鈣矽骨水泥被視為是一個具有潛力的生醫骨填補物，而鍶是人體內的一個微量元素，常被用於治療骨質疏鬆症，主要是因為鍶能誘導成骨細胞活性，刺激骨生成，並且能夠抑制噬骨細胞減少骨吸收，故在本研究中，主要是評估添加鍶之鈣矽骨水泥其物理化學性質以及生物相容性。利用sol-gel的方式來製備含鍶之鈣矽粉體，鍶含量為鍶鈣的莫爾比Sr/(Sr+Ca) ，含量分別為0%、1%、5%以及10%。主要分析方式有晶相分析（XRD）、微結構分析（SEM）、對徑拉伸強度測試（DTS）及硬化時間測試（setting time）。
在結果方面，各組的粉體顆粒大小約在1-5μm。在XRD結果可以觀察到粉體的結晶相在繞射峰2θ = 32°到34°之間，其峰值明顯較大，推測是由於β-Ca2SiO4相，在藉由離子交換後，部分的鈣被鍶所取代，且由於鍶的離子半徑（1.13Å）比鈣（1.00Å）大，在鍶併入鈣矽陶瓷中之後，可能導致峰值的變寬。在混合水之後，可以觀察到結晶相的繞射峰2θ = 29.3°有鈣矽水合（calcium silicate hydrate）的峰值。硬化時間方面，添加10%鍶的硬化時間也從控制組的22分鐘減少到了17分鐘。至於強度結果則並沒有明顯的改變，範圍在2.0~2.4 MPa。因此，包含鍶的鈣矽骨水泥有可能是具有潛力的鈣矽骨填補物。

Calcium silicate cements (CSC) have been regarded as a potential biomaterial for bone graft substitutes. Strontium (Sr) is a trace element in human body and been used for treatment of osteoporosis. Sr is found to induce osteoblast activity by stimulating bone formation and to reduce bone resorption by restraining osteoclasts. The aim of this study was to evaluate the physicochemical properties of Sr-containing CSC. The calcium silicate with equimolar ratio of Ca to Si was used as the control. Various amounts of Sr with a molar ratio of 1%, 5% and 10% for Sr/(Sr + Ca) were added to sol-gel precursors. The major techniques used for characterizing the various specimens included X-ray diffraction (XRD), scanning electron microscopy (SEM), diametral tensile strength and setting time.
As a result, the particle size of calcium silicate ceramics powder ranged from 1 μm to 5 μm. The XRD patterns shows that major diffraction peaks of the four powders were at 2θ between 32 and 34o attributed to β-dicalcium silicate (β-Ca2SiO4) phase. Although the Ca was replaced in part by Sr through ionic exchange, the incorporation of Sr to calcium silicate ceramics may lead to a broadening peak. This can be explained by the fact that the radius of Sr ions (1.13Å) is larger than that of Ca ions (1.00Å), namely, the microstrain effect. After mixing with water, XRD patterns of all cements revealed an obvious diffraction peak around 2θ = 29.3o, corresponding to the calcium silicate hydrate gel, and incompletely reacted inorganic component phases of β-Ca2SiO4. 10% Sr significantly shortened setting time from 22 min for the CSC control to 17 min. The addition of Sr did not affect the strength ranged from 2.0 to 2.4 MPa as these specimens were not significantly different (p > 0.05) from control groups (2.5 MPa). Our findings indicated that Sr-CSC may be a candidate for bone repair.

致謝 I
中文摘要 II
Abstract III
目錄 IV
表目錄 VI
圖目錄 VII
第一章 文獻回顧 1
1-1 生醫材料 1
1-2 生醫材料在硬組織上的應用 2
1-3 骨水泥 4
1-3-1 生物活性玻璃骨水泥 4
1-3-2 鈣磷骨水泥 5
1-3-3 天然高分子骨水泥 5
1-4 鈣矽骨水泥 6
1-5 微量添加物－鍶 6
1-6 高分子－明膠 9
1-7 溶膠凝膠法 9
1-8 研究動機與目的 10
第二章 材料與方法 11
2-1 生醫陶瓷粉體的製備 11
2-2 骨水泥的製備 12
2-3 浸泡實驗 12
2-4 材料特性分析 12
2-4-1 粉體熱重－熱示差分析 12
2-4-2 XRD分析 12
2-4-3 掃描式電子顯微鏡觀察 13
2-4-4 穿透式電子顯微鏡觀察分析 13
2-4-5 骨水泥徑向拉伸強度測試 13
2-4-6 骨水泥硬化時間之測試 14
2-4-7 浸泡後pH值之變化 14
第三章 結果與討論 15
3-1 粉體分析 15
3-1-1 熱重－熱示差分析 15
3-1-2 XRD晶相分析 17
3-1-3 顯微結構分析 19
3-1-4 穿透式電子顯微鏡顯微結構分析 22
3-2 骨水泥分析 23
3-2-1 XRD晶相分析 23
3-2-2 顯微結構分析 25
3-2-3 骨水泥對徑拉伸強度測試 29
3-2-4 骨水泥硬化時間測試 31
3-3 生物活性分析 33
3-3-1 骨水泥浸泡後顯微結構分析 33
3-3-2 骨水泥浸泡後晶相分析 40
3-3-3 骨水泥浸泡後對徑拉伸強度測試 45
3-3-4 浸泡後pH值變化 48
3-3-5 浸泡後離子釋放濃度 50
3-4 生物相容性分析 54
3-4-1 細胞增生 54
3-4-2 細胞型態 55
3-4-3 鈣離子染色 58
第四章 結論 61
第五章 參考文獻 63

[1] “生物體用的陶瓷人工骨骼及其周邊”, 工業技術研究院工業材料研究所編譯資料, No MR058, 1983.
[2] Vincenzini P. Ceramics in sub-stitutive and reconstructive surgery. Elsevier Science Publishers B.V., 1991.
[3] Katthagen BD. Bone regeneration with bone substitutes. Springer-Verlag, Berlin, 1987.
[4] Jarcho M. Calcium phosphate ceramics as hard tissue. Clin Orthop Rel Res 1981;157:259–279.
[5] Kenny SM, Buggy M. Bone cements and fillers: A review. J Mater Sci: Mater Med 2003;14:923–938.
[6] Hench LL, Splinter RJ, Allen WC, Greenlee TK. Bonding mechanism at the interface of ceramic prosthetic materials. J Biomed Mate Res 1971;2:117–141.
[7] Blencke BA, Bromer H, Deutcher K. Glass ceramic-A new bioactive implant material. Med Orthop Tech 1975;95:144–148.
[8] Kokubo T, Shigematsu M, Nagashima Y, Tashiro M, Nakamura T, Yamamuro T, Higashi S. Apatite- and wollastonite containing glass-ceramic for prosthetic application. Bull Inst Chem Res 1982;60:260–267.
[9] Jarcho M, Bolen CH, Thomas MB, Bobick J, Kay JF, Doremus RH. Synthesis and characterization of hydroxyapatite in dense polycrystalline form. J Mater Sci 1976;11:2027–2035.
[10] Balas F, Perez-Pariente J, Vallet-Regi M. In vitro bioactivity of silicon- substituted hydroxyapatite. J Biomed Mater Res 2006;66A:364–375.
[11] Gibson IR, Best SM, Bonfield W. Chemical characterization of silicon- substituted hydroxyapatite. J Biomed Mater Res 1999;44:422–428.
[12] Alexandra EP, Claudia MB, Maria AL, Jose DS, Serena MB, William Bonfield. Ultrastructural comparison of dissolution and apatite precipitation on hydroxyapatite and silicon- substituted hydroxyapatite in vitro and in vivo. J Biomed Mater Res 2004;69A:670–679.
[13] Alexandra EP, Serena MB, Bonfield W. Ultrastructural comparison of hydroxyapatite and silicon- substituted hydroxyapatite for biomedical applications. J Biomed Mater Res 2004;68A:133–141.
[14] Alexandra EP, Patel N, Skepper JN, Best SM, Bonfield W. Comparison of in vivo dissolution process in hydroxyapatite and silicon-substituted hydroxyapatite bioceramics. Biomaterials 2003;24:4609–4620.
[15] Sayer M, Stratilatov AD, Reid J, Calderin L, Stott MJ, Yin X, MacKenie M, Smith TJN, Hendry JA, Langstaff SD. Structure and composition of silicon- stabilized tricalcium phosphate. Biomaterials 2003;24:369–382.
[16] Phong V Phan, Mark Grzanna, James Chu, Anna Polotsky, Ahmed El-Ghannam, David Van Heerden, David S. Hungerford, Carmelita G. Frondoza. The effect of silica- containing calcium- phosphate particles on human osteoblasts in vitro. J Biomed Mater Res 2003;67A:1001–1008.
[17] Kokubo T. Mechanism of Apatite Formation on CaO-SiO2-P2O5 Glasses in a Simulated Body Fluid. J Non Cryst Solids 1992;143:84–92.
[18] Jarcho K, Kay JF, Gumaer KI. Tissue, cellular and subcellular events at a bone-ceramic hydroxyapatite interface. J Bio eng 1997;1:79.
[19] Block MS, Kent JN. Long term evaluation of hydroxylapatite augmentation of deficient mandibular alveolar ridges. J Oral Maxillofac Surg 1984;42:793–796.
[20] Kent JN, Zide MF, Kay JF, Jarcho M. Hydroxylapatite blocks and particles as bone graft substitutes in orthognathic and reconstructive surgery. J Oral Maxillofac Surg 1986;44:597–605.
[21] Zide MF, Kent JN, Machado L. Hydroxylapatite cranioplasty directly over dura. J Oral Maxillofac Surg 1987;45:481–486.
[22] Ono K, Yamamuro T, Nakamura T, Kakutani Y, Kitsugi T, Hyakuna K, Kokubo T, Oka M, Kotoura Y. Apatite-wollastonite containing glass ceramic-fibrin mixtures as a bone defect filler. J Biomed Mater Res 1988;22:869–885.
[23] Yao CH, Chang YL, Lin FH. Preparation and evaluation of β-TCP powder and crosslinked gelatin composite as bone substitute. Chinese J Med Bioeng 1994;14:47–51.

[24] Tamura S, Kataoka H, Matsui Y, Shionoya Y, Ohno K, Michi KI, Takahashi K, Yamaguchi A. The effects of transplantation of osteoblastic cells with bone morphogenetic protein (BMP)/carrier complex on bone repair. Bone 2001;29:169–175.
[25] Saito N, Okada T, Horiuchi H, Ota H, Takahashi J, Murakami N, Nawata M, Kojima S, Nozaki K, Takaoka K. Local bone formation by injection of recombinant human bone morphogenetic protein–2 contained in polymer carriers. Bone 2003;32:381–386.
[26] Den Boer FC, Wippermann BW, Blokhuis TJ, Patka P, Bakker FC, Haarman HJ. Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein-1 or autologous bone marrow. J Orthop Res 2003;21:521–528.
[27] Schmidt RJ, Chung LY, Andrews AM, Spyratou O, Turner TD. Biocompatibility of wound management products: a study of the effects of various polysaccharides on murine L929 fibroblast proliferation and macrophage respiratory burst. J Pharm Pharmacol 1993;6:508–513.
[28] Ding Shinn-Jyh, ShieMing-You, Wang Chuan-Yeh. Novel fast-setting calcium silicate bone cements with high bioactivity and enhanced osteogenesis in vitro. J Mater Chem 2009;19:1183–1190.
[29] Sobel AE, Cohen Y, Kramer B. The nature of the injury to the calcifying mechanisms in rickets due to strontium. Biochem J 1935; 29:2640–2645.
[30] Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68.
[31] Curtis R, Goldhahn J, Schwyn R, Regazzoni P, Suhm N. Fixation principles in metaphyseal bone — a patent based review. Osteoporos Int 2005;16:S54–64.
[32] Guo Dagang, Xu Kewei, Zhao Xiaoyun, Han Yong. Development of a strontium-containing hydroxyapatite bone cement. Biomaterials 2006;26:4073–4083.
[33] Wu Chengtie, Ramaswamy Yogambha, Kwik Danielle, Zreiqat Hala. The effect of strontium incorporation into CaSiO3 ceramics on their physical and biological properties. Biomaterials 2007;28:3171–3181.
[34] Wong CT, Lu WW, Chan WK, Cheung KM, Luk KD, Lu DS. In vivo cancellous bone remodeling on a strontium-containing hydroxyapatite (sr-HA) bioactive cement. J Biomed Mater Res 2004;68A:513–21.
[35] Wong CT, Chen QZ, Lu WW, Leong JC, Chan WK, Cheung KM. Ultrastructural study of mineralization of a strontium-containing hydroxyapatite (Sr-HA) cement in vivo. J Biomed Mater Res 2004;70A:428–35.
[36] Qiu K, Zhao XJ, Wan CX, Zhao CS, Chen YW. Effect of strontium ions on the growth of ROS17/2.8 cells on porous calcium polyphosphate scaffolds. Biomaterials 2006;27:1277–86.
[37] Marie PJ, Ammann P, Boivin G, Rey C. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int 2001;69:121–9.
[38] Rokita E, Mutsaers PHA, Quaedackers JA, Taton G, de Voigt MJA. Bone mineralization after strontium and fluoride treatment in osteoporosis. Nucl Instrum Methods Phys Res B 1999;158:412–7.
[39] Verberckmoes SC, De Broe ME, D’Haese PC. Dose-dependent effects of strontium on osteoblast function and mineralization. Kidney Int 2003;64:534–43.
[40] Jegou Saint-Jean S, Camire CL, Nevsten P, Hansen S, Ginebra MP. Study of the reactivity and in vitro bioactivity of Sr-substituted a-TCP cements. J Mater Sci Mater Med 2005;16:993–1001.
[41] Janes JM, McCaslin F. The effect of strontium lactate in the treatment of osteoporosis. Mayo Clin Proc 1959;34:329–334.
[42] Corradino RA, Wasserman RH. Strontium inhibition of vitamin D3-induced calcium-binding protein (CaBP) and calcium absorption in chick intestine. Proc Soc Exp Biol Med 1970;133:960–963.
[43] Corradino RA, Edel JG, Craig PH, Taylor AN, Wasserman RH. Calcium absorption and the vitamin D 3-dependent calcium-binding protein. I. Inhibition by dietary strontium. Calcif Tissue Res 1971;7:81–92.
[44] Ferraro EF, Carr R, Zimmerman K. A comparison of the effects of strontium chloride and calcium chloride on alveolar bone. Calcif Tissue Int 1983;35:258–260.

[45] Marie PJ, Garba MT, Hott M, Miravet L. Effect of low doses of stable strontium on bone metabolism in rats. Miner Electrolyte Metab 1985;11:5–13.
[46] Marie PJ, Hott M. Short-term effects of fluoride and strontium on bone formation and resorption in the mouse. Metabolism 1986;35:547–551.
[47] Christoffersen J, Christoffersen MR, Kolthoff N, Barenholdt O. Effects of strontium ions on growth and dissolution of hydroxyapatite and on bone mineral detection. Bone 1997;20:47–54.
[48] Wong CT, Lu WW, Chan WK, Cheung KMC, Luk KDK, Lu DS, Rabie ABM, Deng LF, Leong JCY. In vivo cancellous bone remodeling on a Strontium-containing hydroxyapatite (Sr-HA) bioactive cement. Wiley InterScience 2004;428–435.
[49] Ni GX, Lu WW, Xu B, Chiu KY, Yang C, Li ZY, Lam WM, Lu KDK. Interfacial behaviour of strontium-containing hydroxyapatite cement with cancellous and cortical bone. Biomaterials 2006;27:5127–5133.
[50] Panzavolta S, Torricelli P, Sturba L, Bracci B, Giardino R, Bigi A. Setting properties and in vitro bioactivity of strontium-enriched gelatin–calcium phosphate bone cements. J Biomed Mater Res A 2007;965–972.
[51] Wong KL, Wong CT, Liu WC, Pan HB, Fong MK, Lam WM, Cheung WL, Tang WM, Chiu KY, Luk KDK, Lu WW. Mechanical properties and in vitro response of strontium-containing hydroxyapatite/polyetheretherketone composites. Biomaterials 2009;30:3810–3817.
[52] Gudmunsson M, Hafsteinsson H. Gelatin from cod skin as affected by chemical treatments. Journal of Food Science 1997;62(1):37–39.
[53] Choi SS, Regenstein JM. Physicochemical and sensory characteristics of fish gelatin. Journal of Food Science 2000;65(2):194–199.
[54] Ikada Y, Tabata Y. Protein release from gelatin matrices. Adv Drug Delivery Rev 1998;31:287–301.
[55] Kawai K, Suzuki S, Tabata Y, Ikada Y, Nishimura Y. Accelerated tissue regeneration through incorporation of basic fibroblast growth factor-impregnated gelatin microspheres into artificial dermis. Biomaterials 2000;21:489–499.
[56] Balakrishnan B, Jayakrishnan A. Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds. Biomaterials 2005;26:3941–3951.
[57] M. Yamamoto, Y. Ikada, Y. Tabata, Controlled release of growth factors based on biodegradation of gelatin hydrogel. J Biomater Sci Polym Ed 2001;12:77–88.
[58] Kuijpers AJ, Wachem PB van, Luyn MJ van, Plantinga JA, Engbers GH, Krijgsveld J, Zaat SA, Dankert J, Feijen J. In vivo compatibility and degradation of crosslinked gelatin gels incorporated in knitted Dacron. J Biomed Mater Res 2000;51:136–145.
[59] Yao CH, Liu BS, Hsu SH, Chen YS, Tsai CC. Biocompatibility and biodegradation of a bone composite containing tricalcium phosphate and genipin crosslinked gelatin. J Biomed Mater Res 2004;69A:709–717.
[60] Brinker CJ, Scherer GW. Sol-gel Science. The Physics and Chemistry of Sol-gel Processing. Academic Press: Boston, 1990.
[61] Pierre AC. Introduction to Sol-gel Processing. Kluwer: Boston,1998.
[62] Duval C. Inorganic thermogravimetric analysis. New York: Elsevier; 1963. p 274.
[63] Zhao Wenyuan, Chang Jiang. Sol-gel synthesis and in vitro bioactivity of tricalcium silicate powders. Materials Letters 2004;58:2350–2353.
[64] Peital O, Zanotto ED, Hench LL. Highly bioactive P2O5-Na2O-CaO-SiO2 glass-ceramic. J Non Crystal Sol 2001;292:115–126.