20130101; C08L 67/06 20130101; A61L 27/58 20130101;
A61L 27/18 20130101; C08L 67/00 20130101; A61L 27/18 20130101; C08L
71/02 20130101; C08L 67/06 20130101; C08L 67/07 20130101; C08L
67/07 20130101; C08L 67/06 20130101 |
Class at
Publication: |
523/113 ;
523/115; 528/301; 523/447 |
International
Class: |
C08K 003/00; A61F
002/00; C08G 063/66; C08L 063/00 |
Goverment Interests
[0002] This work was funded by the National Institutes of Health
R01-AR44381 and R01-DE13031.
Claims
1. A polymer network comprising poly(propylene fumarate) and
poly(ethylene glycol).
2. An injectable, in situ crosslinkable, biodegradable composite
formulation comprising poly(propylene fumarate) and poly(ethylene
glycol).
3. The composition according to claim 2, further including
beta-tricalcium phosphate.
4. The composition according to claim 2 wherein the composition
exhibits a temperature increase of less than 2.degree. C. during
cross linking.
5. The composition according to claim 2 wherein the composition
exhibits a gel point between 5-15 minutes.
6. An injectable, in situ crosslinkable, biodegradable carrier for
cell transplantation, comprising poly(propylene fumarate) and
poly(ethylene glycol).
7. The composition according to claim 4, further including
beta-tricalcium phosphate.
8. The composition according to claim 2 wherein the composition
exhibits a temperature increase of less than 2.degree. C. during
cross linking.
9. The composition according to claim 2 wherein the composition
exhibits a gel point between 5-15 minutes.
10. An injectable, in situ crosslinkable, biodegradable carrier for
bioactive drug delivery, comprising poly(propylene fumarate) and
poly(ethylene glycol).
11. The composition according to claim 5, further including
beta-tricalcium phosphate.
12. The composition according to claim 2 wherein the composition
exhibits a temperature increase of less than 2.degree. C. during
cross linking.
13. The composition according to claim 2 wherein the composition
exhibits a gel point between 5-15 minutes.
Description
RELATED CASES
[0001] The present case claims the benefit of U.S. provisional
applications Ser. No. 60/129577, filed Apr. 16, 1999, and entitled
"Development of Biodegradable Bone Cement Based on Poly(Propylene
Fumarate) and a Macromer," Ser. No. 60/146,991, filed Aug. 3, 1999,
and entitled "Synthesis of Poly(Propylene Fumarate) by Acylation of
Propylene Glycol in the Presence of a Proton Scavenger," Ser. No.
60/167,328, filed Nov. 24, 1999, and entitled "Preparation of an
Injectable, in situ Polymerizable and Biodegradable Biomaterial
Based On Poly(Propylene Fumarate) and Biodegradable Cross linking
Reagents," and Ser. No. 60/167,388, filed Nov. 24, 1999, and
entitled "Injectable Biodegradable Polymer Composites Based on
Poly(Propylene Fumarate) Cross linked with Poly(Ethylene
Glycol)-Dimethacrylate and .beta.-Tricalcium Phosphate," all of
which are incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0003] This invention relates to a compound for replacing or
reconstructing rigid or semi-rigid living tissue. More
particularly, the present invention relates to compositions
comprising poly(propylene fumarate) cross linked with poly(ethylene
glycol) and methods for making these compositions.
BACKGROUND OF THE INVENTION
[0004] In the field of tissue engineering, degradable biomaterials
usually serve as a scaffold to provide mechanical support and a
matrix for the ingrowth of new tissue. As new tissue forms on the
scaffold, the biomaterial degrades until it is entirely dissolved.
The degradation products are eliminated through the body's natural
pathways, such as metabolic processes.
[0005] One example of the use of such biomaterials is as a
temporary bone replacement. It is often desired to replace or
reconstruct all or a portion of a living bone, such as when a bone
has been broken or has been resected as a result of a bone tumor.
In these instances, the missing bone can be replaced with a
mechanical device, such as a pin, plate or the like, or it can be
replaced with an implant that is designed to more closely resemble
the original bone itself. Often these implants comprise
biodegradable polymeric compounds or parts made from such
compounds. It is contemplated that bone tissue will grow back into
the pores of the implant and will gradually replace the entire
implant as the implant itself is gradually degraded in the in vivo
environment. For obvious reasons then, such implants should be
biocompatible and non-toxic.
[0006] Poly(propylene fumarate) (PPF) is one such polymer.
Poly(propylene fumarate) (hereinafter "PPF") is an unsaturated
linear polyester that degrades in the presence of water into
propylene glycol and fumaric acid, degradation products that are
easily cleared from the human body by normal metabolic processes.
Because the fumarate double bonds in PPF are reactive and cross
link at low temperatures, PPF has potential to be an effective in
situ polymerizable biomaterial. The high mechanical strength of
cured PPF matrices and their ability to be cross linked in situ
makes them especially suitable for orthopedic application. Another
advantage of cured PPF matrices is that they biodegrade into
non-toxic propylene glycol and fumaric acid. On the basis of these
unique properties, PPF has been formulated as bone cement, an
orthopaedic scaffold for bone tissue regeneration, and a drug
delivery system.
[0007] Several PPF-based formulation methods have been evaluated by
varying such parameters as the molecular weight of PPF and the
choice of cross linking reagents. For example, U.S. Pat. No.
5,733,951 discloses a composite mixture incorporating P(PF), a
cross linking monomer (N-vinyl pyrrolidone), a porogen (sodium
chloride), and a particulate phase (.beta.-tricalcium phosphate)
that can be injected or inserted into skeletal defects of irregular
shape or size.
[0008] The properties of some PPF composites can be tailored for
specific applications by varying different parameters, including
crosslinking density and molecular weight of PPF. PPF composite
formulations can include a porogen such as NaCl for initial
porosity and a particulate ceramic such as .beta.-TCP for
mechanical reinforcement and increased osteoconductivity. PPF
composite formulations can also include a vinyl monomer such as
N-vinyl pyrrolidone, which serves as a crosslinking reagent.
However, because this monomer is toxic, any unreacted amount during
polymerization in situ may present a problem.
[0009] Poly(ethylene glycol), (PEG), is a hydrophilic polyether
that has received much attention for use in biomaterials because
low molecular weight PEG is passively excreted by the body. PEG has
also been covalently bound to polyesters in an effort to increase
polyester biocompatibility. The use of acrylated PEG as a nontoxic
crosslinking reagent to produce polymer networks with acrylated
poly(lactic acid) has been reported. To date however, PPF-based
polymers cross-linked with PEG have not been made. Hence, it
remains desirable to provide a poly(propylene fumarate) cross
linked with poly(ethylene glycol) and a method for making it. The
method for making would preferably include a method for controlling
the mechanical properties of the resulting polymer.
SUMMARY OF THE INVENTION
[0010] The present invention comprises new, injectable
biodegradable polymer composites based on PPF cross linked with
biocompatible PEG-DMA and, if desired, .beta.-TCP. The invention
further provides the ability to control the crosslinking
characteristics of the polymerizing composites and the mechanical
properties of cross linked composites by varying the .beta.-TCP
content and the double bond ratio of PEG-DMA/PPF. The PPF/PEG-DMA
networks produced according to the present invention have
clinically acceptable gel times, cross-linking temperature
increases of less than 2.degree. C., and are suitable for use as
injectable, biodegradable carriers for cell transplantation or drug
delivery.
[0011] As used herein, the term "network" refers to polymeric
molecules that have been cross linked so as to effectively form a
continuous molecule. The term "gel" is sometimes used to refer to
the same type of cross linked systems.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] For a better understanding of the present invention,
reference will be made to the attached Figures, wherein:
[0013] FIG. 1 is a schematic chemical diagram illustrating a
possible reaction scheme for crosslinking of PPF with PEG-DMA;
[0014] FIG. 2 is a plot illustrating the dependence of compressive
strength at yield of PEG-DMA/PPF composites on the double bond
ratio of PEG-DMA/PPF for composites incorporating .beta.-TCP (33 wt
%) and cross linked polymers without .beta.-TCP, both dry and
wet;
[0015] FIG. 3 is a plot illustrating the dependence of compressive
modulus of PEG-DMA/PPF composites on the double bond ratio of
PEG-DMA/PPF for composites incorporating .beta.-TCP (33 wt %) and
crosslinked polymers without .beta.-TCP both tested dry and wet;
and
[0016] FIG. 4 is a plot illustrating the water content of
PEG-DMA/PPF composites incorporating .beta.-TCP and cross linked
polymers without .beta.-TCP as a function of the double bond ratio
of PEG-DMA/PPF after equilibrium in PBS.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
[0017] The present invention includes novel PPF-based polymers and
a method for making those polymers. The novel polymers comprise PPF
cross linked with PEG, in which the fraction of PEG can be varied
to control, among other things, the crosslinking characteristics of
the composites, including the maximum crosslinking temperature and
the gel point, and the properties of the cross linked composites,
including its compressive strength and modulus and its water
holding capacity.
Synthesis of PPF
[0018] PPF is preferably prepared by the method generally described
in co-pending application Ser. No. PCT/US99/07912, filed Apr. 9,
1999, and entitled "Synthesis of Poly (Proplyene Fumarate) by
Acylation of Propylene Glycol in the Presence of a Proton
Scavenger," which is incorporated herein by reference. Briefly,
fumaryl chloride is added to a solution of propylene glycol in
methylene chloride at 0.degree. C. under nitrogen in the presence
of K.sub.2CO.sub.3. After addition of fumaryl chloride, the
reaction mixture is stirred for an additional 2 hours at 0.degree.
C. and then water is added to dissolve the inorganic salt. The
organic phase is separated and dried over Na.sub.2SO.sub.4. After
filtration of the mixture and evaporation of the solvent, the
resulting di(2-hydroxylpropyl) fumarate is converted to PPF by
transesterification at 160.degree. C. and 0.5 mm Hg.
[0019] The resulting polymer can be purified by solution
precipitation, forming a viscous liquid. Gel permeation
chromatography with a differential refractometer can be used to
determine polymer molecular weight distributions.
Crosslinking of PPF
[0020] According to the present invention, PPF is crosslinked with
PEG-DMA. FIG. 1 shows a possible reaction scheme for this reaction.
In preferred reaction, PPF is mixed with PEG-DMA. An amount of BP
is dissolved in CH.sub.2Cl.sub.2 and the solution is added to the
PEG-DMA/PPF mixture. If desired, .beta.-TCP is added, followed by
the addition of DMT under rapid stirring for 10 s. Once
polymerization starts to take place, a cross linked polymeric
network is formed in 10 to 15 min. The light brown polymeric
network can be washed with acetone and then water to remove
possible unreacted monomers.
Experimental
Materials
[0021] Fumaryl chloride (Aldrich, Milwaukee, Wis.) was purified by
distillation under nitrogen atmosphere. Propylene glycol,
poly(ethylene-glycol)-dimethacrylate (PEG-DMA) (of number average
molecular weight 875, liquid), benzoyl peroxide (BP), anhydrous
potassium carbonate, Beta-tricalcium phosphate (.beta.-TCP)
particles (100 mesh), N,N-dimethyl-p-toluidine (DMT), and all
solvents were purchased from commercial sources and used as
received.
Experimental Design
[0022] Eight composite formulations were examined to assess the
effects of PEG-DMA/PPF double bond ratio and .beta.-TCP content on
the maximum crosslinking temperature and gel point of the
polymerizing composite pastes and also the compressive strength at
yield, compressive modulus and equilibrium water content of the
crosslinked composites. The different compositions of the composite
formulations are set out in Table 1. The double bond ratio of
PEG-DMA/PPF was used instead of the weight ratio because PEG-DMA is
a macromer. It was calculated as follows: PEG-DMA/PPF double bond
ratio=PEG-DMA/PPF weight ratio.times.(PPF number average molecular
weight/PEG-DMA number average molecular weight).times.(2/n), where
n is the average number of fumarate double bonds in a PPF chain
calculated as: n=(PPF number average molecular weight-76)/156.
1TABLE 1 BP and DMT contents are 0.3 wt % and 0.15 wt %,
respectively, for all formulations. (Percentage of BP, DMT and
.beta.-TCP based on total amount of PEG-DMA and PPF.) Weight ratio
Double bond ratio .beta.-TCP of PEG- of content Formulation DMA/PPF
PEG-DMA/PPF (wt %) 1 1 0.38 0 2 2 0.75 0 3 3 1.13 0 4 5 1.88 0 5 1
0.38 33 6 2 0.75 33 7 3 1.13 33 8 5 1.88 33
[0023] Fumaryl chloride was added dropwise to a solution of
propylene glycol in methylene chloride at 0.degree. C. under
nitrogen in the presence of K.sub.2CO.sub.3. After addition of
fumaryl chloride, the reaction mixture was stirred for an
additional 2 h at 0.degree. C. and then water was added to dissolve
the inorganic salt. The organic phase was separated and dried over
Na.sub.2SO.sub.4. After filtration of the mixture and evaporation
of the solvent, the formed di(2-hydroxylpropyl) fumarate was
converted to PPF by transesterification at 160.degree. C. and 0.5
mm Hg. The produced polymer was purified by solution precipitation
forming a viscous liquid.
[0024] Gel permeation chromatography with a differential
refractometer (Waters 410, Milford, Mass.) was used to determine
polymer molecular weight distributions. A Phenogel column
(300.times.7.8 mm, 5 nm, mixed bed, Phenomenex, Torrance, Calif.)
and a Phenogel guard column (50.times.7.8 mm, 5 nm, mixed bed,
Phenomenex) were employed for a chloroform eluent flow rate of 1
ml/min. Polystyrene standards were utilized to obtain a calibration
curve for calculating the polymer molecular weights.
[0025] In a typical reaction, 2 g PPF were mixed with 2 g PEG-DMA
as a crosslinking reagent. 12 mg BP were dissolved in 0.1 ml
CH.sub.2Cl.sub.2 and the solution was added to the PEG-DMA/PPF
mixture. .beta.-TCP was added for those composites incorporating
.beta.-TCP, followed by the addition of 6 .mu.l DMT under rapid
stirring for 10 s.
Maximum Temperature
[0026] The temperature profile was recorded throughout the
crosslinking process in a glass vial of 10 mm diameter and 24 mm
length immersed into a 37.degree. C. static water bath. The
crosslinking mixture was placed in the glass vial and a
thermocouple was inserted to half the depth of the vial. The
temperature was measured every minute until it dropped to
37.degree. C. and the maximum temperature was recorded.
Gel Point
[0027] The gel point corresponding to the onset of the formation of
a polymer network was measured using known viscometry methods. The
crosslinking mixture was placed in a Teflon mold of 10 mm diameter
and 15 mm height attached to the temperature controlled plate of a
rheometer. The addition of DMT to the crosslinking mixture defined
time zero. A cylindrical, stainless steel parallel plate geometry
of 8 mm diameter was lowered until it was immersed approximately 1
mm into the polymer solution. An oscillatory program consisting of
a time sweep at an oscillatory frequency of 1 Hz and magnitude of
0.5% strain was used to monitor the viscosity as the composite
cured. The gel point was recorded as the time when the polymer
viscosity suddenly increased.
Mechanical Properties
[0028] The mechanical properties of PEG-DMA/PPF composites with
.beta.-TCP and PEG-DMA/PPF networks were determined under
compression. For specimen preparation, the crosslinking mixture was
placed into cylindrical vials of 6 mm diameter. After 6 h, the
cross linked composites were removed from the vials and cut to 12
mm length cylinders using a diamond saw. The specimens were tested
using an 858 Material Testing System mechanical testing machine,
following the guidelines set in ASTM F451-95. Samples were
compressed at a crosshead speed of 1 mm/min until failure with the
load versus deformation curve recorded throughout. The compressive
modulus was calculated as the slope of the initial linear portion
of the stress-strain curve. The compressive strength at yield was
defined by drawing a line parallel to the slope defining the
modulus, beginning at 1.0% strain. The intersection of this line
with the stress-strain curve was recorded as the compressive
strength at yield. For the mechanical testing of wet specimens, the
12 mm length and 6 mm diameter cylinders were placed in phosphate
buffered saline (PBS, pH 7.4) for 24 h. Specimens were swollen to
approximately 14 mm length and 7 mm diameter, and were tested
immediately upon removal from PBS as described above for dry
specimens.
Equilibrium Water Content
[0029] The equilibrium water content of PEG-DMA/PPF composites with
.beta.-TCP and PEG-DMA/PPF networks was determined by gravimetry
with cylindrical specimens of 6 mm diameter and 12 mm height. The
specimens were washed with 10 ml CH.sub.2Cl.sub.2 to remove any
unreacted components, air-dried for one day, and vacuum-dried for 6
h. The weight of the dried specimens was then recorded (W.sub.1).
Subsequently, specimens were immersed in PBS at room temperature.
The weight of the specimens was monitored periodically and recorded
when it reached an equilibrium value (W.sub.2), which occurred
after approximately after 24 h. The equilibrium water content was
calculated as [(W.sub.2-W.sub.1)/W.sub.2].times.100%.
Statistical Analysis
[0030] All experiments were conducted in triplicate except, for the
mechanical testing where n=5. The data were expressed as
means.+-.standard deviation. Single factor analysis of variance
(ANOVA) was used to assess statistical significance of results.
Results
[0031] PPF with number average molecular weight of 1500
(corresponding to an average of 9.1 fumarate double bonds per
macromolecular chain) and polydispersity index of 1.87 was obtained
after 6 h transesterification. The proton NMR data were:
.sup.1H-NMR (250 MHz, CDCl.sub.3): .delta. 1.28 (m, CH.sub.3), 4.26
(m, CH.sub.2), 5.27 (m, CH), 6.84 (bs, CH=). The integration ratio
of the vinyl protons to methyl protons was 2 to 3.4.
[0032] The temperature increase during polymerization is an
important consideration for injectable, in situ polymerizable
formulations. The maximum crosslinking temperature was not affected
(p>0.05) by the double bond ratio of PEG-DMA/PPF or the
.beta.-TCP content, as shown in Table 2 below. The maximum
temperature increase for in vivo cross linking for the eight tested
formulations was 1.5.degree. C. and an average of 39.7.degree. C.
was calculated for the tested formulations. This relatively small
temperature increase makes the present formulations very suitable
for in situ polymerization and is much lower than the 94.degree. C.
reported for a conventional poly(methyl methacrylate) (PMMA) bone
cement tested under similar conditions. The present results also
agree with those for injectable hydrogels of poly(propylene
fumarate-co-ethylene glycol). The minimal temperature increase also
makes the present formulations ideal for use as carriers for cells
and/or bioactive molecules or drugs. This is because a excessive
temperature increase can cause cell death or loss of drug
bioactivity.
2TABLE 2 Maximum crosslinking temperature and gel point for eight
composite formulations. Data are presented as means .+-. standard
deviation for n = 3. Maximum Temperature Gel point Formulation
(.degree. C.) (min) 1 39.4 .+-. 0.8 12.6 .+-. 2.5 2 39.8 .+-. 1.0
12.0 .+-. 2.0 3 39.6 .+-. 0.8 10.3 .+-. 1.8 4 40.0 .+-. 1.1 8.1
.+-. 0.6 5 39.5 .+-. 0.6 12.3 .+-. 2.2 6 39.9 .+-. 1.2 11.8 .+-.
2.0 7 39.4 .+-. 0.9 9.7 .+-. 1.5 8 40.0 .+-. 1.5 8.0 .+-. 1.0
[0033] The gel point data measured under an oscillatory program are
also shown in Table 2. The double bond ratio of PEG-DMA/PPF and the
.beta.-TCP content did not have an effect (p>0.05) on the gel
point, which varied from 8.0.+-.1.0 to 12.3.+-.2.2 min, which is
within the range of 5-15 minutes desirable for clinical use, and
was not affected by the P-TCP content (p>0.05). In addition, the
decrease of gel point with increasing PEG-DMA/PPF double bond ratio
was not significant (p>0.05). An increase of the PEG-DMA/PPF
double bond ratio should increase the number of active double bonds
of methacrylate which may reduce the time frame for crosslinking
but also decrease the relative concentration of fumarate double
bonds.
[0034] An increase in the PEG-DMA/PPF double bond ratio resulted in
an increase in both compressive strength at yield and compressive
modulus of the networks and cross linked composites, regardless of
whether they were tested dry or wet (p<0.05), as shown in FIGS.
2 and 3. FIGS. 2 and 3 show, respectively, the dependence of the
compressive strength at yield and the compressive modulus of
PEG-DMA/PPF composites on the double bond ratio of PEG-DMA/PPF for
composites incorporating .beta.-TCP (33 wt %)
(.box-solid.,.box-solid.) and crosslinked polymers without
.beta.-TCP (O,.circle-solid.). Both were tested dry
(O,.quadrature.) and wet (.circle-solid.,.box-solid.). Error bars
represent means.+-.standard deviation for n=5
[0035] The incorporation of .beta.-TCP caused a further enhancement
of the mechanical properties (p<0.05). The compressive strength
at yield of the networks tested dry ranged from 5.9.+-.1.0 to
11.2.+-.2.2 MPa, whereas that of the cross linked composites
incorporating .beta.-TCP ranged from 7.8.+-.0.1 to 12.6.+-.0.8 MPa.
The compressive modulus was in the range of 30.2.+-.13.5 to
58.4.+-.6.2 MPa and 41.4.+-.1.0 to 76.0.+-.1.3 MPa for specimens
without .beta.-TCP and incorporating .beta.-TCP, respectively. The
compressive strength at yield and compressive modulus of the
networks and composites with .beta.-TCP tested wet were lower than
the corresponding values of specimens tested dry. For example, in
the wet state, the compressive strength at yield of specimens
without .beta.-TCP was in the range of 2.2.+-.0.5 to 3.5.+-.0.5
MPa. PEG is a hydrophilic polyether and its incorporation into a
PPF network forms a hydrogel with decreased mechanical properties.
The reinforcement of the mechanical properties of PEG-DMA/PPF
crosslinked composites by .beta.-TCP was not significant for
specimens tested wet.
[0036] The equilibrium water content of PEG-DMA/PPF networks
increased from 21.7.+-.0.2 to 30.7.+-.0.2% as the PEG-DMA/PPF
double bond ratio increased from 0.38 to 1.88, as shown in FIG. 4.
FIG. 4 shows the water content of PEG-DMA/PPF composites
incorporating .beta.-TCP (.box-solid.) and crosslinked polymers
without .beta.-TCP (O) as a function of the double bond ratio of
PEG-DMA/PPF after equilibrium in PBS. Error bars represent
means.+-.standard deviation for n=3. Incorporation of .beta.-TCP
into the cross linked composites reduced their water content
(p<0.05).
[0037] The present method for making PPF avoids the addition of a
catalyst, which might otherwise be brought into the cross linked
composite with PPF as an impurity. Moreover, the absence of a
catalyst minimizes the reaction of the fumarate double bonds during
PPF synthesis. The proton NMR spectrum of PPF indicated that the
integration ratio of the vinyl protons to the methyl protons was
2:3.4, which was close to the ratio of 2:3.33 calculated from the
number average molecular weight, thus suggesting no loss of PPF
unsaturation.
[0038] The crosslinking density of PEG-DMA/PPF networks increased
with the PEG-DMA/PPF double bond ratio resulting in increased
mechanical properties of the PEG-DMA/PPF networks and crosslinked
composites. The mechanical properties of the PEG-DMA/PPF networks
did not suggest a PEG-DMA self-polymerization. This phenomenon can
occur in PPF networks crosslinked with N-vinyl pyrrolidone due to
formation of long cross links. No apparent volume changes were
observed upon crosslinking.
[0039] Hence, it is possible to cross link PPF with PEG-DMA to form
biodegradable hydrogels with tailored mechanical properties by
varying the PEG-DMA/PPF double bond ratio. Although the mechanical
properties of porous hydrogels may prove insufficient for
replacement of human trabecular bone, the use of injectable, in
situ crosslinkable hydrogels holds promise for the engineering of
softer orthopaedic tissues such as cartilage.
* * * * *