Indian Journ al of Engineering & Materi als Sciences Vol. 7, June 2000, pp. 160- 166

Diethylene glycol acrylate-n-vinyl pyrrolidone copolymer resins for bone cement applications

D Celina, Vinoy Thomas & Muthu Jayabalan*

Polymer Division, Biomedical Techno logy Wing, Sree Chitra Tirunallnstitute for Medical Sciences and Technology, Thiruvananthapuram 695 012, India

"Department of Appli ed Chemi stry, Cochin Un iversity of Science and Technology, Kochi , India

Received 17 May 1999; accepted 2 April 2000

Biodegradable and injectable monomer diethylene glyco l acrylate (DGA) and diethylene glycol acrylate-II -vin yl pyrro­lidone (DGA-VP) blends have been prepared and evaluated their suit abilit y for bone cement app licati ons . Studies on the setting of the monomer DGA and the blend DGA-VP have been carried ou t using a free rad ical initi ator. Lower sctting time is observed with the monomer in compari son with that of the blend . The degradation of cured PDGA and P(DGA-VP) polymeri c materi als has been evaluated in simulated physiologicailluids. Studies on degradation in hydrol yti c and oxidati ve medi a reveal faster degradati on during initi al period of aging foll owed by slower and steady state degradation. /11 vitro deg­rJdation studi es show more hydrol ytic degradation in PDGA whi le both hydrol yti c and oxidative degradation in P(DGA­VP) in co mpari son to that of PDG A. Also, the biocompati ble comollomer (VP) en hances biodegradati on of aliphatic poly­ester PDG A.

Acrylic and methacry lic po lymers have a long hi story of c linical use in orthopedics 1.2. These po lymers are used as bone cement for jo int repl acement, bone fi xa­tion plates and li gaments. The current standard for bone cement is usuall y so ld as two-component sys­tems with one component primaril y consisting of methyl methacry late monomer and the other cons ist­ing of PMMA mi cro sphere and initi ators. Mixing and trending the two components together produces a putty set up to form a glassy solid . Another self­curing porous acrylic bone cement pro mi ses im­provement in crania facial reconstruc ti o ll" . But, be ing biolog ically inert , PMMA ac ts as a barrier to fracture healing and does not permit direct bonding by host bone4

.5

. PMMA is vulnerable to the accumu lati on of fati gue damage due to repeated mec hanica l load and starts loosening at the inte rface of cement bone. There are other di sadvantages assoc iated with ac rylic bone cements such as shrinkage, brittleness of cured acrylic product , leac hing of residual monomers and acce l­e rator (d imeth yl p-toludine) and infl ammatory reac­tion . Biodegradable bone cements are used in ortho­pedic app lications6

, Bone cements from material s made of biodegradabl e polymers are des igned to degrade ill vivo in a controlled manner over a prede­termined period . The advantages o f the degradabl e material s are: (i) they do not have to be removed after

*For correspondence

use by secondary surgery because the formed degra­dati on products can be excreted from the body via natura l pathways, and ( ii ) progress ive loss of degrad­ab le implant materials will lead to regeneration of healing ti ssues .

Aliphatic polyeste r and degradabl e acryl ates are found to be a lte rnative bone cement to PMMA bone cements w ith added advantages. These are biode­graded under ill vivo environment and removed by body metabo lic pathways. The main mechanisms of biodegradation are hydrol ytic, oxidative and envi­ronmental stress corrosion. For hydrolyt ic and oxida­ti ve degradation of a liphatic pol yeste rs, presence of a comonomer plays an important facto r for c ross linking reaction, bonding strength and biodegradation. II-Vinyl pyrrolidone, a principal component o f il ydro­ge l contac t lenses? and bi ocompatible copo lymers8 used as comonomer, can cross- link ac ry li c monomer in the presence of a free radical initiator. Therefore, it was planned to synthes ize a DGA-VP compound and to study its setti ng c haracte ristics and in vitro degra­dation of the cured res in to explore the poss ibility of developing a low molecular weight , inj ectable and fast setting bone cement compos ite.

Experimental Procedure Materials

The used compound s di ethy lene glyco l (digo l), acrylic acid, Il-vinyl pyrrolidone, acetone and p-

, ,

CELIN el al. : DGA-VP COPOLYMER RESINS FOR BONE CEMENT APPLICATIONS 161

toluene sulphonic acid were of analytical grade. Digol was vacuum dried at 60 °C for I h.

Synthesis of DGA monomer and DGA-VP blend For preparing DGA monomer, 21.224 g (0.2 M) of

digol was accurately weighed into a three necked R.B. fl ask containing 28.824 g (0.4 M) acrylic acid. 0.50048 g of p-toluene sulphonic ac id was added to it as catalyst. The mixture was refluxed with stirring for about 45 min at 68°C. After cooling the reacti on mixture to room temperature, rotary evaporation was carried out to remove the byproduct water. DGA was obtained as a pale yellow viscous liquid . The DGA­VP blend was prepared by blending 5 g each DGA and n-viny l pyrrolidone.

Evaluation of the monomer and blend Determinati on of doughing time and time for set­

ting - Doughing time and setting time of DGA monomer and DGA-VP blend were eva luated as per the ISO 5833/1- I 999E procedure. 5 g of the monomer was taken separate ly in two clean test tubes and 0.08 g benzoyl peroxide (BPO) was added to it. To one of the test tubes, 5g of n-vinyl pyrrolidone co­monomer was added to the reaction mixture. The contents of the test tubes were mixed thoroughly . The doughing and setting times were noted at 37 °C. The ex periment was repeated at 50 0C. The time required for forming and adhering fibers between a glass and the surface of the sett ing mass was noted as doughing time. The maximum exothermic temperature atta ined during the setting was noticed . The average of the sum of the ambient and maximum exothermic tem­peratures was found. The time taken to reach the av­erage temperature was taken as sett ing time.

Preparation and studies on cured polymers Cross-linked pol ymer and copolymer products

wctre prepared fro m DGA and DGA-VP respectively using benzoyl peroxide. Infrared spectral studies were carried out for cured PDGA and P(DGA-YP) sam­ples. Solid samp les were masticated in mortar and pestle and the fine powders were lIsed for mak ing

Acry li c acid

p -Toluene sulfoni c ac id

KBr pe llet for recording the spectrum. A Nicolet (Im­pact 4 10) Ff-IR instrument was used fo r this purpose. The solubil ity of the two polymers in different non­polar and polar so lvents was studi ed. The used sol­vents were: benzene, toluene, carbon tetrachloride, chloroform, ace tone, methanol, dioxane, te trahydrofu­ran, N.N-dimethyl acetamide and dichloromethane. The cross-linking density of the cured materials was determined from the value of swelling coefficient by subjecting the polymer to swell in dimethyl acetamide solvent for 2 days as reported earlier9

. Hardness was measured based on the res istance of the cured materi­als to the penetration of an indendor of a specific di­mension measured in the calibrated dia l of a Shore A-durometer as per ASTM standard D 2240-8 I .

Studies on ill vitro biodegradation of cured PDGA and P(DGA-VP)

The in vitro biostabi lity of the cured polymer PDGA and copolymer P(DGA-VP) was investi gated in simulated biological fluids as described earlier 'o. The used medi a were: phosphate buffered saline (PBS), Ringer's solution and 30% hydrogen peroxide solution as oxidation medium. The cured sheets of PDGA and P(DGA-YP) with uniform dimension s were weighed accurately and immersed in different med ia at 37 °C. The material was taken ou t, dried and weight loss was determined on alternate days. The weight loss (%) was plotted agai nst duration of expo­sure and re lat ive aging stability was examined .

Results and Discussion Synthesis of diethylene glycol acrylate (DGA) monomer

The DGA monomer was prepared by bulk polym­eri zation. The reaction proceeds to the formation of a pale yellow, viscous compound in the presence of p­to luene sulfonic acid catalyst as shown in Eq . ( I ) :

Characterization of the monomer and blend

The essential properties of a hard ti ssue ad hesive (bone cement ) are short setting time and controlled biodegradability. The short duration of setting enables faster processi ng . Setting characteri stics are a measure

Digol

... ( I )

CH2 = CH- COO-CH2 -CH2 -0- CH2 - CH2 -OOC-CH = CH2 + 2 H20 Diethylene glycol ac rylate (DGA)

162 INDIAN J ENG. MATER. SCI., JUNE 2000

Table I - Selling characteri stics of monomer and blend compounds

Monomer! Composition by weight (g) Temperature Setting time

Blend Monomer BPO n-VP (0C)

DGA 5 0.08 0 37 17hl5min

DGA-nVP 5 0.08 5 37 23 h 35 min

DGA 5 0.08 0 50 2 h 25 min

DGA-nVP 5 0.08 5 50 9 h

CH2 = CH- COO-CH2 -CH2 -0- CH2 - CH2 -OOC-CH = CH?

Benzoyl peroxide, 37/50 DC 1 R

I· I \

CH2 - CH- COO-CH2 -CH2 -0- CH2 - CH2 -OOC-CH - CH2

CH2 -- CH- COO-CH2 -CH2 - 0 - CH2 - CH2 -OOC-CH - CH2 . ..(2)

to testify the quality of a adhesive. The setting time of the DGA and DGA-YP blend is given in Table I. The setting reaction of DGA monomer is mediated through crosslinking reaction with its double bond by free radical initiation . Monomers or oligomers with vinyl groups are usually polymerized or crosslinked with comonomer by chemical initiation by free radical catalysts ' 1.l2. The cross-linking reaction is shown in Eq. (2):

The setting time of the blend is extended to slightly higher duration with the addit ion of comonomer, /1-VP in DGA (Table I ). The increase in setting time with the addition of n-VP is due to chain propagation reaction at 37,oC. The effect of temperature on the setting time of DGA is also reported in Table I. It is found that as the environmental temperature increases, the setting time also decreases. A significant r€duction of setting time is observed with DGA monomer alone (2 h & 25 min .) if it is set under the ·initip.1 temperature condition of 50 °C. The studies also reveal that the setting time of PDGA and P(DGA-VP} can be reduced substantially if the set-

ting is carried out with an accelerator viz. N,N-dimethyl aniline. The crosslinking reaction of vinyl oligomers has been proposed by Hartung and Berger. '2 The chain propagation reaction of the present vinyl based PDGA and P(DGA-VP) with comonomer is shown in Eg. (3):

Studies on cured PDGA and P(DGA-VP)

The FrIR spectra of PDGA and P(DGA-VP) are given in Figs I and 2, respective ly. The infrared spectral analysis data reveal peaks for =C=O stretch­ing for ester [173 1.44 (s) fo r PDGA and 1740 cm-'(s) for P(DGA-VP)], =C=O stretching of acrylic [1178.09 (s) for PDGA and 1170 cm-'(m) fo r P(DGA­VP)], -C-O- stretching of ether [1100.08 (s) for PDGA and 1100. 14 cm-'(m) for PCDGA-VP)], and =C-H bending of CH2=CH [1425.IO(m) for PDGA and 1420.89 cm-'(m) for PCDGA-VP)] . PCDGA-VP) polymer reveals responses at 1200 cm-'( m) for vinyl pyrrolidone additionally. PDGA and PCDGA-VP) are not sol uble in benzene, toluene, carbon tetrachloride and chloroform. These material s are sparingly soluble

CELIN el al. : DGA-VP COPOLYMER RESINS FOR BONE CEMENT APPLICATIONS 163

CH2 = CH- COO-CH2 -CH2 -0- CH2 - CH2 -OOC-CH = CH2

BPO / 37-50 °c ... (3)

CH2 - CH - COO - CH2

l - CH2 - 0 - CH2 - CH2 - OOC - CH - CH2

I - [-CH2-CH

I

LY

Fig. I - Ff- IR spectra of cured PDGA

in the so lvents methanol, dioxane, tetrahydrofuran , N,N-dimethyl acetamide and dichloromethane. How­ever, in acetone, PDGA is sparingly soluble and P(DGA-VP) is insoluble.The studies on solubility reveal that these cured materi als are reasonabl y crosslinked The cross link ing density of the cured materials, as reported in Table 2, is lower fo r PDGA

I CH-CHr ]m-

Fig. 2 - Ff- IR spectra of cu red P(DGA-VP)

than that fo r the P(DGA-VP) . T he higher cross linking density of the latter is attributed to the higher degree of crosslinking through viny l pyrrolidone comono­mer. T he hardness of the cured materi als is also gIven in Table 2. Higher hardness IS observed in the case of P(DGA-VP) which is due to the higher crosslinking density --and lower molecular weight between cross li nks in compari son with that of PDGA.

164 IND IAN J ~NG. MATER. SCI., JUN E 2000

Studies on ill vitro biodegradation of cured PDGA and P(DGA-VP)

The aging in simulated body fluids, Ringer's solu­tion and phosphate buffered saline (PBS) can induce hYdrolytic degradat ion . Aging in 30% hydrogen per­oxide solution can induce oxidative degradation . The data on aging studies for PDGA polymer, as given in Fig. 3, reveal faster degradation during initial aging followed by slow degradati on reaching a steady state condition during subsequent aging. Among the aging media, higher initial weight loss was noticed in Ringer's solution. However, PDGA completely de­fo rmed and degraded in PBS after 10 days of ag ing. The fast degradation of thi s polymer in hydrolytic med ia is due to ester hydrolysis. The data on weight loss of P(DGA-VP) are presented in Fig. 4. The higher weight loss was observed initi all y fo ll owed by a steady state conditi on in different media as in PDGA polymer. P(DGA-VP) also underwent com­plete deformati on with degradation in PBS medium after 10 days. P(DGA-VP) showed relati ve ly hi gher maximum weight loss (%) than PDGA (Table 2). The higher weight loss and faster degradation in P(DGA­VP) is due to higher hydrophilic character of n-vinyl pyrrolidone and absorption of the medi a. Hydrophili c po.lymers absorb more polar compounds. When com­paring the influence of degradati on media on the deg­radation of PDGA, maximum weight loss was ob­served in Ringer's so lution. However, for P(DGA-VP) max imum weight loss was observed in Ringer's solu­tion and oxidation medium. This suggests that while the major degradation of PDGA is med iated by hy­drolysis, the degradation of P(DGA-VP) is mediated by both hyd rolysis and oxidation. The weight loss in hydrogen perox ide medium is due to oxidative degradation of the ether linkage -CH2 -O-CHr of the polymer though the ether linkage is stable in the hydrolytic medi a.

The ether linkages present in polymers such as polyether undergo ox idative degradation 11. Though, ethers are relativel y stab le towards bases, ox idi zing agents and reducing agents, they readil y undergo cleavage by acids'-l sllch as hydrogen perox ide (pH 3.1). The ox idative degradation of PDGA and P(DGA-VP) is shown in Eq. (4). The hydrogen adja-

cent to a carbonyl group of the ether linkage is sus­ceptible for abstraction by ox idant free radicals as shown here. The crosslinking reacti on takes pl ace with hydrogen abstraction. However, prolonged ox i­dation results in the cleavage of crosslinked polymer leading to fragmentation of the product.

Conclusions

Studies on setting of the monomer DGA and the blend DGA-VP in the presence of free radical initia­tors reveal lower setting time with the monomer in

10

" " Fig. 3 - Dcgradation of' cured PDGA in simulatcd physiological

fluid s

.-- ----, t2

Ou, .. IoooGll'UPOSWl fD-yo;)

I

Fig. 4 - Degradation of' cured P(DGA-VP) in simulated physIO­logical fluid s

Tablc 2-Charactcristics of' the cu red materials

CU:'ed matcri al Molecu lar weight Crosslink dcnsi ty Hardness Maxi mum weight loss during degradation (%)

betwecn crosslinks (x IO') (Shore A) Ringcr's solut ion PBS H20 2solulion

PDGA 2 14- 4.6729 38 59.37 45.26 35.1

P(DGA.-V P) 138 7.2464 44 75.11 67.58 75.68 ---

CELIN et al. : DGA-VP COPOLYMER RESINS FOR BONE CEMENT APPLICATIONS 165

HOO' + H'

Initiation

+ Off

PDGA / P(DGA-VP)

Propagation

(a) -- CH2 - CH2 - 0 - .CH - CH2-- + HOO· --. -- CH2 - CH2 - 0 - f=H - CH2-­

OOH

(b) -- CH2 - CH2 - 0 - CH - CH2-- -.. -- CH2 _. CH2 - 0 - CH - CH2-- + OH

I I OOH .0

Crosslinking

-- CH2 - CH2 - 0 - CH - CH2--

I ... (4)

-- CH2 - CH2 - 0 - CH - CH2--

comparison with that of the blend . The in vitro bio degradation studies in Ringer's s;)lution, phosphate buffered saline and hydrogen peroxide reveal faster degradation during initial period of aging followed by slow and steady state degradation of both PDGA and P(DGA-VP) polymers. The influence of Ringer's so­lution in the degradation of PDGA was found to be more as compared to that with the other two media, viz. PBS and hydrogen peroxide. But, the influence of Ringer's solution and hydrogen peroxide on the deg­radation of P(DGA-VP) is more or less equal. This reveals that PDGA is more prone to hydrolytic degra­dation and P(DGA-VP) is more prone to hydrolytic and oxidative degradation . The degree of weight loss was more with P(DGA-VP) in comparison with that in PDGA. The higher weight loss in the former is due to the hydrophilic characte[ introduced by n-vinyl pyrrolidone comonomer. Therefore, it is conc luded that the biocompatible comonomer (VP) enhances

biodegradation of the aliphatic po lyester (PDGA), intended for use as biodegradable bone cement.

Acknowledgements

Sincere thanks are due to the Head, Biomedical Technology Wing, and the Director, Sree Chitra Tirunal Institute for Medical Sciences and Technol­ogy, for providing the facilities to carry out these in­vestigations .

References

Gerhart T N, Hages W G, & Sterri S H, J Orthop Res, 4 ( 1986) 76.

2 Gerhart T N, Miller R L, Kleshinski J E & Hayes W G, J Biomed Mater Res, 22 (1988) 10971.

3 Hill R G, Bates J F, Lewi es T.O & Ress N J, Biomaterials, (1983) 112.

4 Charnle Y J, ACI)'lic cement in orthopedic surgery (Will iams Wilkins, Bal timore), 1970.

166 INDIAN J ENG. MATER. SCI., JUNE 2000

5 Enis J E, Mc Collough M C & Cooper J S, Clill Orlllop, 105 . ( 1974) 283.

6 Goldstein T N, Matthews L, Kuhn J & Holli ster S . .1 Biomecll , 24(1991) 135.

7 Willi ams 0 F, Biocolllpalibi/i1y ill clillical praclice (CRC Press, BocaRaton. Florida), 1982,33.

8 Va le B H & Greer R T , .I Biollled Maler Res, 16 ( 1982) 471.

9 Jayabalan M, Lizymol P P & vinoy Thomas, PolYIIl liller , 49 (2000) 88.

10 vinoy Thomas, Jayabalan M & Sandhya S, .I Biolllaler Appl (in press) .

I I Chen J, Jo S & Park K. in Halldbook of Biodegradable Polymers, edited by Oomb A J , Kost J & Wi seman 0 M (Harwood Academic Pub .. Amsterdam), 1997,203 .

12 Hartung H A & Berger S E,.1 Appl PolYII/ Sci , 6 ( 1962) 474. 13 Wu . Y, Sellitti C, Anderson J M, Hiltncr A, Lodoen G A, &

Payet C R, .I Appl PolYIll Sci. 46 (1992) 20 I. 14 Morri son R T & Boyd R N, Orgallic chell/is")" Second

edition (Allyn & Bacon, Inc, Boston), 1972,567.