臺灣博碩士論文加值系統

鈣磷系骨水泥（CPC）由於具有優異的生物相容性及引骨性，因此在牙科及外科手術上常用來當作填充修補材料。植入前，所有的生醫材料都必須經過消毒滅菌處理，本論文第一部分就是在探討四鈣磷酸鹽(TTCP)和由TTCP為原料之鈣磷系骨水泥經不同γ-ray照射劑量消毒滅菌後，對其結構、機械性質、工作時間、硬化時間、孔隙度及抗壓強度的影響。
實驗結果發現，在低劑量組(0-30 kGy)骨水泥的硬化時間為10-12分鐘，然而在高劑量組(40-120 kGy)其硬化時間縮短為8-10分鐘。不同劑量的γ-ray對於本實驗四鈣磷酸鹽骨水泥的孔隙度及抗壓強度均無明顯的影響。所有CPC試片的pH值落在8.5-9.1的相對窄區間內。當γ-ray的劑量為10或20kGy時，四鈣磷酸鹽-氫氧基磷灰石轉換率與無經過γ-ray照射的試片相同，但是當γ-ray的劑量為30 kGy時，轉換率明顯升高並達到一個最高值，隨著照射劑量繼續增加(40-120 kGy)轉換率快速下降。 當γ-ray的劑量增加，骨水泥的表面形態變的較為多孔狀且磷灰石的顆粒也會變大。由TEM的選區繞射及晶格影像分析可觀察到，當四鈣磷酸鹽粉末經由120kGy的γ-ray照射後，四鈣磷酸鹽粉末顆粒表面會被打出小孔洞，且γ-ray會誘發磷灰石相生成於四鈣磷酸鹽粉末表面。
CPC在植入體內時，除了會與骨頭接觸外，也會與周圍的軟組織接觸，且軟組織一般認為比起骨組織更容易產生發炎反應，所以在研究CPC與骨頭間的反應前，通常會先將CPC植入皮下觀察其生物相容性。
本論文第二部分是以TTCP為原料之CPC製成柱狀試片，分別浸泡在Hanks’人工體液及植入大白鼠皮下進行研究。結果顯示，浸泡在Hanks’人工體液的CPC試片，表面型態比體內測試的試片較為粗糙且多孔，試片表面覆蓋一層細小的磷灰石結晶。當CPC試片植入皮下4週或是更長的時間，其表面被纖維莢膜軟組織所包覆，此纖維軟組織主要是以平行試片表面的方向成長，在試片更外層的軟組織包含了大量的脂肪細胞，這層纖維莢膜的厚度並不是固定的，當植入時間由4週增加到12週時，其厚度有明顯的增加，12週以後厚度就無顯著的改變。植入皮下試片的周圍並無多型態間葉細胞、骨母細胞及骨細胞被觀察到，這表示CPC試片植入大白鼠皮下並無誘骨性。
CPC製成的柱狀試片不論浸泡在Hanks’人工體液或是植入大白鼠皮下，再經過1天實驗後其相皆已轉換成磷灰石相，只有很小量的TTCP相在1週後仍存在。由XRD和FTIR分析顯示，體外與體內實驗的結果皆十分相似，這表示在此兩種環境下有相似的相轉換反應。CPC試片浸泡在Hanks’人工體液之平均孔隙度，其值在浸泡4週到24週明顯大於浸泡1天和1週。植入大白鼠皮下不同週期(1天到24週)的CPC試片，其孔隙度無明顯的變化。CPC試片浸泡在Hanks’人工體液之徑向拉伸強度，在浸泡到4週時，強度大幅度的衰退；然而體內測試CPC試片之徑向拉伸強度在整個實驗週期(1天到24週)仍保有其強度，無衰退的現象。
本論文第三研究部分，將探討CPC植入後的吸收率，這是CPC最重要的性質之ㄧ。本實驗將CMRT實驗室發展出之CPC，植入紐西蘭大白兔大腿骨遠端內踝，以有系統及定量的方式研究CPC吸收率和植入位置的關連性。結果顯示，本實驗所使用之CPC在所有實驗週期中，植入材與骨骼的接觸面無引起發炎反應、無產生骨疽，在試片周圍也無纖維狀的莢膜被發現。CPC植入後與海棉骨相當緊密的接合在一起，植入1週後，CPC顯示為緻密的結構無空孔被發現；植入4週後，所有的植入材被新生骨所包覆；植入12和24週後，在植入材與骨頭的界面顯示更廣的再塑作用。
由組織切片分析結果顯示，CPC與宿主的骨頭有極佳的結合。植入4週後，在鑽孔處與植入材之間，因CPC被吸收所產生的空孔皆由大量的新生骨所填滿，由再塑區可發現，CPC被吸收，類骨母細胞排列於植入材表面形成活性新生骨，新生血管、骨細胞和骨單位皆在植入材表面被觀察到；植入12週後，新生骨在鑽孔處發展成網狀結構，植入之CPC與新生骨完全的結合，CPC被蝕骨細胞吸收且被新生骨分割成孤島狀，到處可觀察到被吸收之CPC由成熟的板狀骨所取代；植入24週後，大量的新生骨長入並取代CPC，活性再塑作用相當全面，殘留之CPC與新生骨間之界面變的不易分辨。
本研究顯示CPC之吸收率對於植入部位的變化相當敏感，整體而言，在所有的植入部位，吸收率會隨著植入時間的增加而上升。分區來看，當CPC植入4週或是更長的時間(12及24週)， CPC之吸收率在外層處(近皮質骨部位)明顯大於在內層處(海棉骨部位)。當植入週期為24週時，在皮質骨處之CPC幾乎完全被吸收，骨骼之再塑形作用在此時幾乎完成。

Due to its superior biocompatibility and osteoconductivity, calcium phosphate cement (CPC) has been suggested for use as a filling material in dental and orthopedic applications. Before implantation, all of biomaterials need to be sterilized. The first purpose of the present study is to investigate the γ-radiation effect with different doses on the structure and properties, such as working/setting time, porosity, and compressive strength, of the single-phase tetracalcium phosphate (TTCP) powder and its derived calcium phosphate cement (CPC).
Experimental results show that low-dosed (0-30 kGy) CPC has a setting time of 10-12 min, while high-dosed (40-120 kGy) CPC has a setting time of 8-10 min. The low dose γ-radiation does not significantly change porosity volume fraction or compressive strength of the CPC. The pH values of all CPC samples fell in a relatively narrow band with a band width of 8.5-9.1 (in terms of pH value). With a dose of 10 or 20 kGy, the TTCP-apatite conversion ratio does not change much. With 30 kGy, the conversion ratio significantly increases and reaches a maximum value. With further increase in dose, the conversion ratio quickly declines. With increasing γ-ray dose, the CPC morphology becomes more porous/loose and apatite particles become larger in size. When exposed to high dose (120 kGy) γ-ray, TTCP structure is radiation-damaged and γ-ray-induced formation of apatite is confirmed by TEM/SAD/lattice imaging analyses.
It is worth noting that sometimes CPC is not only in contact with bone, but also with the surrounding soft tissues. Apparently not only CPC-bone interaction, the interaction between CPC and soft tissue also needs to be evaluated. These soft tissues are generally considered to show a more severe inflammatory response than bone. Therefore, before implanting in bone CPC need to implant subcutaneously in order to observe the biocompatibility.
The second part of the study contained a pre-hardened, TTCP-derived CPC was immersed in Hanks’ solution as well as subcutaneously implanted into abdomen of rats. The implant-soft tissue interfacial morphology was examined and properties of the CPC were evaluated under both in vitro and in vivo conditions.
The results indicate that surface of the immersed samples appeared rougher and more porous than that of the implanted samples and was covered with a layer of tiny, presumably apatite crystals. The CPC samples implanted for 4 weeks or longer were surrounded by a layer of fibrous tissue, which was further surrounded by a soft tissue capsule comprising numerous fat cells. The soft tissue capsule had a non-uniform distribution in thickness, which increased most significantly between 4 and 12 weeks after implantation.
None of polymorphic cells, osteoblast cells or bone cells adjacent to the implant were observed. The majority of original TTCP powder was transformed into apatite after one day of either immersion in Hanks’ solution or implantation. The average porosity values of samples immersed in Hanks’ solution for 4 weeks or longer were significantly larger than those immersed for 1 day or 1 week. The porosity values of samples implanted for different times were not significantly different. The DTS values of Hanks’ solution-immersed samples largely decreased after a few weeks of immersion. The implanted samples maintained their strengths throughout the study.
Thirdly, one primary focus of the present study was to clarify the crucial resorption-location relationship of a recently developed single-phase TTCP-derived CPC implanted in rabbit femur in a systematic and quantitative way.
Gross examination of retrieved CPC/bone composite samples indicated that the CPC implant did not evoke inflammatory response, necrosis or fibrous encapsulation in surrounding bony tissues. Histological examination revealed excellent CPC-host bone bonding. At 4 weeks, the resorption-induced voids between terminals of bone defects and implants were largely filled with new bone. CPC resorption, new blood vessels, osteocytes, osteons and osteoblast-like cells lining up with active new bone were observed at remodeling sites. At 12 weeks, a new bone network was developed within femoral defect, while CPC became islands incorporated in the new bone. At this stage, crevices filled with lamellar new bone structure were frequently observed. At 24 weeks, bone ingrowth and remodeling activities became so extensive that the interface between residual cement and new bone became less identifiable.
In general, at all implant locations the resorption ratio values increased with implantation time, while at all implantation times the resorption ratios decreased from the exterior (cortical site) to the interior (cancellous site) of implants. At the end of 24 weeks, CPC was almost completely resorbed and bone remodeling almost finished at the cortical site.

中文摘要……………………………………………………………………………………1
Abstract……………………………………………………………………………………3
誌謝…………………………………………………………………………………………5
總目錄………………………………………………………………………………………6
圖目錄………………………………………………………………………………………11
表目錄………………………………………………………………………………………15
第一章 總緒論……………………………………………………………………………17
1-1 導言………………………………………………………………………………18
1-2 生醫材料的定義…………………………………………………………………18
1-3 生醫材料之歷史發展……………………………………………………………19
1-4 生醫材料之分類…………………………………………………………………23
1-4-1 依材料種類分類…………………………………………………………………23
1-4-2 依活性分類………………………………………………………………………24
1-5 骨科植入材之性質要求…………………………………………………………26
1-6 人體硬組織結構成分及性質簡介………………………………………………29
1-7 氫氧基磷灰石性質簡介…………………………………………………………36
第二章 理論基礎與文獻回顧……………………………………………………………41
2-1 鈣磷系骨水泥的發展與簡介……………………………………………………42
2-1-1 前言………………………………………………………………………………42
2-1-2 磷酸鈣鹽類生醫陶瓷分類與發展………………………………………………43
2-1-3 鈣磷系鹽類的溶解相圖…………………………………………………………46
2-1-4 鈣磷系鹽類水解形成氫氧基磷灰石……………………………………………49
2-1-5 鈣磷系骨水泥的優點及應用……………………………………………………52
2-2 消毒滅菌方法的發展與簡介……………………………………………………55
2-2-1 消毒滅菌的發展史………………………………………………………………54
2-2-2 消毒滅菌方法的分類……………………………………………………………56
2-2-3 消毒滅菌方法對生醫植入材性質的影響………………………………………66
2-2-4 研究動機及目的（I）……………………………………………………………69
2-3 動物實驗理論基礎與文獻回顧…………………………………………………70
2-3-1 動物實驗的重要性………………………………………………………………70
2-3-2 實驗動物選擇……………………………………………………………………73
2-3-3 植入部位選擇……………………………………………………………………74
2-3-4 植入週期選擇……………………………………………………………………78
2-3-5 測試影響評估……………………………………………………………………80
2-4 鈣磷系骨水泥體外與體內(皮下植入)性質測試之理論基礎與文獻回顧……81
2-4-1 體外測試…………………………………………………………………………81
2-4-2 影響體外測試機械性質之因素…………………………………………………83
2-4-3 CPC皮下植入之文獻回顧…………………………………………………………85
2-4-4 研究動機及目的(Ⅱ)……………………………………………………………89
2-5 鈣磷系骨水泥吸收率之理論基礎與文獻回顧…………………………………90
2-5-1 鈣磷系骨水泥與骨組織之反應…………………………………………………90
2-5-2 鈣磷系骨水泥吸收率量測方法之文獻回顧……………………………………94
2-5-3 研究動機及目的(Ⅲ)……………………………………v………………………97
第三章 實驗步驟與方法…………………………………………………………………98
3-1 γ-ray消毒滅菌法對骨水泥性質影響之實驗方法及步驟………………………99
3-1-1 鈣磷系骨水泥材料製備…………………………………………………………99
3-1-2 抗壓強度測試……………………………………………………………………99
3-1-3 工作及硬化時間的測量………………………………………………K………100
3-1-4 硬化期間pH值分析………………………………………………………………101
3-1-5 X光繞射分析………………………………………………………………………101
3-1-6 四鈣磷酸鹽-氫氧基磷灰石相對相轉換率的計算………………………………102
3-1-7 孔隙度量測………………………………………………………………………102
3-1-8 掃描式電子顯微鏡分析…………………………………………………………103
3-1-9 傅立葉轉換紅外線光譜分析……………………………………………………103
3-1-10 穿透式電子顯微鏡分析…………………………………………………………104
3-2 鈣磷系骨水泥體外與體內(皮下植入)實驗其表面型態與機械性質測試之實驗
步驟與方法………………………………………………………………………108
3-2-1 鈣磷系骨水泥材料製備…………………………………………………………108
3-2-2 骨水泥體外徑向拉伸強度測試…………………………………………………108
3-2-3 骨水泥體內徑向拉伸強度測試…………………………………………………109
3-2-4 pH值測試…………………………………………………………………………110
3-2-5 孔隙度量測………………………………………………………………………110
3-2-6 X光繞射分析………………………………………………………………………111
3-2-7 傅立葉轉換紅外線光譜分析……………………………………………………111
3-2-8 掃描式電子顯微鏡分析…………………………………………………………111
3-2-9 組織切片製作之步驟與方法……………………………………………………112
3-2-10 體內植入試片表面纖維組織厚度量測方法……………………………………115
3-3 鈣磷系骨水泥植入紐西蘭大白兔大腿骨遠端內踝吸收率之實驗步驟與方法122
3-3-1 鈣磷系骨水泥材料製備…………………………………………………………122
3-3-2 動物實驗方法與植入步驟………………………………………………………122
3-3-3 CPC吸收率量測之步驟與方法……………………………………………………124
3-3-4 X光繞射分析………………………………………………………………………125
3-3-5 傅立葉轉換紅外線光譜分析……………………………………………………125
第四章 結果與討論………………………………………………………………………129
4-1 γ-ray消毒滅菌法對鈣磷系骨水泥性質影響之結果與討論……………………130
4-1-1 表面顏色觀察……………………………………………………………………130
4-1-2 工作及硬化時間測量結果………………………………………………………130
4-1-3 硬化過程pH值的變化……………………………………………………………131
4-1-4 抗壓強度測試結果………………………………………………………………131
4-1-5 X光繞射分析………………………………………………………………………132
4-1-6 四鈣磷酸鹽-氫氧基磷灰石相轉換率分析………………………………………133
4-1-7 傅立葉轉換紅外線光譜分析……………………………………………………133
4-1-8 孔隙度量測結果…………………………………………………………………134
4-1-9 掃描式電子顯微鏡表面型態觀察………………………………………………134
4-1-10 穿透式電子顯微鏡分析結果與討論……………………………………………135
4-2 鈣磷系骨水泥體外與體內(皮下植入)實驗其表面型態與機械性質測試之結果與討論……………………………………………………………………………………………156
4-2-1 組織切片觀察……………………………………………………………………156
4-2-2 掃描式電子顯微鏡表面型態觀察………………………………………………157
4-2-3 X光繞射分析………………………………………………………………………158
4-2-4 傅立葉轉換紅外線光譜分析………………………………………………………159
4-2-5 實驗過程pH值的變化……………………………………………………………159
4-2-6 孔隙度量測結果與討論…………………………………………………………160
4-2-7 徑向拉伸強度結果與討論………………………………………………………160
4-3 鈣磷系骨水泥植入大白兔大腿骨遠端內踝吸收率之結果與討論……………174

4-3-1 CPC植入大白兔大腿骨遠端內踝不同週期之反應結果…………………………174
4-3-2 組織切片觀察……………………………………………………………………175
4-3-3 CPC植入大白兔大腿骨遠端內踝其吸收率之結果與討論………………………176
4-3-4 X光繞射分析………………………………………………………………………179
4-3-5 傅立葉轉換紅外線光譜分析……………………………………………………180
第五章 總結論……………………………………………………………………………191
參考文獻……………………………………………………………………………………195
作者簡介及論文著作………………………………………………………………………207

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