macromolecular symposia crosslinked copolymers with degradable oligo(lactide) branches

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JOURNAL TITLE: 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: 1

MONTH: January

YEAR: 1996

PAGES: 149–162

ISSN: 1022-1360

OCLC #:

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Macromol. Symp. 103,149-162 1996)

149

CROSSLINKED COPOLYMERS WITH DEGRADABLE

OLIGO(LACTIDE)

BRANCHES

Barbara Sandnee, Simone Steurich

Martin-Luther-UniversitiitHalle-Wittenberg

Fachbereich Chemie, Geusaer Str., 06217 Merseburg, Germany

Siegfried Wartewig

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 copolymerization of 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, tetrahydro-

furfuryl methacrylate, ri(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.

1996 Huthig & Wepf Verlag, Zug

CCC

1022-1360/95/$04.00



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-hydroxy-

ethyl 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.

.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-dimethacryloyl-

oligoflactone) was obtained by termination with methacryloyl chloride. Amphiphilic graft

copolymers and amphiphilic copolymer networks were obtained by copolymerization of the

a-

mono- 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,L-

dilactide, diglycolide and e-caprolactone. We report here the crosslinking copolymerization n

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-

nd 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),

N-

vinylimidazole (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-toluidineDMpT) was distUed under vacuum in an argon

atmosphere.

Synthesis of macromo nomers

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 m olar ratio

of 7:3

with 9.09 mol-% Bis-GM A, using

0.56

mol-% Mg O as a catalyst. The m ixture was stirred at

130 C

for about 2 hours until

a l l

dilactide and diglycolide had reacted co mpletely. The molar m asses were controlled by m eans

of gel-penneation chromatography (GPC).

Preparation of composites

Com posites were prepared by chemically curing mixtures of the m acromono mer with HE MA ,

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 ab out

10

min.

Analysis

GPC

The gel-permeation chromatography measurements were carried out

on

a Knauer device

equipped w ith a K nauer differential refractometer. For determination of the molecular weight

three

Hibar

RT

columns (PS I, PS4, PS20) and for

analyzing

the extracts two Waters Styragel

HR1 columns were used. Tetrahydrofuran (THF)erved as solvent. The mo lecular weight w as

calibrated relatively to m onodisperse polystyrene.



153

Laser Ram an 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-'. n

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 Clmin.

Micro hardness

Microhardness was measured on a Fischerscop H 100 using a Vickers diamond. Composites

were tested at 22 C at a force of 1000mN 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 mn onto the sample until contacting. Then the speed was increased to

10

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

2 F

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:

130°C.

2-6

h

v

c=o

I

CH-CHI

=o

FH-CH?

, O n

-

H

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

n

of oligo(L,L-

1actide)s against the time. Oligomerization was initiated with Bis-GMA and catalyzed by

N-

vinylimidazole (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).

0 1 2 3 4

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: ---0--- 1 : 0.3

NVI,

O 1

:0.2

MgO,

0 :

0.03 Sn(I1) octoate,---*---ithout 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 racemization during the oligomerization of L,L-

dilactide; this may be a further advantage. However, from the medical point of view, MgO and

NVI (the latter can be incorporated by copolymerization nto the polymer network) should be

preferred.

Differences between Gn calculated and a n ound 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 copolymexization of oligoflac tide) macromonom ers

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 com onomers. The redox system DBPO -DMpT was used as an initiator

at room temp erature.

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 a t 1640 and 1719

an-',

ith the aromatic CH= band at 1455

an-

s

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 m acromonomer

- HEMA

mixture

(7:3

W w t) (curve

1)

and

its copolymer (curve 2 ) heat cured with 0.5 w t . 4 D BPO a t 80 C for

2

h without fiuer

The

decrease of the band intensities monitored during the redo x initiated curing cycle is shown

in Fig.

3

at

various

times

at

24°C.

The

course

of

po lyrn eht ion 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

r

-

E

.-#

-

Wavenumber/cm-'

Fig.

3.

Laser

Raman

spectra of a macromonomer - HEMA 7:3 wt/wt) copolymedtion with

0.4 wt.-% DBPO and 0.22wt.- 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=C ouble bond conversion, calculated from the

simultaneous

decrease in

intensity of the

two

bands at 1640 an-' nd 1719 an- , n 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

nd 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

comonomersHEMA and

THFM

espectively, were almost completely 2 6 %) incorporated

into the organic network matrix. In contrast, the conversion of the macromonomer was only

about70

%.

This result explains the high conversion of C=C ouble 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 doub le bonds, calculated from --- ----=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

f the composites were obtained by DMA. Composites

with HEMA show the highest

TG

Table 1).

This

is consistent with the differences between T G

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 m icrohardness measurements, d o 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 TEGD MA .

Distinctions between the com posites 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

of

monomers /% DL

Conversion

/% of

LL

-

Macromonomer DL

- Diluent LL

DL

wt.-% Macromonomer

LL

in copolymer DL

TGPC

LL

DL

Microhardness MPa LL

DL

E - modulus /GPa LL

DL

Diametral tensile strength /MPa DL

40 wt.-

diluent,

52.5

wt.-% hydroxylapatite)

70.0

65.3

62.4

71.0

212

213

4.5

4.8

13.8

74.3

78.2

64.8

70.3

96.4

96.5

61.1

63.0

71.8

79.2

262

264

4.8

5.1

8.5

83.6

80.0

77.6

72.7

97.6

97.1

65.0

63.6

57.0

68.3

263

2 17

4.6

5.1

8.7



160

Released ac id /%

50

T i m e / d ay s

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

macromonomers

(1:lO

mol/mol)

--- ---

,L-dilactide,

---0---

L,L-dilactide and

---.--

,L-

dilactide and glycolide 7:3 mol/mol) with HEMA (7 ; wt/wt), 45 wt.-% silanized hydroxyl

apatite, stored in citric a c i d phosphate buffer solution (pH

7.4)

without enzymes, at

37

OC

Released ac id /%

T i m e / d a ys

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

macromonomers

(1:

10 mol/mol) --- ---,L-dilactide, ---o---L,L-dilactide and

.

,L-

dilactide and glycolide

7:3

mol/mol) with THFM

(7

:

3 wt/wt),

45

wt.-% silanized hydroxyl-

apatite, stored in citric acid/ phosphate buffer solution (pH 7.4) without enzymes, at 37 C

CONCLUSIONS

A conv enient method of synthesis for m acromonom ers of oligo(1actide)s and also coo ligomers

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 HEM A,

THFM

and TEGDMA, respectively, in the presence of

inorganic fillers results

in

290

%

conversion of C=C double bonds, and 70

-

80 % conversion



162

(10)

1

1)

H. R. Kricheldorf,

J.

Meier-Haack, Makromol. Chem. 194 ,7 15 (199 3)

DE 29

14

988 (1980).

Consortium f i i

elektrochemische Industrie GmbH,

invs.: K.

Marquardt;

Chern.

Abstr

9 4 , 6 6 4 2 4 ~1981)

B.

Sandner,

R.

Schreiber, Makromol. Chem. 193 ,2 763 (199 2)

B.

Sandner,

R.

Schreiber,

U.

Matschinske, 2nd Dresden Polymer Discussion. 1988.

Preprints L 31, p. 181

(12)

(13)

macromolecular symposia crosslinked copolymers with degradable oligo(lactide) branches

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