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1 Biomaterials Research (2005) 9(4) : Biomaterials Research 7 The Korean Society for Biomaterials ³ Bis-GMA Oligolactide w w w x w p Preparation of Biodegradable Hybrid Bone Cements Containing New Bis-GMA Derivatives and Oligolactide w 1 *Á 1,2 Á Ÿ 1 Á 2 Dong Keun Han 1 *, Bang-Ju Park 1,2, Kwang-Duk Ahn 1, and Yong-Ok Chin 2 1 Š Š e tg, 2 Š h Š 1 Biomaterials Research Center, Korea Institute of Science and Technology, Seoul , Korea 2 Department of Radio Communication Engineering, Kyunghee University, Suwon, Korea (Received October 5, 2005/Accepted November 10, 2005) In order to endow biodegradability to the existing Bis-GMA bone cement, novel biodegradable hybrid 3MA mix bone cements were prepared by using Bis-GMA derivatives (3MA and their mixture) as a prepolymer, AW-GC as a bioactive inorganic filler, and lactide-based oligomer, GL7-Ac as a biodegradable material. The obtained biodegradable bone cements showed suitable curing time of min. Polymerization shrinkage of the biodegradable bone cements increased with increasing benzoyl peroxide (BPO) concentrations and decreasing oligolactide contents, whereas their mechanical properties displayed inverse trends with the results of polymerization shrinkage. In addition, the biodegradable bone cements were degraded very slowly after immersion in phosphate buffered saline solution for 28 days, but maintained still high mechanical property. Therefore, newly biodegradable hybrid 3MA mix bone cements containing both AW-GC and GL7-Ac oligolactide are expected to be useful for high-performance biocompatible bone cements that would be replaced with the existing PMMA and Bis-GMA bone cements. Key words: Bone cement, 2,2-Bis[4(2-hydroxy-3-methacryloyloxypropoxy)phenyl]propane (Bis-GMA) derivatives, Apatite and wollastonite containing glass-ceramic (AW-GC), Mechanical property, Biodegradability d ƒ Œf f ƒ(f, implant) ff f sej f hš hœ z j Šf Š. Œf hd ƒ h f f igš ftf e Š Š hd e hhš h h, h r f d Š hf Š. Š l f f Šl f f h f f e Š f Š. f f h r Š g ƒf ŒŠh i, f ŒŠ, h h l Š thš f df f hhš ihf Š ƒ l f h l, Œ, t f f hhf Š f f f. 1,2) g ˆŒ f ƒ e ~} fƒ(pmma), f x 2,2- bis[4(2-hydroxy-3-methacryloyloxypropoxy)phenyl]propane (Bis-GMA) f 3 l f. 3) PMMA ƒ f hš thš f fš Šl *sf hf: dkh@kist.re.kr h f Œ ~. Š tf jš v fh tf dv fš h ~ f hhf l f. 4,5) f Š hf Š eš PMMA ƒf vhg Šf Š PMMA powder h igš f f l vhg thš f ~ lš f. 6) PMMA ƒ jšf ƒ f vhg f f dv l Š f fš hf f Š f xl Š f. 7) Bis-GMA ƒ PMMA ƒ ƒ f vhg f f lh dv hydroxyapatite (HA)wf Œ Š vhg ftf dvf f h f ~ f fš ƒ ff Š thš f Š. 8,9) Kokubo 10,11) f l tœ f vhg[apatite and wollastonite containing glass-ceramic (AW-GC), HA, glass bead β- tricalcium phosphate (β-tcp)] dš if PMMA ƒ Š, vhg dš d h 205

2 206 Š Á já Áld thš f d Šf Š. Š Bis-GMA ƒ jš MMA t Š h f jš f vš h f ef h, ƒ f il(soft tissue)f Œ f f f l lhhf hšš Šl f j f f. 12) f Š gh Š f f Bis-GMA ƒf hhf f f Š Š eš } l f f. tm Bis-GMA ƒ ftf } h fš hdf Š h v eš Bis-GMA urethane dimethacrylate (UDMA) 3) Bis-GMA e t 13,14) dš ff, m Bis-GMA ƒf f eš alumina, 15) nanoscale HA 16) jš lh 17) f t h dš f. Š PMMA ƒ hœd d d ifƒ s hrh lf fš f ef hrh g f f. f t v Š elšl f ƒ, ƒ s f f. Š MMA t ev f j. 18) f PMMA ƒf hf Š e Š ƒf thš f f lšjf. j ƒ Š lf t Š ƒ t Š e Š thš f f f j f. ƒ d Š l starch/ cellulose acetate blend, 19,20) poly(propylene glycol-fumarate), 21) poly(dl-lactic-co-glycolic acid) (PLGA) microparticles, 22) chitosan, 23,24) d lactose 25) f h f. f Š Š ƒ Š lf Š f e ƒ d t f Šj. Š Š ƒ Š h ŠeŠ l hf vf Š f f u Šf lf ff~ Š f. f ƒ f j f Bis-GMA lšf hi ƒf l f f Œ fš. 13,14) l, Bis-GMAf Šo o ~} fƒ xœš ~} fƒ 3 4 f 3MA 4MA hišf Bis-GMAf hf Š f f f ƒ t f h fš tœ vhg vlš f hf h h f } ~ f. t e Š eš Š Š Š lf oligolactide poly(l-lactic acid) (PLLA) t Š f 3MA Šf Œ Š ƒ h iš f, h h Š ƒ f Bis- GMA control Š. ³ v s w ƒf d ƒ d f Bis-GMA e t fh Š f f Š Š. 13) l, Bis-GMA methylene chloride f triethylamine methacrylic anhydride t Š f 1f fš work-upš Bis-GMAf e t(3ma 4MA).» t tœ f vhgf apatite and wollastonite containing glass-ceramic (AW-GC, (j) ƒ, Š )f } 4 µmf f dš. 26) ƒ f Š f f eš AW-GC fff f β-tcp s f f silane coupling agentf 3-(trimethoxysilyl) propyl methacrylate (γ-mps) s Š fj Šf e Š. 13,27) w w Š l dš oligolactidef GL7 triacrylate (GL7-Ac) fh Š Š Š. 28) l, glycerol (G) L-lactide (L) stannous octoate 130 o C 6 f z h GL7 triol (GL7-OH)f Š Š f, f f dichloromethane f triethylamine acryloyl chloride ss 0 o C 6, Š 42 fš uihf fj Šf Še GL7-Ac. Š f PLLA( f : 11, Resomer, Boehringer Ingelheim, Germany) Š eš control dš. w p ƒ e f j f Š Bis-GMA e tf 3MA mixture (3MA mix, Bis-GMA/3MA/ 4MA=45/45/10 wt%)f 2 l i dš. e f ƒ h v vhg ff f ŒŠ h f eš h(triethylene glycol dimethacrylate, TEGDMA, Aldrich)f ef 6:4(wt%) h iš. ƒ t e Š eš Š lf GL7-Ac oligolactide PLLAf Š f 5-10 wt% Š t Š. Š benzoyl peroxide (BPO, wt%, Aldrich) h d, N,N-dimethyl-ptoluidine (DMPT, 1.1 wt%, Aldrich)f hf Œ f j jštlh d f hydroquinone (HQ, 150 ppm, Aldrich)f jš lh d. Š ƒ 30 wt%f ƒ ( TEGDMA) 70 wt%f vhg(aw-gc)f ŒŠ f Figure 1 f hybrid type f ŒŠŠ. l, hybrid type f ƒf e, Š lf ŠŠ e - ŒŠ t h BPO DMPT HQ ŒŠ ff, o f ŒŠ jšf ŠŠ tf gx(ultrasonicator, Fisher Biomaterials Research 2005

3 Bis-GMA e t Oligolactide ŠeŠ Šf Œ Š ƒf hi 207 Figure 1. Preparation scheme using hybrid mixing method of biodegradable bone cements. Scientific, ) dš e - f v Š f e Š. w p p sƒ Bis-GMA e tf 3MA 4MA ŠeŠ 3MA mixf ŒŠh i Proton Nuclear Magnetic Resonance ( 1 H-NMR, 600 MHz, Bruker, f) Fourier Transform Infrared Spectroscopy (FTIR, Bruker, f) ŒfŠ f, Š lf GL7-OH GL7-Acf Š 1 H-NMR ŒfŠ. e - ŠŒ fš hi ƒf Œ jš v f Linometer RB404 (R&B, Š ) whš. Š ƒf h j v ( : l 6mm f 12 mm) ( : mm) Instron fg (0.5 mm/min, Instron, ) dš Š. ƒf Š ƒ f phosphate buffered saline (PBS, ph 7.4) d f 37 o C 28f xl ~ f iš j f Š. m f 5-6 whš unpaired Student t-test ŠŠ. š 3MA Mix v s w Bis-GMA f igš f Šf fš f h f l f. f Š hf fš Bis-GMA f ƒ hd w f hh f h d f f Œ f hf f. Bis-GMAf (-OH) ~} fƒ xœ f Bis-GMA e t(3ma 4MA) Bis-GMAf ghf f, xœ f jš f l Š f h f l f f e ( ƒ )f d f. 3MA mix Š Bis-GMA methacrylic anhydridef ef ihšf Šl Bis-GMA, 3MA 4MA 45:45:10 wt% f 3MA mix Š Š f. 3MA mixf Š e f 90%f f, f Š f w} (TLC) y f Š ŠŠ f ŒŠh i 1H-NMR FTIR ŒfŠ. 1 H-NMR controlf Bis-GMA Š 3MA mix fj Šf l Š f Š FTIR 3MA mix 3500 cm 1 sf Šf Š f g ff ŒfŠ f. w Oligolactide w ƒf Š lf t Š ƒ f Š e Š d ilf tš Š j f. Š l d oligolactidef GL7-Ac glycerol L-lactide fdš h GL7-OH Š Š f fj Šf fš GL7-Ac Š Š. 28) Š GL7-OH GL7-Ac f ŒŠh i 1 H-NMR ŒfŠ f, GL7-Acf f f 3,168f. l, GL7-OHf d, G-CH 2 OH (δ 3.73) peakf l L-CH (δ 5.16) L-CH-OH (δ 3.73) peakf h e f glycerolf l f 3 f arm Š lactidyl unit 7 f h, glycerol GL7 triol hf hœ ff f. f glycerol f 3 f hydroxyl groupf L-lactide t jš ff ~. Š GL7-Acf d r l, L-OH (δ 2.85) peakf l Ac-CH 2 =CH (δ ) L-CH 3 (δ 1.56) peakf h e f GL7-OH f h acrylate hœ ff ŒfŠ f. w p p Figure 2 jš hf BPOf Š ƒf Œ jš v f ~ f. t Š ƒ jšf Œ f f BPOf l Š Œ f Š. f if Š l Še Bis-GMA ƒf d h Œ (6-8 )f ~ f Š lf Œ f g f. 14) g ˆŒ PMMA ƒ hd e rf ff 10 h f Œ f f f f Š lf ŠeŠ ƒf Œ h Š f. Š ƒf Œ jš v f BPOf Vol. 9, No. 4

4 208 Š Á já Áld Figure 2. Curing time and polymerization shrinkage of biodegradable bone cements as a function of BPO concentration: (A) 2.0, (B) 2.3, and (C) % l Š % l Š. jš h dš BPOf jš v Œ h hš f. BPOf l Š Œ f e l l h f l Šl jš v f hf l Š hth f f x f. h Š f BPO Š f ŠdŠ jštlhf DMPT 1.1 wt%, jš lhf HQ 150 ppmf d BPOf 2.3% uhi f. Figure 3f Š lf GL7-Ac oligolactidef Š Š ƒf Œ jš v f ~ f. Œ f Š lf oligolactidef Š f l Š g f f Š t Š lf oligolactide e Š h f f f tg fš jšf ŠŠ f l. Š j Š v f Š lf oligolactidef Š f l Š 8 5.5% Š if f jš v f f jšf g l hf h f l f. h Š f f hf ƒf jš v f h f f h f f ŒŠi f uhœšf f h ~ f. 13) f d f jš v f l h f d Š ƒ lš Š l f oligolactide ŠeŠ Š ƒf d GL7-Ac Š f 5% h Š. w p» p Figure 4 jš hf BPOf Š ƒf v ~ f. Š ƒf v BPOf l Š l Š 2.3% f Š f. f BPOf h f h f l f f Š BPOf 2.3%f u f v ~. Figure 5 Š lf GL7-Ac oligolactidef Š Š ƒf v ~ f. Š ƒf v Š lf ŠeŠl f Š ƒ g f GL7-Ac oligolactide t Š f l Š v Š. f GL7-Ac oligolactide l Š ƒf Š f l Š hf e f l fš h f l f. Figure 6f l i f Š ƒf v ~ f. Š ƒf d Bis-GMA 3MA mix, Š lf ŠeŠ ŠeŠ f, PLLA GL7-Ac Š GL7-Ac oligolactidef Š f hf v l Š. hthf Š lf ŠeŠ 3MA mix ƒf v u f f Figure 3. Curing time and polymerization shrinkage of biodegradable bone cements as a function of GL7-Ac contents: (A) 0, (B) 1, (C) 5, and (D) 10. Figure 4. Compressive strengths of biodegradable bone cements as a function of BPO concentration (p < 0.05, N=5). Biomaterials Research 2005

5 Bis-GMA e t Oligolactide ŠeŠ Šf Œ Š ƒf hi 209 Figure 5. Compressive strengths of biodegradable bone cements as a function of GL7-Ac contents (p < 0.05, N=5). Figure 7. Bending strengths of various biodegradable bone cements (p < 0.05, N=6). Figure 6. Compressive strengths of various biodegradable bone cements (p < 0.05, N=5).. Figures 7 8f Š ƒf h j ef ~ f, Figure 6f v f f e Š f ~. h ƒ f i Š, 3MA mix Bis- GMA } h f ~ f 3MA mixf ƒ fj Šf Œ vhg fj Šf l Š l f Š f } f. Š fj Šf f Š lf GL7-Ac t Š f fj Šf PLLA t Š f h f. fe ƒf e f jš PLLA fj Šf l fl jš r Š l f GL7-Ac lh jš r Š f. fj Šf f Š lf GL7-Acf Š f l Š ƒ Figure 8. Young's modulus of various biodegradable bone cements (p < 0.05, N=6). f e f Š f l h f hf Š f. f hf ƒf h vhgf i Œ ~f ~ f, dš AW- GC Š ƒf d HA β-tcp f tœ vhg h f d Š f, 14) f Š g fxš. 8,9) f AW- Vol. 9, No. 4

6 210 Š Á já Áld Figure 9. Biodegradable behaviors of various biodegradable bone cements. GC vhh ft dv f f Ca P fš HAw f Œ f tl z h f f h f. 9) w p w p Figure 9 l i f ƒf Š f ~ f. ƒ 28f PBS d xlš f l Š Š f h l Š j f f f f 1% fš }l. Š Š lf Še 3MA mix ƒ f l Š Š f f l f PLLA Š lf Še Š 3MA mix ƒ g f Š f. h thf 3MA mix Bis-GMA, GL7-Ac PLLA Š GL7-Ac oligolactidef Š f f Š f l Š f, 29) f h Š h h f h f f Š l f f. Š lf ŠeŠ ƒ t Š e Š Œ f tlš f f. f Š f Š ƒ hiš eš l s Š f lf d f ) f Š Š ƒ t jf t l sf ihf llš j f l Š f. f e ƒ if Šf Œ f. Š f Š Š ƒ l ff u ŒŠ f Š h Š eš l hf vš f. 30) g l Š l Š h dš 3MA ƒ hiš f Š Š h f v f j f. Bis-GMA e t Š lf GL7-Ac oligolactide Š Š f f f ŠeŠ f Š 3MA ƒ hiš. hi Š 3MA mix ƒ f Œ h f jš v f l hf h f h Š. Š lf t Š f h f Š f Š f l Š tœ lf Š h f t Š f ƒ hi f f f. f f Bis-GMA e t oligolactide Še Š ƒ if PMMA Bis-GMA ft ƒf hhf Š Šf h f dš ff f. fe r f (2M15430)le fš f hf f. š x 1. J. B. Park, The Biomedical Engineering, J. D. Bronzino (Ed.), CRC Press, Boca Raton, 1995, p J. A. Planell, M. M. Vila, F. J. Gil, and F. C. M. Driessens, Encyclopedic Handbook of Biomaterials and Bioengineering, D. L. Wise (Ed.), Marcel Dekker, New York, 1995, Vol. 2, p S. Deb, L. Aiyathurai, J. A. Roether, and Z. B. Luklinska, Development of high-viscosity, two-paste bioactive bone cements, Biomaterials, 26, (2005). 4. S. Torrado, P. Frutos, and G. Frutos, Gentamicin bone cements: characterisation and release (in vitro and in vivo assays), Int'l J. Pharm., 217, (2001). 5. D. F. Williams Materials Science and Technology, in Medical and Dental Materials, R. W. Cahn, P. Haasen, and E. J. Kramer (Eds.), VCH, Weinheim, 1992, Vol S. Shinzato, T. Nakamura, T. Kokubo, and Y. Kitamura, A new bioactive bone cement: Effect of glass bead filler content on mechanical and biological properties, J. Biomed. Mater. Res., 54, (2001). 7. F. Miyaji, Y. Morita, T. Kokubo, and T. Nakamura, Surface structural change of bioactive inorganic filler-resin composite cement in simulated body fluid: Effect of resin, J. Biomed. Mater. Res., 42, (1998). 8. M. Kobayashi, T. Nakamura, J. Tamura, T. Kokubo, and T. Kikutani, Bioactive bone cement: Comparison of AW-GC filler with hydroxyapatite and β-tcp fillers on mechanical and biological properties, J. Biomed. Mater. Res., 37, (1997). 9. M. Kobayashi, T. Nakamura, Y. Okada, A. Fukumoto, T. Furukawa, H. Kato, T. Kokubo, and T. Kikutani, Bioactive bone cement: Comparison of apatite and wollastonite containing glass-ceramic, hydroxyapatite, and β-tricalcium phosphate fillers on bone-bonding strength, J. Biomed. Mater. Res., 42, (1998). 10. Y. Okada, K. Kawanabe, H. Fujita, K. Nishio, and T. Nakamura, Repair of segmental bone defects using bioactive bone cement: Comparison with PMMA bone cement, J. Biomed. Mater. Res., 47, (1999). 11. S. Shinzato, M. Kobayashi, W. F. Mousa, M. Kamimura, M. Neo, Biomaterials Research 2005

7 Bis-GMA e t Oligolactide ŠeŠ Šf Œ Š ƒf hi 211 K. Choju, T. Kokubo, and T. Nakamura, Bioactive bone cement: Effect of surface curing properties on bone-bonding strength, J. Biomed. Mater. Res. Appl. Biomater., 53, (2000). 12. T. Yamamuro, T. Nakamura, H. Iida, K. Kawanabe, and Y. Matsuda, Development of bioactive bone cement and its clinical applications, Biomaterials, 19, (1998). 13. H. J. Im, K.-D. Ahn, J.-M. Kim, and D. K. Han, Preparation and characteristics of novel organic-inorganic hybrid bone cements containing Bis-GMA derivatives, Biomater. Res., 7, (2003). 14. B.-J. Park, K.-D. Ahn, Y.-O. Chin, and D. K. Han, Preparation of novel bioactive hybrid bone cements containing Bis-GMA derivatives as a prepolymer, to appear. 15. K. Nishio, M. Neo, H. Akiyama, Y. Okada, T. Kokubo, and T. Nakamura, Effects of apatite and wollastonate containing glassceramic powder and two types of alumina powder in composites on osteoblastic differentiation of bone marrow cells, J. Biomed. Mater. Res., 55, (2001). 16. Q. Fu, N. Zhou, W. Huang, D. Wang, L. Zhang, and H. Li, Preparation and characterization of a novel bioactive bone cement: Glass based nanoscale hydroxyapatite bone cement, J. Mater. Sci. Mater. Med., 15, (2004). 17. M. Kobayashi, T. Nakamura, T. Kikutani, K. Kawanabe, and T. Kokubo, Effect of polymerization reaction inhibitor on mechanical properties and surface reactivity of bioactive bone cement, J. Biomed. Mater. Res. Appl. Biomater., 43, (1998). 18. M. Santin, A. Motta, A. Borzachiello, L. Nicolais, and L. Ambrosio, Effect of PMMA cement radical polymerization on the inflammatory response, J. Mater. Sci. Mater. Med., 15, (2004). 19. I. Espigares, C. Elvira, J. F. Mano, B. Vazquez, J. S. Roman, and R. L. Reis, New partially degradable and bioactive acrylic bone cements based on starch blends and ceramic fillers, Biomaterials, 23, (2002). 20. L. F. Boesel, J. F. Mano, and R. L. Reis, Optimization of the formulation and mechanical properties of starch based partially degradable bone cements, J. Mater. Sci. Mater. Med., 15, (2004). 21. D. D. Frazier, V. K. Lathi, T. N. Gerhart, and W. C. Hayes, Ex vivo degradation of a poly(propylene glycol-fumarate) biodegradable particulate composite bone cement, J. Biomed. Mater. Res., 35, (1997). 22. P. Q. Ruhe, E. L. Hedberg, N. T. Padron, P. H. M. Spauwen, J. A. Jansen, and A. G. Mikos, Biocompatibility and degradation of poly(dl-lactic-co-glycolic acid)/calcium phosphate cement composites, J. Biomed. Mater. Res., 74A, (2005). 23. S. B. Kim, Y. J. Kim, T. L. Yoon, S. A. Park, I. H. Cho, E. J. Kim, I. A. Kim, and J.-W. Shin, The characteristics of a hydroxyapatitechitosan-pmma bone cement, Biomaterials, 25, (2004). 24. L.-C. Lin, S.-J. Chang, S. M. Kuo, S. F. Chen, and C. H. Kuo, Evaluation of chitosan/β-tricalcium phosphate microspheres as a constituent to PMMA cement, J. Mater. Sci. Mater. Med., 16, (2005). 25. M. Otsuka, M. Sawada, Y. Matsuda, T. Nakamura, and T. Kokubo, Effects of water-soluble component content on cephalexin release from bioactive bone cement consisting of bis- GMA/TEGDMA resin and bioactive glass ceramics, J. Mater. Sci. Mater. Med., 10, (1999). 26. N. J. Dunne and J. F. Orr, Influence of mixing techniques on the physical properties of acrylic bone cement, Biomaterials, 22, (2001). 27. S. Shinzato, T. Nakamura, T. Kokubo, and Y. Kitamura, Bioactive bone cement: Effect of silane treatment on mechanical properties and osteoconductivity, J. Biomed. Mater. Res., 55, (2001). 28. D. K. Han and J. A. Hubbell, Synthesis of polymer network scaffolds from L-lactide and poly(ethylene glycol) and their interaction with cells, Macromolecules, 30, (1997). 29. C. H. Kim, K. O. Park, and J. K. Kim, Synthesis and characterization of bone ingrowth associated with bone cement co-polymerized with a biodegradable material, Biomater. Res., 9, (2005). 30. J. G. E. Hendriks, J. R. van Horn, H. C. van der Mei, and H. J. Busscher, Backgrounds of antibiotic-loaded bone cement and prothesis-related infection, Biomaterials, 25, (2004). Vol. 9, No. 4

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