本研究主要將探討具有溫度敏感性的水膠 methoxy polyethylene glycol-co-poly(lactic-coglycolic acid) (mPEG–PLGA)混摻不同比例碳酸鍶最為鍶離子傳輸上之應用。先將D,L-lactide(LA)、glycolide(GA)單體與mPEG進行開環聚合反應，在固定單體莫耳比(LA:GA=78:22)合成具有溫度敏感性水膠mPEG-PLGA。將碳酸鍶混摻於水膠溶液中，其混摻比例分別為水膠與碳酸鍶的重量比(Gel:Strontium=G1S0、G5S1、G3S1及G1S1)。於體外測量其釋放速率、物理性質、成膠性質、降解情況及細胞毒性等等，並進行體內測試，經由皮下注射HE染色切片觀察發炎情況。
各種混摻比例皆可於低濃度水溶液中自組裝形成微胞，其臨界微胞濃度介於80~110 ppm之間，經由熱力學分析其形成微胞為不可逆自發行為。而粒徑量測及TEM結果顯示mPEG-PLGA的奈米微胞會隨著溫度的上升而聚集，造成粒徑大小增加。由相轉換測試結果可知，20wt%為最低濃度下，成膠溫度低於人體溫度37°C，其成膠溫度為25°C左右。由流變儀結果可得mPEG-PLGA其機械強度、黏度隨著溫度而變化，這也證實了mPEG-PLGA具有溫度敏感性。
從體外pH值變化量結果可知，碳酸鍶可與酸進行反應，此可減緩pH值因降解而下降的趨勢。而由於pH值下降減緩也造成降解速率減慢，進而達到長期釋放的效果。鍶離子釋放結果顯示， mPEG-PCL的C1S1比較其釋放量遠小於mPEG-PLGA的G5S1、G3S1及G1S1，這是由於mPEG-PCL在降解過程中產生酸性較少，無法與碳酸鍶做反應進而釋放出鍶離子。而由細胞毒性測試的結果可知，加入碳酸鍶的G5S1、G3S1、G1S1在降解過程中，pH值的提升造成細胞毒殺性相對降低，其中G1S1生物相容性較佳。同時在動物皮下HE切片染色結果得知，加入碳酸鍶的組別能有效的改善mPEG-PLGA酸化造成的發炎反應，同時減緩降解速率達到長期釋放的效果。綜合以上結果，我們認為利用mPEG-PLGA溫感性水膠混摻碳酸鍶對於骨質疏鬆症的治療是具有潛力的。

The objective of this study was to discuss the thermosensitive hydrogel methoxy polyethylene glycol-co-poly(lactic-coglycolic acid) (mPEG–PLGA) amphiphilic diblock copolymers mixed with different weight ratio strontium carbonate for osteoporosis treatment. A series of amphiphilic diblock copolymer was synthesized by ring-opening polymerization of mPEG,D,L-lactide and glycolide. The initial ratio of monomers in PLGA was LA/GA=78/22. Blending strontium carbonate into the polymer solution with weight ratio (Gel:Strontium carbonate =G1S0, G5S1, G3S1 and G1S1). The copolymer was characterized via ¹H-NMR, FT-IR and GPC. The physical properties of a series of composite gels, including the critical micelle concentration (CMC), particle sizes, rheological behavior, morphology of composite gels, and sol–gel transition, were characterized in vitro. These results revealed that addition of strontium carbonate do not significantly interfere with gel-forming mechanisms. As the temperature increased, micelle aggregation was observed by DLS and TEM. As results of sol-gel transition , 20 wt% hydrogel of the gelling temperature below body temperature 37 ° C, and its gelation temperature approximately 25 °C . In vitro pH change test showed that the strontium carbonate can react with hydrogen ions, which effectively raise the pH value. Raising pH value caused degradation to slow, thus achieving long-term release. The concentration of strontium ions released on the first day reached effective concentration to treat osteoporosis. Higher cell viability was observed in the composite gels with more strontium carbonate, as shown in the MTT assay and the live and dead stain.
Based on the above results, mixing mPEG–PLGA with strontium carbonate may hold greater promise than mPEG–PLGA alone for osteoporosis therapy.

1. 內政部戶政司-人口年齡結構指標.
2. Cooper, C., The crippling consequences of fractures and their impact on quality of life. Am J Med, 1997. 103(2A): p. 12S-17S; discussion 17S-19S.
3. McCaslin, F.F., et al.,, The Effect of Strontium Lactate in the Treatment of Osteoporosis. Proc Staff Meetings Mayo Clin, 1979. 34: p. 329-334.
4. Kaplan, D., Biopolymers from renewable resources. Macromolecular systems, materials approach. 1998, Berlin ; New York: Springer. xviii, 417 p.
5. Chandra, R. and R. Rustgi, Biodegradable polymers. Progress in Polymer Science, 1998. 23(7): p. 1273-1335.
6. Gilding, D.K. and A.M. Reed, Biodegradable Polymers for Use in Surgery - Polyglycolic-Poly(Actic Acid) Homopolymers and Copolymers .1. Polymer, 1979. 20(12): p. 1459-1464.
7. Eling, B., S. Gogolewski, and A.J. Pennings, Biodegradable Materials of Poly(L-Lactic Acid) .1. Melt-Spun and Solution-Spun Fibers. Polymer, 1982. 23(11): p. 1587-1593.
8. Miller, R.A., J.M. Brady, and D.E. Cutright, Degradation Rates of Oral Resorbable Implants (Polylactates and Polyglycolates) - Rate Modification with Changes in Pla-Pga Copolymer Ratios. Journal of Biomedical Materials Research, 1977. 11(5): p. 711-719.
9. DF., W., Some observations on the role of cellular enzymes in the in vivo degradation of polymers., in Corrosion and degradation of implant materials.1979. p. 61~75.
10. Hollinger, J.O. and J.P. Schmitz, Restoration of Bone Discontinuities in Dogs Using a Biodegradable Implant. Journal of Oral and Maxillofacial Surgery, 1987. 45(7): p. 594-600.
11. Vunjak-Novakovic, G., et al., Bioreactor cultivation conditions modulate the composition and mechanical properties of tissue-engineered cartilage. Journal of Orthopaedic Research, 1999. 17(1): p. 130-138.
12. Yoo, H.S. and T.G. Park, Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Control Release, 2004. 96(2): p. 273-83.
13. KW Leong, V.S., R Langer, Synthesis of polyanhydrides: melt-polycondensation, dehydrochlorination, and dehydrative coupling. Macromolecules, 1987: p. 705-712.
14. Ibim, S.E., et al., Preliminary in vivo report on the osteocompatibility of poly(anhydride-co-imides) evaluated in a tibial model. J Biomed Mater Res, 1998. 43(4): p. 374-9.
15. Chiba, M., J. Hanes, and R. Langer, Controlled protein delivery from biodegradable tyrosine-containing poly(anhydride-co-imide) microspheres. Biomaterials, 1997. 18(13): p. 893-901.
16. Rosen, H.B., et al., Bioerodible polyanhydrides for controlled drug delivery. Biomaterials, 1983. 4(2): p. 131-3.
17. Barat, A., H.J. Ruskin, and M. Crane, 3D multi-agent models for protein release from PLGA spherical particles with complex inner morphologies. Theory in Biosciences, 2008. 127(2): p. 95-105.
18. Tracy, M.A., et al., Factors affecting the degradation rate of poly(lactide-co-glycolide) microspheres in vivo and in vitro. Biomaterials, 1999. 20(11): p. 1057-1062.
19. Wichterle, O. and D. Lim, Hydrophilic Gels for Biological Use. Nature, 1960. 185(4706): p. 117-118.
20. Lim, F. and A.M. Sun, Microencapsulated Islets as Bioartificial Endocrine Pancreas. Science, 1980. 210(4472): p. 908-910.
21. Yannas, I.V., et al., Synthesis and Characterization of a Model Extracellular-Matrix That Induces Partial Regeneration of Adult Mammalian Skin. Proceedings of the National Academy of Sciences of the United States of America, 1989. 86(3): p. 933-937.
22. Tasdelen, B., et al., Investigation of drug release from thermo- and pH-sensitive poly(N-isopropylacrylamide/itaconic acid) copolymeric hydrogels. Polymers for Advanced Technologies, 2004. 15(9): p. 528-532.
23. Hoffman, A.S., Hydrogels for biomedical applications. Advanced Drug Delivery Reviews, 2012: p. 18~23.
24. Afify, A.M., et al., Purification and Characterization of Human Serum Hyaluronidase. Archives of Biochemistry and Biophysics, 1993. 305(2): p. 434-441.
25. Choi, Y.S., et al., Study on gelatin-containing artificial skin: I. Preparation and characteristics of novel gelatin-alginate sponge. Biomaterials, 1999. 20(5): p. 409-417.
26. Duranti, F., et al., Injectable hyaluronic acid gel for soft tissue augmentation - A clinical and histological study. Dermatologic Surgery, 1998. 24(12): p. 1317-1325.
27. Atala, A., et al., Endoscopic treatment of vesicoureteral reflux with a chondrocyte-alginate suspension. J Urol, 1994. 152(2 Pt 2): p. 641-3; discussion 644.
28. Lee, K.Y. and D.J. Mooney, Hydrogels for tissue engineering. Chem Rev, 2001. 101(7): p. 1869-79.
29. Jeong, B., et al., Biodegradable block copolymers as injectable drug-delivery systems. Nature, 1997. 388(6645): p. 860-862.
30. Kim, M.S., et al., In vivo osteogenic differentiation of rat bone marrow stromal cells in thermosensitive MPEG-PCL diblock copolymer gels. Tissue Eng, 2006. 12(10): p. 2863-73.
31. Marie, P.J., Strontium ranelate: a physiological approach for optimizing bone formation and resorption. Bone, 2006. 38(2 Suppl 1): p. S10-4.
32. Ferraro, E.F., R. Carr, and K. Zimmerman, A Comparison of the Effects of Strontium Chloride and Calcium-Chloride on Alveolar Bone. Calcified Tissue International, 1983. 35(2): p. 258-260.
33. Morohashi, T., et al., Effects of Strontium on Calcium-Metabolism in Rats .2. Strontium Prevents the Increased Rate of Bone Turnover in Ovariectomized Rats. Japanese Journal of Pharmacology, 1995. 68(2): p. 153-159.
34. Ammann, P., et al., Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats. Journal of Bone and Mineral Research, 2004. 19(12): p. 2012-2020.
35. Delannoy, P., D. Bazot, and P.J. Marie, Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice. Metabolism-Clinical and Experimental, 2002. 51(7): p. 906-911.
36. Peppas, N.A. and J.J. Sahlin, A Simple Equation for the Description of Solute Release .3. Coupling of Diffusion and Relaxation. International Journal of Pharmaceutics, 1989. 57(2): p. 169-172.
37. Lai, P.L., et al., Effect of mixing ceramics with a thermosensitive biodegradable hydrogel as composite graft. Composites Part B-Engineering, 2012. 43(8): p. 3088-3095.
38. Shinoda, K. and E. Hutchinson, Pseudo-Phase Separation Model for Thermodynamic Calculations on Micellar Solutions. Journal of Physical Chemistry, 1962. 66(4): p. 577-&.
39. Kim, M.S., et al., Preparation of methoxy poly(ethylene glycol)/polyester diblock copolymers and examination of the gel-to-sol transition. Journal of Polymer Science Part a-Polymer Chemistry, 2004. 42(22): p. 5784-5793.
40. Jeong, B., et al., Thermogelling biodegradable polymers with hydrophilic backbones: PEG-g-PLGA. Macromolecules, 2000. 33(22): p. 8317-8322.
41. Anumolu, S.S., et al., Doxycycline hydrogels with reversible disulfide crosslinks for dermal wound healing of mustard injuries. Biomaterials, 2011. 32(4): p. 1204-17.