臺灣博碩士論文加值系統

　　CPC（calcium phosphate cement）磷酸鈣骨水泥是以等量的鹼性TTCP（Ca4（PO4）2O）與酸性DCPA（CaHPO4）或DCPD（CaHPO4.2H2O）混合，以水作為硬化溶液，在室溫下可合成氫氧基磷灰石(Hydroxyapatite；簡稱HA)；而氫氧基磷灰石具有良好的生物相容性與生物活性，植入人體後不會引起毒性，不刺激組織，具有引導骨骼向內生長，及在骨骼外組織誘導骨細胞分化生長的能力。

　　本實驗室已發展出非常適合作為生醫植入材的骨水泥，但仍須改善其植入後機械性質退化的速率，希望其得以與骨細胞生長的速率達成穩定的平衡，以有效修補並重建缺損的骨組織。

　　本研究內容主要是針對鈣磷系骨水泥以動物實驗後之機械性質、微結構及生物性質做一系列的探討，比較一般以體外模擬人工體液(Hanks’Solution)與實際植入於動物體內時，材料機械性質與微結構隨著時間的變化而產生的差異性。發現機械性質有很大的不同，且體內環境並不比體外環境來的嚴苛，或許可藉此提供此類鈣磷系骨水泥改良的基礎。

　　CPC (calcium phosphate cement) is synthesized by mixing equal amout of alkaline TTCP (Ca4(PO4)2O) and acid DCPA (CaHPO4) or DCPD (CaHPO4.2H2O); setting with pure water to synthesize HA (Hydroxyapatite). HA has superior biocompatibility, bioactivity, and osteoconduction, without any toxicity or irritation after implantation.

　　CMRT laboratory have researched a kind of bone cement which is suitable for biomedical implantation. But the cement still need to improve the decay rate of mechanical properties after implantation. It is expect to achieve a stable equilibrium with bone growing rate to reinforce the damaged bone tissues.

　　This investigate is to probe into the mechanical properties, microstructure, and biological properties after animal implantation. Compare with the cement immersing in Hanks’ Solution. The result showed a great differentiation of mechanical strength between the in vivo test and in vitro test. The information also provide the direction of this material’s improvement.

第一章 緒論………………………………………………………….1
1-1 前言……………………………………………………………….1
1-2 研究動機及目的………………………………………………….3

第二章 磷酸鈣生醫材料…………………………………………….8
2-1 修補用之生醫材料……………………………………………….8
2-2 生醫陶瓷的種類………………………………………………….9
2-3 磷酸鈣鹽類(CaP)……………………………………………….11
2-3-1 磷酸鈣鹽類(CaP)的特性…………………………………….11
2-4 氫氧基磷灰石……………………………………………………12
2-4-1 氫氧基磷灰石的特性…………………………………………12
2-4-2 氫氧基磷灰石的晶體結構……………………………………13
2-4-3 氫氧基磷灰石在不同環境下的穩定性………………………14
2-4-4 氫氧基磷灰石結構中離子的取代現象………………………16
2-5 鈣磷系骨水泥(calcium phosphate bone cement, CPC)……17
2-5-1 鈣磷系骨水泥之特性…………………………………………17

第三章 理論基礎與文獻回顧………………………………………26
3-1 骨科植入生醫材料所需之性質…………………………………26
3-2 體外測試與體內測試……………………………………………26
3-3 體外測試(in vitro test)…………………………………….27
3-3-1 鈣磷系骨水泥浸泡人工體液之體外測試……………………28
3-3-2 溶解(dissolution)行為…………………………………….28
3-3-3 析出(precipitation)行為……………………………….…29
3-3-4 影響體外測試機械性質之因素………………………………31
3-4 體內測試(in vivo test)………………………………………31
3-4-1 實驗動物選擇…………………………………………………31
3-4-2 植入部位選擇…………………………………………………33
3-4-3 植入週期選擇…………………………………………………34
3-4-4 測試影響評估…………………………………………………35
3-4-5 鈣磷系骨水泥植入骨骼組織後之反應………………………36
3-4-6 鈣磷系骨水泥植入骨骼外組織後之反應……………………38
3-4-7 細胞對植入物的反應…………………………………………41

第四章 實驗方法與步驟……………………………………………48
4-1 試片的製備………………………………………………………48
4-2 實驗動物之準備…………………………………………………49
4-3 手術用具及器材…………………………………………………49
4-4 動物體內植入實驗(in vivo test)……………………………50
4-5 體外模擬浸泡實驗(in vitro test)………………………….51
4-6 硬化時間測試(setting time) ……………………………….52
4-7 pH值測試…………………………………………………………52
4-8 抗壓強度測試……………………………………………………53
4-9 徑向拉伸強度測試………………………………………………54
4-10 孔隙率測試(porosity)……………………………………….54
4-11 X光繞射分析……………………………………………………55
4-12 紅外線光譜分析……………………………………………….56
4-13 掃描式電子顯微鏡…………………………………………….57

第五章 結果與討論…………………………………………………68
5-1 硬化時間測試……………………………………………………68
5-2 pH值測試…………………………………………………………70
5-3 抗壓強度測試……………………………………………………72
5-4 徑向拉伸強度測試………………………………………………78
5-5 孔隙率分析………………………………………………………81
5-6 X光繞射分析…………………………………………………….87
5-7 紅外線光譜分析…………………………………………………92
5-8 掃描式電子顯微鏡分析…………………………………………97

第六章 結論……………………………………………………….125

第七章 參考文獻………………………………………………….126

Agins H.J., Alcock N.W., Bansal M., Salvati E.A., Wilson Jr. P.D., Pellicci P.M., Bullough P.G., “Metallic wear in failed titanium-alloy total hip replacements. A histological and quantitative analysis”, J. Bone Joint Surg., 70A:347-356,(1988)

Atsuro Yokoyama, Satoru Yamamoto, Takao Kawasaki, Takao Kohgo, Masanori, “Development of calcium phosphate cement using chitosan and citric acid for bone substitute materials, Biomaterials 23, 1091-1101, (2002)

“Biological evaluation of medical devices-part 6: Test for local effects after implantation” International standard, ISO 10993-6

Bohner M., Theiss F., Apelt D., Hirsiger W., Houriet R., Rizzoli G., Gnos E., Frei C., Auer J.A., von Rechenberg B., “Compositional changes of a dicalcium phosphate dihydrate cement after implantation in sheep”, Biomaterials 24, 3463-3474, (2003)

Callaghan J.J., “Current concerts review: The clinical results and basic science of total hip arthroplasty with porous-coated prostheses”, J. Bone Joint Surg., 75A:299-310, (1993)

Chow L.C., Hirayama S., Takagi S., Parry E., “Diametral tensile strength and compressive strength of a calcium phosphate cement: Effect of applied pressure.”, J. Biomed Mater Res: 53: 511-517, (2000)

Daculsi G., “Biphasic calcium phosphate concept applied to artificial bone, implant coating and injectable bone substitute” Biomaterials 19 1473-1478, (1998)

David Knaack, Goad M.E.P., Maria Aiolova, Christian Rey, Ali Tofighi, Pramod Chakravarthy, D. Duke Lee, “Rosorbable Calcium Phosphate Bone Substitute” J Biomed Mater Res (Appl Biomater) 43: 399-409, (1998)

de Groot K., “Medical applications of calcium phosphate bioceramics”, The Centennial Memorial Issue of The Ceramic Society of Japan, 99: 943-953, (1991)

Doi Yutaka, Takezawa Y, Shibata S, Wakamatsu N, Kamemizu H, Goto T,, Self-setting apatite cement 6:53-58(1987)

Doremus R.H., “Review Bioceramics” J. Mater. Sci.,vol.27, 285-297, (1992)

Driessens F.C.M., Boltong M.G., Bermudez O., Planell J.A., Ginebra M.P., Fernandez E., “Effective formulations for the preparation of calcium phosphate bone cements”, Journal of materials science: Materials in medicine 5: 164-170, (1994)

Geesink R.G.T., de Groot K., Klein C.P.A.T., “Chemical Implant Fixation Using Hydroxy-apatite Coatings.” Clin Orthop 225, 147-170, (1987)

Grover L.M.,Knowles J.J.,Fleming G.J.P., Barralet J.E., “In vitro ageing of brushite calcium phosphate cement”, Biomaterials 24 4133-4141, (2003)

Heimke G., “The Aspects and Methods of Fixation of Bone Replacement” Osseo-Integrated Implant vol.1, Materials & Joint Replacement, CRC Press Inc., 1-26, (1990)

Hench. L.L. “Bioactive Glass and Glass-Ceramic, A Perspective.” CRC Handbook of Bioactive Ceramics.I:3-4, (1990)

Hench L.L., “Bioceramics: From Concept to Clinic”, J. Am Ceram. Soc., vol.74,[7], 1487-1510, (1991)

Hench L.L., Ethridge E.C., “Biomaterials, an interfacial approach”, Biophysics and bioengineering series, vol.4, Academic Press, New York, (1982)

Heughebaert M., Le Geros R.Z., Gineste M., Guilhem A., Bonel G., “Physicochemical characterization of deposits associated with HA ceramics implanted in non-osseous sites.” J. Biomed Mater Res: 22: 257-268, (1988)

Hiroshi Yamasaki, Hidetaka Sakai, “Osteogenic response to porous hydroxyapatite ceramics under the skin of dogs”, Biomaterials, vol.13
Hulbert S.F., Bokros J.C., Hench L.L., Wilson J., Heimke G., “Ceramic in clinical application, past, present and future”, Ceramics Applications, P. Vincenzini, pp. 3-27, Elsevier, Amsterdam-oxford-New York-Tokyo, (1987)

Hulbert S.F. et al., “Bioactive ceramic-bone interface”. CRC Handbook of bio. I: 3-6, (1991)

Hulbert S.F., Hench L.L., Forbers D., Bowman L.S., “History of bioceramics”, Ceram. Internat., 8:131-140, (1982)

Jian Dong, Toshimasa Uemura, Yoshio Shirasaki, Tetsuya Tateishi, “Promotion of bone formation using highly pure porous β-TCP combined with bone marrow-derived osteoprogenitor cells”, Biomaterials, 23: 4493-4502, (2002)

Jinawath S., Sujaridworakun P., “Fabrication of porous calcium phosphates”, Materials Science and Engineering C22:41-46, (2002)

Jones T.C., “ The value of animal models Am.” J. Pathol. 101: s3-s9, (1980)

Klein C., de Groot K., Chen W. Li Y. Zhang X., “Osseous substance formation induced in porous calcium phosphate ceramics in soft tissues.”, Biomaterials 15: 31-34, (1994)

Kokubo T., “Recent progress in glass-based materials for biomedical applications”, The Centennial Memorial Issue of The Ceramic Society of Japan, 99: 965-973, (1991)

Kunio Ishikawa, Shozo Takagi, Laurence C. Chow, Yoshiko Ishikawa, Edward D. Eanes, Kenzo Asaoka, “Behavior of a calcium phosphate cement in simulated blood plasma in vitro”, Dent Mater 10: 26-32, (1994)

Leadec R.W., Padgett G.a., “The genesis and validation of animal models Am.” J. Pathol. 101: s11-s16, (1980)

LeGeros R.Z., Orly I., Gregoire M., Daculsi G., “Substrate surface dissolution and interfacial biological mineralization”, in The Bone-Biomaterial interface, J.E. Davies ed., University of Toronto Press, Toronto, Canada, pp. 76-88, (1991)

Li Y., Klein CPAT, Chen W., Zhang X, de Groot K., “ An important aspect of biphasic calcium phosphate bioceramics: formation of bone in non-osseous tissues.”, Synthesis and Characterization of Bone-like Minerals: Macroscopic Approach and Microscopic Emulation. Leiden: The Netherlands, 35-45, (1994)

Ooms E.M., Egglezos E.E., Wolke J.G.C.,. Jansen J.A, “Soft-tissue response to injectable calcium phosphate cements.” Biomaterials 24 749-757, (2003)

Park J.B., “Biomaterials Science and Engineering”, Plenum Press, New York and London, (1985)

Park J.B., Lakes R.S., “Biomaterials: an introduction”, Plenum Press, second edition., New York, (1992)

Ratner B.D., “Biomaterials science: an introduction to materials in medicine”, Academic Press, San Diego, (1996)

Ravaglioli A., Krajewski A., “Bioceramics: Materials, Properties, Applications”, Chapman & Hall Press, pp.44-45, (1992)

Ripamonti U., “The morphogenesis of bone in replicas of porous hydroxyapatite from conversion calcium carbonate exoskeletons of coral., J. Bone Joint Surg, 73A: 692-703, (1991)

Silver F.H., “Biomaterials, medical devices, and tissue engineering: and integrated approach”, Chapman & Hall, first edition., New York, (1994)

Soballe K., “Hydroxyapatite ceramic coating for bone implant fixation” ACTA Orthopaed. Scandinm Supplem., 64:1-58, (1993)

Tanahashi M, “Fibrous hydroxyapatite grown in the gel system: effects of pH of the solution on the growth rate and morphology.”, J. Mater. Sci: Material in Medicine 3:48-53, (1992)

Toth J.J., Lynch K.L., Hackbarth D.A., “Ceramic-induced osteogenesis following subcutaneous implantation of calcium phosphates.”, Ducheyne P., Christiansen O. eds., Bioceramics. Vol.6, Butterworth-Heinemann, 9-14, (1993)

Van Eeden S.P., Ripamonti U., “Bone differentiation in porous hydroxyapatite in baboons is regulated by the geometry of the substratum: implications for reconstructive craniofacial surgery.”, Plast Reconstr Surg: 93: 1563-1570, (1990)

Wroblewski B.M., “15~21 Year Result of the Charnley Low Friction Arthroplasty” Clin. Orthop. vol.211, 30, (1986)

Yamasaki H., “Heterotopic bone formation around porous hydroxyapatite ceramics in the subcutis of dogs.” Jpn. J. Oral Biol., 32, 190-192, (1990)

Yamasaki H., Sakai H., “Osteogenic response to porous hydroxyapatite ceramics under the skin of dogs.”, Biomaterials: 13: 308-312, (1992)

Youji Miyamoto, Kunio Ishikawa, Hirokazu Fukao, Masahiro Sawada, Masaru Nagayama, Masayuki Kon, Kenzo Asaoka, “In vivo setting behaviour of fast-setting calcium phosphate cement”, Biomaterials, 16: 855-860, (1995)

Zongjian Yang, Huipin Yuan, Weidong Tong, Ping Zou, Weiqun Chen and Xingdong Zhang, “Osteogenesis in extraskeletally implanted porous calcium phosphate ceramics: variability among different kinds of animals”, Biomaterials, vol .17 No.22, (1996)

Zhang X., Zhou P., Zhang J., Chen W. Wu C., “A study of hydroxyapatite ceramics and its osteogenesis.” Ravaglioli A., Krajewski A.J., eds., Bioceramics and the Human Body. London: Elsevier Applied Science, 408-416, (1991)

李澤民,“電漿熔射生醫玻璃塗層與氫氧基磷灰石塗層特性研究” (1993),國立成功大學材料及工程研究所碩士論文

經濟部陶瓷技術手冊 Chap.31