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Macromolecular symposia

USER JOURNAL TITLE: Macromolecular Symposia

ARTICLE TITLE:

Crosslinked copolymers with degradable oligo(lactide) branches

ARTICLE AUTHOR:

Barbara Sandner, Simone Steurich and Siegfried War

VOLUME:

103

ISSUE:

MONTH:

January

YEAR:

1996

PAGES:

149162

ISSN:

1022-1360

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149

Macromol. Symp. 103,149-162 (1996)

CROSSLINKED COPOLYMERS WITH DEGRADABLE

OLIGO(LACTIDE) BRANCHES

Barbara Sandnee, Simone Steurich

Martin-Luther-UniversitiitHalle-Wittenberg
Fachbereich Chemie, Geusaer Str., 06217 Merseburg, Germany
SiegfriedWartewig

Martin-Luther-UniversitiitHalle-Wittenberg
Fachbereich Physik, Hoher Weg 7,06120 Halle, Germany

Abstract: Methods for preparation of oligo(lact0ne) macromonomers end-capped

with methacrylate groups are summarized. The conversion of C=C double bonds
during the crosslinldng copolymerizationof the macromonomers has been studied
by means of Laser Raman spectroscopy at room temperature. Glass transition,
mechanical properties and the degradation rate of composite materials prepared by
copolymerization in the presence of hydroxylapatite may systematically be
influenced both by the type of lactone monomer, e.g. D,L- or L,L-dilactide,
diglycolide, and the comonomer, e.g. 2-hydroxyethyl methacrylate, tetrahydrofurfurylmethacrylate,tri(ethy1ene glycol) dimethacrylate.
The composites should be useful as bone implant materials with lower
polymerization exotherm and better biocompatibility than conventional materials
based on methyl methacrylate.

INTRODUCTION
The biodegradable polyesters of various lactones are of special interest for medical applications
because products of degradation, e.g. lactic and glycolic acid, occur in human metabolism.

0 1996 Huthig & Wepf Verlag, Zug

CCC 1022-1360/95/$04.00

150

Consequently, poly(L,L-lactide) (PLLA) has been found to be a suitable material, e.g. for the
temporary fiition of bone fractures (Ref. 1). In the ideal case, pins, screws or plates of PLLA
should degrade by hydrolysis at such a rate that its loss is compensated for by new bone. The
amorphous parts of the semi-crystalline PLLA are preferentially hydrolyzed. The consequence
may be a too rapid loss of mechanical strength of the fmtion element (Ref. 2). On the other
hand, degradation by hydrolysis may cease too early without formation of sufficient free
volume for new bone tissue. Therefore, the application of crosslinked polymers from
poly(1actone)s containing polymerizable carbon double bonds has been proposed to attain an
optimum balance between polymer degradation, mechanical strength and bone regeneration
(Ref. 3).
Unsaturated oligoesters were prepared, e.g. by reaction of a mixture of D,L-dilactide and
glycolic acid with 2-butene-1,4-diol followed by esterification of the resulting oligomeric diols
with fumaric acid (Ref. 3). These oligoesters were polymerized by dibenzoyl peroxide (DBPO)
initiator at 70-100 "C for 24 h. Glass transition and degradation by hydrolysis of the obtained
crosslinked polyester Nms were studied. A much faster weight loss partially associated with
disintegration of these fiims compared to films of both high molecular weight poly(D,L-lactide)
and poly(L,L-lactide) was observed during hydrolysis.
Acrylates and methacrylates are monomers of higher reactivity than fumarates. Water soluble
diacrylate macromonomers of triblock copolymers BAB with A = poly(ethy1ene glycol) and B
= either oligo(D,L-lactide) or oligo(g1ycolide) were prepared by esterification of a,ohydroxy

terminated BAB with acryloyl chloride (Ref. 4). The macromonomers polymerized rapidly by

UV irradiation in the presence of a photoinitiator in aqueous buffered solution forming

hydrogels which should be suitable for bum dressings, surgical adhesives etc.
The oligo(e-capro1actone)triol from trimethylolpropane was esterified with methacryloyl
chloride and the resulting macromonomer was copolymerized with styrene and methyl
methacrylate, respectively (Ref. 5).
Transesterification of ethylene glycol with the ethyl ester of lactic acid in molar ratios of
between 1:2 and 1:6 yielded a,@-dihydroxyoligo(1actide)s.

The latter were directly esterified

with methacrylic acid catalyzed by p-toluenesulphonic acid (Ref. 6). Esterification of a,@-

dihydroxy-oligo(1actide)s with succinic anhydride was used to synthesize oligomers with

carboxylic endgroups which were then reacted with glycidyl methacrylate (Ref. 6).

Y. Gnanou and P. Rempp (Ref. 7) reported the endcapping of ohydroxypoly(&-caprolactone)

with methacrylic ester groups by either the moderate carbodiimide method or by reacting with
methacryloylimidazole, respectively. The attempts of the same authors to synthesize
macromonomers directly by oligomerization of &-caprolactone initiated with the lithium

151

&oxide of Cisopropenylbenzyl alcohol were not satisfactory. The initiation rate was low
compared to the rate of the propagation reaction resulting in macromonomers with broad
niolecular weight distribution.
The aluminium monoakoxide prepared by the reaction of triethylaluminium with 2-hydroxyethyl methacrylate (HEMA) has proved as a suitable and very effective initiator for the
polymerization of both e-caprolactone (Ref. 8) and D,Ldilactide (Ref. 9). According to Ph.
Dubois et al. (Refs. 8, 9), the mechanism of these lactone polymerizations involves the
coordination of the lactone at the aluminium &oxide group followed by the lactone insertion
into the weakened Al-oxygen bond. The molecular weights predictable from the ratio of
monomer and initiator at complete conversion, as well as the relatively narrow molecular
weight distribution

m,.,m. I1.2) of the macromonomers, support the assumption of a living

polymerization. The polymerization reaction was stopped by addition of aqueous HCl forming
the a-methacryloyl, whydroxy-oligoflactone) macromonomer. The Go-dimethacryloyloligoflactone) was obtained by termination with methacryloyl chloride. Amphiphilic graft
copolymers and amphiphilic copolymer networks were obtained by copolymerizationof the amono- and the Gwdimacromonomer, respectively,with HEMA.
However, the methods of macromonomer synthesis mentioned here, include multistep
reactions, also the preparation of the diethylaluminium &oxide

of HEMA and the

polymerization of the lactone initiated by this &oxide have to be performed in an organic

solvent (Refs. 7, 8). Broadly such reaction conditions seem a relatively unsuitable prerequisite
to apply ta oligo(1actone) macromonomers for medical purposes, therefore, we have used the
initiation of the lactone polymerization by alcohols catalyzed both by Lewis bases (Ref. 10) as
well as Lewis acids as described in Ref. 11. Various P-hydroxyesters of methacrylic acid have
been found by us to act as effective initiators of the oligomerization, e.g. of L,L- and D,Ldilactide, diglycolide and e-caprolactone. We report here the crosslinking copolymerization in
the presence of inorganic fillers, their degradation behaviour and some thermal and mechanical
properties.

EXPERIMENTAL PART
Materials
2-Hydroxyethyl methacrylate (HEMA), tetrahydrofurfuryl methacrylate (THFM), tri(ethy1ene
glycol) dimethacrylate (TEGDMA) (all from Riihm Chemische Fabrik GmbH) were used as

152

received. BisphenolA-bis(2-hydroxypropylmethacrylate) (Bis-GMA) was synthesized as

described in Ref. 12. Hydroxylapatite (Osprovit) (Cerasiv GmbH) was silanized with 1 wt.- %
trimethylsilylpropyl methacrylate (Fluka AG) in acetone. L,L-and D,L-dilactide (Boehringer
Ingelheim KG) were purified by recrystallization from ethyl acetate (distilled over calcium
hydride) and dried over P4010 in vacuo.' Glycolide (Boehringer Ingelheim KG), Nvinylimidazole (Riedel-de Haen AG), Sn(II)octoate (Sigma Chemical Co.) and MgO
(Laborchemie Apolda) were used as received. Dibenzoyl peroxide (DBPO) was recrystallized
from chloroform. N,N-dimethyl-p-toluidine(DMpT) was distUed under vacuum in an argon
atmosphere.
Synthesis of macromonomers
Macromonomers were synthesized by reaction of D,L-dilactide, L,L-dilactide or mixtures of
L,L-or D,L-dilactide with diglycolide in a molar ratio of 7:3 with 9.09 mol-% Bis-GMA, using
0.56 mol-% MgO as a catalyst. The mixture was stirred at 130 "C for about 2 hours until a l l

dilactide and diglycolide had reacted completely. The molar masses were controlled by means
of gel-penneation chromatography (GPC).
Preparation of composites
Composites were prepared by chemically curing mixtures of the macromonomer with HEMA,
TEGDMA or THFM in a ratio 7:3 by weight in the presence of 45 wt.-% silanized
hydroxylapatite at 37 "C for 24 h.
Initiator DBPO (0.4 wt.-% related to the whole monomer mixture) was added to one half of
the monomer mixture, with the activator DMpT in equimolar amount added to the other half.
Time from start of mixing to setting was about 10 min.
Analysis

GPC
The gel-permeation chromatography measurements were carried out on a Knauer device
equipped with a Knauer differential refractometer. For determination of the molecular weight

three Hibar RT columns (PSI, PS4, PS20) and for analyzing the extracts two Waters Styragel
HR1 columns were used. Tetrahydrofuran (THF)served as solvent. The molecular weight was
calibrated relatively to monodisperse polystyrene.

153

Laser Raman spectroscopy

Raman spectra were recorded with a Bruker Fourier transform infra-red spectrometer IFS 66
equipped with the Raman module FRA 106. A diode pumped Nd:YAG laser which emits
radiation at 1064 nm was used as the excitation source. The scattered radiation was collected
at 180 " to the source. Typical spectra were recorded at a laser power of 300 mW at sample
location and a resolution of 4 an-'.In order to obtain a good signal to noise ratio, typically,

200 scans were avaraged. To monitor the curing of monomer mixtures, spectra were recorded
every 21 s after a handling time of about 50 to 80 s with 5 scans.
The manipulation and evaluation of the spectra were carried out using the Bruker OPUS
soilware package. Generally, Raman intensities were determined as integrated band intensities.

Monomer conversion
Pulverized samples (about 0.5 g) were shaken in THF for 8 hours at room temperature.
Insoluble components were separated to determine the conversion. The extract was analyzed
by GPC to determine the proportion, of macromonomer to the comonomers HEMA and

THFM, respectively.
Dynamic mechanical analysis (DMA)
Dynamic mechanical analysis was performed on a Perkin Elmer DMA 7 in parallel plate mode
at a frequency of 1.00 Hz with a dynamic stress of 800 mN and a static stress of 1200 mN. The
heating rate was 5 "Clmin.

Microhardness
Microhardness was measured on a Fischerscop H 100 using a Vickers diamond. Composites
were tested at 22 "C at a force of 1000 mN for 14.5 s.

Diametral tensile strength

Samples (6 mm diameter d, 3 mm thickness t) cured at 37 "C for 24 h were measured on a
tcnsile testing machine (M30K by J. J. Lloyd I n s k e n t s ) with a 30 kN load cell.

154

The sample was diametrally placed on a steel cylinder. The steel cylinder of the crosshead was
lowered at 0.5 rmn/min onto the sample until contacting. Then the speed was increased to 10

d m i n and the sample was loaded until fracture. At least 6 samples were tested.
The load F at fracture was used to calculate the diametral tensile strength CTT:

2F

Degradation
Cured samples, 2 mm in thickness, 10 mm in depth and 15 mm in length, were stored in a
buffered solution @H 7.4, citric acid/sodium dihydrogenphosphate buffer) at 37 "C. Every week
the solution was renewed. The released acid in the removed solution was determined by
potentiometric titration with 0.05 M KOH.

RESULTS AND DISCUSSION

Synthesis of macromonomers
Bis-GMA has been proved by our studies to be an effective initiator for the oligomerization of

L,L- and D,Ldilactide as well as their cooligomerization with diglycolide according to the
following general reaction scheme:

130C. 2-6 h

c=o

c=o

CH-CHI

FH-CH?

n
H

n-

0
H

155

The macromonomers prepared with n = 10 are hard and brittle solids at room temperature.
They soften becoming highly viscous liquids at about 40 "C.
Fig. 1 shows as an example the increase in number-average molecular weight Mn of oligo(L,L1actide)s against the time. Oligomerization was initiated with Bis-GMA and catalyzed by Nvinylimidazole (NVI), MgO and Sn(JI)octoate, respectively, as well as without my additional
catalyst.
Concerning the latter case, it must be noted that Bis-GMA was prepared using 0.8 mol-% of
NVI as a catalyst, therefore, there is some catalyst present also for the subsequent

oligomerizationof L,L-dilactide.

Mn calculated from the ratio of dilactide to Bis-GMA initiator, was obtained at 130 OC after 2
to 6 hours reaction time depending on the type and the content of the catalyst (Fig. 1).

Time / h
Fig. 1. Synthesis of macromonomers from Bis-GMA and L,Ldilactide (1:lO mol/mol), at
130 OC, @, talc. = 2000 g mor'. Mole ratios of Bis-GMA to catalyst:
---O---

1 : 0.2 MgO, ---0--1 : 0.03 Sn(I1) octoate,

---*---

---0--- 1 : 0.3 NVI,

without catalyst

Stannous octoate, the most commonly used catalyst for the polymerization of dilactides, is
obviously also the most effective one for the synthesis of the macromonomers (Fig. 1).
Additionally, Snm) octoate does not cause any racemizationduring the oligomerization of L,Ldilactide; this may be a further advantage. However, from the medical point of view, MgO and
NVI (the latter can be incorporated by copolymerizationinto the polymer network) should be

preferred.
Differences between Gn calculated and a n found experimentally by GPC (Fig. 1) may be
caused by the inappropriate calibration with polystyrene and / or by the depolymerization

156

reaction. The molecular weight distribution calculated from the GPC measurements was
relatively narrow with

a, / a, = 1.2 to 1.3.

Crosslinking copolymexizationof oligoflactide) macromonomers

Macromonomers from Bis-GMA with dilaaide (1:lO mol/mol) as well as dilactide and
diglycolide (1:7:3 mol/mol) were copolymerized with HEMA, THFM and TEGDMA,
respectively, as diluent comonomers. The redox system DBPO-DMpT was used as an initiator
at room temperature.
Fig. 2 shows the differences of the Laser Raman spectra between a macromonomer - HEMA
mixture, and its copolymer obtained by curing initiated with DBPO at 80 "C without inorganic

filler. The expected decrease of the intensity of the C-C stretching vibrational band at 1640

cm-'(CH2= twisting vibration) and 1719 cm" (C=O band of the methacrylate monomers) is
clearly visible. The bands at 1640 and 1719 an-',with the aromatic CH= band at 1455 an-'as
the reference were chosen to determine the conversion of the methacrylate C=C double bonds
during the polymerization reaction.

Wavenumber/cm-'

Fig. 2. Laser Raman spectra of a macromonomer - HEMA mixture (7:3 W w t ) (curve 1) and
its copolymer (curve 2 ) heat cured with 0.5 w t . 4 DBPO at 80 "C for 2 h without fiuer

The decrease of the band intensities monitored during the redox initiated curing cycle is shown
in Fig. 3 at various times at 24C. The course of polyrnehtion could not be followed in the
presence of hydroxylapatite, because its Raman bands overlap those of the monomers and
polymers. However, quartz powder does not show any bands in the frequency region of

157

interest. Therefore, it was used as the filer for the Raman spectroscopic studies of composite
curing.

.-v1
E

r
E

.-#

Wavenumber/cm-'
Fig. 3. Laser Raman spectra of a macromonomer - HEMA (7:3 wt/wt) copolymedtion with
0.4 wt.-% DBPO and 0.22 wt.-% DMpT at 24 "C.without filler.

Curing times: curve 1: 0 s, curve 2: 195 s, c w e 3: 216 s, curve 4: 237 s, curve 5: 300 s
The increase of the C=Cdouble bond conversion, calculated from the simultaneous decrease in
intensity of the two bands at 1640 an-'and 1719 an-',on the curing time of a composite,
indicates that both bands give the same result (Fig. 4). The conversion is extraordinarilyhigh,
being greater than 90 % compared to about 50 % with dental filling composites containing Bis-

GMA and TEGDMA (Ref. 13).

However, the content of residual monomers in composites should be evaluated as a more
significant characteristic for medical purposes. The overall conversion of monomers in
composites from both the L,L- and D,L-dilactide macromonomers wfth different diluent
monomers was found to be 65 to 84 % (by extraction Table 1). The composition of the extract
was determined by GPC and also given in Table 1, indicating that the low molecular weight
comonomers HEMA and THFM,respectively, were almost completely (2 96 %) incorporated
into the organic network matrix. In contrast, the conversion of the macromonomer was only
about 70 %. This result explains the high conversion of C=C double bonds observed by Raman

158

spectroscopy, because the weight content of C=C double bonds of the macromonomer is
comparatively low.
Conversion 1%

Curing time /seconds

Fig. 4.Curing of Bis-GMA - D,L-dilactide - macromonomer (molar ratio 1 : 10) with HEMA
(macromonomer : HEMA = 7 : 3 by weight, 0.4 wt.-% DBPO, 45 wt.-% silanized quartz
powder, at 23 "C ). Conversion of C=C double bonds, calculated from

---+---C=C band at

1640 cm-', ---0----C=O band at 1719 cm-'

Properties of composites with crosslinked oligo(1actide) methacrylates
The glass transition temperatures TO of the composites were obtained by DMA. Composites
with HEMA show the highest TG(Table 1). This is consistent with the differences between TG

of HEMA and THFM homopolymers as well as the lower overall conversion of monomers in
composites with TEGDMA. Accordingly, the composites with HEMA also have a larger
microhardness than those obtained with TEGDMA. However, the elastic moduli E given in
Table 1 and calculated from the microhardness measurements, do not differ between the three
types of composites, within the limits of the experimental error. The composites with
TEGDMA possess a higher diametral tensile strength than the other two, which is obviously
caused by the crosslinking effect of TEGDMA.
Distinctions between the composites were also observed regarding their degradation behaviour
(Fig. 5 and 6). The composites with the more hydrophilic HEMA monomer degrade more
rapidly when the macromonomer branches contain only D,L- or L,L-dilactide, furthermore, the
introduction of diglycolide into the branches results not only in the expected increase of the
degradation rate, but also the differences between the copolymers with HEMA and THFM
disappear. A higher degradation rate of composites with oligo(D,L-lactide) branches as

159

compared with those with oligo(L,L-lactide) branches was observed corresponding to the
behaviour of the homopolymers.
Table 1.

Composition and properties of composites obtained from Bis-GMA

lactide

(1:lO mol/mol) macromonomers with TEGDMA, HEMA and THFM (7 : 3 wt/wt) by redox
initiated polymerization (0.4 wt.-% DBPO rel. to monomers) in the presence of 45 wt.-%
silanized hydroxylapatite at room temperature

Type of lactide

Diluent monomers

macromonomer

TEGDMA

HEMA

THFM

Overall conversion

LL

70.0

74.3

83.6

of monomers /%

DL

65.3

78.2

80.0

Conversion /% of

LL

64.8

77.6

- Macromonomer

DL

70.3

72.7

- Diluent

LL

96.4

97.6

DL

96.5

97.1

wt.-% Macromonomer

LL

61.1

65.0

in copolymer

DL

63.0

63.6

TGP C

LL

62.4

71.8

57.0

DL

71.0

79.2

68.3

LL

212

262

263

DL

213

264

2 17

LL

4.5

4.8

4.6

DL

4.8

5.1

5.1

DL

13.8

8.5

8.7

Microhardness/MPa

E - modulus /GPa

Diametral tensile strength /MPa

(40 wt.-% diluent, 52.5

wt.-% hydroxylapatite)

160

Released acid /%

50

Time /days

---.---

Fig. 5 In vitro degradation of copolymer composites from Bis-GMA endcapped

macromonomers (1:lO mol/mol)

---+---D,L-dilactide, ---0---L,L-dilactide and

L,L-

dilactide and glycolide (7:3 mol/mol) with HEMA (7 ; 3 wt/wt), 45 wt.-% silanized hydroxyl
apatite, stored in citric acid phosphate buffer solution (pH 7.4) without enzymes, at 37 OC

Released acid /%

Time /days

---.---

Fig. 6 In vitro degradation of copolymer composites from Bis-GMA endcapped

macromonomers (1: 10 mol/mol)

---+---D,L-dilactide, ---o---L,L-dilactide and

L,L-

dilactide and glycolide (7:3 mol/mol) with THFM (7 : 3 wt/wt), 45 wt.-% silanized hydroxylapatite, stored in citric acid/ phosphate buffer solution (pH 7.4) without enzymes, at 37 "C

CONCLUSIONS
A convenient method of synthesis for macromonomers of oligo(1actide)s and also cooligomers
with diglycolide both endcapped with methacrylate groups, e.g. of Bis-GMA, has been
developed. The redox initiated copolymerization of these macromonomers with the
biocompatible comonomers HEMA, THFM and TEGDMA, respectively, in the presence of
inorganic fillers results in 290 % conversion of C=C double bonds, and 70 - 80 % conversion

161

of monomers. These high values are favourable for medical purposes. Composites with very

similar thermal and mechanical properties, but with distinct differences in degradation
behaviour can be selectively prepared. The composites should be useful as bone implant
materials with lower polymerization exotherm and better biocompatibility than conventional
materials based on methyl methacrylate.

ACKNOWLEDGEMENT
Financial support of this work by the Deutsche Forschungsgemeinschaftin the framework of
the Innovationskolleg ,,Neue Polymermaterialien durch gezielte Modifiiierung der
G r e n z s c h i c h t s t n / Grenzschichteigenschaftenin heterogenen Systemen", by the Dr. Otto
Rohm Foundation and the Funds of the Chemical Industry of Germany is gratefully
acknowledged. Furthermore we would like to thank Dr. Biertigel for the microhardness
measurements. B. Sandner is thankful to the Department of Biomaterials in Dentistry (Director
Prof. Dr. M. R. Anseau) of the London Hospital Medical College for promoting a Visiting
Professorship.

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