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研究生:劉百栓
研究生(外文):Bai-Shuan Liu
論文名稱:以天然交聯劑綠梔子素交聯明膠結合三鈣磷酸鹽粉末之新骨科替代材料的研製與評估
論文名稱(外文):Preparation and Evaluation of a Novel Composite Combined with Genipin Cross-linked Gelatin and TCP Powder as Bone Substitute
指導教授:徐善慧徐善慧引用關係
指導教授(外文):Shan-Hui Hsu
學位類別:博士
校院名稱:國立中興大學
系所名稱:化學工程學系
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:138
中文關鍵詞:明膠綠梔子素三鈣磷酸鹽骨科替代材料
外文關鍵詞:GelatinGenipinTricalcium phosphateBone substitute.
相關次數:
  • 被引用被引用:21
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本研究目的為研製與評估一種新的骨科替代材料的適用性與生物適應性,期望材料不但方便於外科手術操作與具有良好的生物適應性之外,更希望植入材料在生物體內的溶解與析出速率,完全符合自然組織的重建模式,並可迅速參與新生組織的形成,使整個材料在植入一段時間之後,完全地被吸收及取代,而成為自然組織的一部份。
本研究以綠梔子素與明膠進行交聯反應,再添加三鈣磷酸鹽之陶瓷粉末,以完成GGT 複合材料之製備。材料特性分析方面,首先以不同添加量的綠梔子素交聯明膠,進行材料交聯程度之評估;之後以最適化添加量的綠梔子素交聯明膠,進行材料最小交聯反應時間之測定。此外,將GGT 材料浸泡於去離子水中,以進行浸泡液中材料釋出各成份濃度之定量分析;以及浸泡於模擬體液中,進行材料體外降解速率之測定。生物適應性評估方面,首先以骨母細胞培養及新生鼠頭蓋骨器官培養之體外測試,評估GGT 材料對骨母細胞生長的促進性或抑制性及促使缺陷骨組織修復的作用。此外,以老鼠皮下植入及兔體頭蓋骨植入之體內測試,評估GGT 材料在生物體內對免疫系統所產生的反應及實際應用於骨缺陷處的填充效應。
材料特性分析結果顯示,綠梔子素添加量達0.5wt%左右時,材料中明膠的交聯程度幾乎已達飽和,若以此添加量與明膠溶液進行交聯反應時,則至少需要經過一天的交聯反應時間,才可使材料達到完全的交聯反應;且在降解速率的測定結果顯示,若以綠梔子素作為交聯劑,可有效地降低GGT 複合材料的降解速率。由體外生物適應性評估結果顯示,當綠梔子素濃度增加至100ppm以上時,將會對骨母細胞造成明顯的生物毒性現象,而GGT 材料於浸泡期間所釋出的明膠及鈣離子,則具有促進骨母細胞增生與分化的能力;而由頭蓋骨器官培養結果發現,GGT 0.5wt%材料對於缺陷骨組織,具有骨引導與促進骨再生的能力。最後由體內生物適應性評估結果顯示,GGT 複合材料於老鼠皮下具有優異的生物適應性;且由兔體頭蓋骨植入實驗結果證實,此填充材料將不致造成植入部位的發炎等生物毒性現象,而且由X 光片顯示GGT 材料具有促進受傷骨組織的癒合能力。
This study prepares and evaluates the feasibility and biocompatibility of adopting a novel composite used as a bone substitute. This composite will hopefully be clinically effective and have good biocompatibility, and to be completely degradable by regenerated tissue after a suitable recovery time.
The GGT composite, combined with genipin cross-linked gelatin and tricalcium phosphate ceramic powders, was produced. First, the cross-linking ability of genipin at various concentrations on the gelatin was studied. Then, the minimal time for completing the cross-linking reaction between gelatin and genipin at the optimal concentration was determined. The substances released from the composites after they were soaked in de-ionized distilled water were analyzed. After the composites were soaked in simulated body fluid, the in vitro degradable rates were determined. Moreover, osteoblastic cell culture and neonatal rat cranial organ culture were used in an in-vitro test, to elucidate whether the substances released from the composites could facilitate the growth of bone cells and the osteoconductivity of the composite on new bone formation. Subcutaneous implantation in rats and the rabbit cranial defect model were used in an in-vivo test, to evaluate the compatibility of the tissue and the potential for accelerating the reconstruction of defective bone of the composites.
Results indicated that complete cross-linking reaction in the genipin-fixed gelatin occurred when 0.5 wt% of genipin was added. At least one day was required to complete the cross-linking reaction between gelatin and 0.5 wt% genipin. In the degradation study, the genipin used as cross-linking reagent could affect the rate of degradation of the composite. Cytotoxic tests revealed that 100 ppm of the genipin in the culture medium was the turning point, over which cytotoxicity to osteoblasts was exhibited. The gelatin and calcium ions were continuously released from the composites in the soaking solution, promoting proliferation and differentiation of the osteoblasts. Additionally, the composites had excellent biocompatibility and could produce osteoconduction for the regenerating bone tissues. Finally, the composites were shown not to be able to reduce biocompatibility during subcutaneous implantation in rats. In the rabbit cranial defect implant test, the composites demonstrated good tissue biocompatibility and were verified progressive growth of new bone into the calvarium defect, by radiographic evaluation.
目錄
頁碼
中文摘要…………………………………………………………………I
英文摘要…………………………………………………………………II
謝誌………………………………………………………………………III
目錄………………………………………………………………………IV
圖索引……………………………………………………………………VIII
表索引……………………………………………………………………XI
第一章 緒論…………………………………………………………… 1
1-1 前言…………………………………………………………………1
1-2 生醫骨科材料需具備的條件………………………………………3
1-3 生醫骨科材料的分類………………………………………………5
1-3-1 自然性骨科材料…………………………………………………5
1-3-2 人工合成骨科材料………………………………………………7
1-4 生醫骨科材料的臨床應用…………………………………………10
1-4-1 骨科材料臨床應用型式…………………………………………10
1-4-2 骨骼修復…………………………………………………………10
1-4-3 骨骼填充材料當前的研究重點…………………………………12
1-5 研究動機及目的……………………………………………………14
第二章 理論基礎……………………………………………………… 16
2-1 骨骼的組織與組成…………………………………………………16
2-1-1 骨骼的組織結構…………………………………………………16
2-1-2 骨骼的組成成份…………………………………………………17
2-2 骨細胞與骨骼重建機制……………………………………………19
2-2-1 骨細胞成份………………………………………………………19
2-2-2 骨骼重建機制……………………………………………………21
2-3 陶瓷材料的選擇……………………………………………………23
2-4 明膠的化學與物理特性……………………………………………25
2-4-1 膠原蛋白的分子結構與化學組成………………………………25
2-4-2 膠原蛋白的免疫排斥性與物理特性……………………………26
2-4-3 明膠的製備………………………………………………………27
2-4-4 明膠的生物降解特性……………………………………………28
2-4-5 明膠的交聯反應機制……………………………………………28
2-5 生物適應性評估理論………………………………………………31
2-5-1 體外測試(in-vitro test)…………………………………… 31
2-5-2 體內測試(in-vivo test)………………………………………32
第三章 實驗材料與方法……………………………………………… 34
3-1 實驗流程……………………………………………………………34
3-2 GGT 複合材料的研製………………………………………………37
3-2-1 實驗材料介紹……………………………………………………37
3-2-1.1 陶瓷材料--三鈣磷酸鹽(TCP)粉末………………………… 37
3-2-1.2 高分子材料--明膠(Gelatin)……………………………… 37
3-2-1.3 天然交聯劑--綠梔子素(Genipin)………………………… 38
3-2-2 實驗材料製備……………………………………………………39
3-3 材料特性分析………………………………………………………41
3-3-1 交聯程度評估……………………………………………………41
3-3-1.1 交聯指數分析…………………………………………………41
3-3-1.2 膨潤度測定……………………………………………………43
3-3-1.3 熱性質評估……………………………………………………43
3-3-2 最小交聯反應時間測定…………………………………………44
3-3-3 GGT 複合材料浸泡液濃度測定…………………………………45
3-3-4 GGT 複合材料降解速率測定……………………………………46
3-4 生物適應性評估……………………………………………………47
3-4-1 骨母細胞培養--體外測試………………………………………47
3-4-1.1 骨母細胞培養…………………………………………………47
3-4-1.2 骨母細胞培養測試……………………………………………48
3-4-1.3 骨母細胞增生的生化指標--MTT 色度分析法………………50
3-4-1.4 骨母細胞分化的生化指標--ALP 活性分析法………………52
3-4-2 老鼠頭蓋骨器官培養--體外測試………………………………53
3-4-2.1 器官培養實驗步驟……………………………………………53
3-4-2.2 器官培養實驗評估……………………………………………55
3-4-3 老鼠皮下植入--體內測試………………………………………56
3-4-3.1 皮下植入實驗步驟……………………………………………56
3-4-3.2 生物降解速率測定……………………………………………58
3-4-3.3 組織適應性評估………………………………………………58
3-4-4 兔體頭蓋骨植入實驗--體內測試………………………………59
3-4-4.1 植入材料試片製作……………………………………………59
3-4-4.2 動物手術程序…………………………………………………61
3-4-4.3 頭蓋骨植入實驗評估…………………………………………64
第四章 結果與討論…………………………………………………… 66
4-1 材料特性分析結果與討論…………………………………………66
4-1-1 交聯程度評估結果………………………………………………66
4-1-1.1 交聯指數分析結果……………………………………………66
4-1-1.2 膨潤度測定結果………………………………………………69
4-1-1.3 熱性質評估結果………………………………………………71
4-1-2 最小交聯反應時間測定結果……………………………………72
4-1-3 GGT 複合材料浸泡液濃度測定結果……………………………74
4-1-3.1 殘餘綠梔子素含量測定結果…………………………………74
4-1-3.2 明膠含量測定結果……………………………………………77
4-1-3.3 鈣離子含量測定結果…………………………………………79
4-1-4 GGT 複合材料降解速率…測定結果……………………………81
4-2 生物適應性評估結果與討論………………………………………83
4-2-1 骨母細胞培養--體外測試結果…………………………………83
4-2-1.1 綠梔子素毒性測試結果………………………………………83
4-2-1.2 明膠細胞培養結果……………………………………………85
4-2-1.3 鈣離子細胞培養結果…………………………………………89
4-2-1.4 浸泡液毒性測試結果…………………………………………91
4-2-1.5 GGT 材料與細胞共培養結果…………………………………94
4-2-2 老鼠頭蓋骨器官培養--體外測試結果…………………………97
4-2-2.1 定性分析結果…………………………………………………97
4-2-2.2 定量分析結果…………………………………………………105
4-2-3 老鼠皮下植入試驗--體內測試結果……………………………107
4-2-3.1 生物降解速率測定結果………………………………………107
4-2-3.2 組織適應性評估結果…………………………………………109
4-2-4 兔體頭蓋骨植入實驗--體內測試結果…………………………114
4-2-4.1 組織適應性評估結果…………………………………………114
4-2-4.2 骨再生作用評估結果…………………………………………117
第五章 結論與展望…………………………………………………… 123
參考文獻…………………………………………………………………127
個人簡介…………………………………………………………………137
附錄(期刊發表)…………………………………………………………138
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