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研究生:蜜瑪拉
研究生(外文):VAIJAYANTHIMALA.V
論文名稱:Fluorescent Nanodiamonds for Biomedical Applications: Cytotoxicity, In vitro and In vivo studies
論文名稱(外文):螢光奈米鑽石於生醫上之應用: 毒性、活體外與活體內之研究
指導教授:張煥正倪其焜
指導教授(外文):Chang, Huan-ChengNi, Chi-Kung
口試委員:張煥正倪其焜韓肇中李仲良黃國柱
口試日期:2011-8-29
學位類別:博士
校院名稱:國立清華大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2011
畢業學年度:100
語文別:英文
論文頁數:125
中文關鍵詞:螢光穩定性螢光奈米鑽石細胞倍增時間活體幹細胞活體影像
外文關鍵詞:Fluorescent NanodiamondsFlowcytometryEndocytosisExocytosisInvivo imaging
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Fluorescent nanodiamond is a novel carbon based nanoparticle with a variety of important and unique properties such as photostability, biocompatibility, facile surface functionalizability making it as a novel nanoparticle for both in vitro and in vivo applications. Nanodiamond upon high energy ion beam irradiation and subsequent annealing at high temperature, results in the formation of (N-V)0 and (N-V)- defect centers which emit far red fluorescence under visible light excitation. Aforementioned properties make FND as a robust nanoparticle for cell labeling, cell tracking, in vitro and in vivo imaging applications.

In brief, this research begins with the cytotoxicity studies of FNDs in various cell lines. Our studies suggested that FNDs are biocompatible to different cell lines including HeLa, 3T3-L1 and 489-2.1 cells. Further studies showed that the FND cellular uptake is by energy dependent, clathrin mediated endocytosis. Based on the cell doubling time measurements, we found ~10% of FNDs are exocytosed both in short term as well as in long term. In addition to the fluorescence, light scattering also serve as an important parameter that could be utilized during cell sorting. Furthermore, FNDs can serve as an alternative probe to the commonly used dye like CFSE. We have demonstrated the feasibility of using FNDs for in vivo imaging. Injected FNDs accumulate in axillary lymph node and we also developed a new powerful methodology for the quantitation of FNDs in tissues and organs. Finally, we have also demonstrated that FND can be used as a fluorescent marker for in vivo stem cell tracking. In conclusion, FND can serve as an ideal nanoparticle for different biological applications.

螢光奈米鑽石為碳原子組成的新穎材料,許多重要且獨特的性質,如:螢光穩定性、生物相容性、表面修飾多元性等,使其成為生物體外及活體影像應用的重要材料。經過高能離子束靶擊及高溫淬火的奈米鑽石內,產生(N-V) 0、(N-V)- 缺陷中心,以可見光激發此類缺陷中心 , 可放出近紅外波長的螢光。上述性質使螢光奈米鑽石具有細胞標記、細胞追蹤及生物體外及活體影像應用的潛力。 此篇論文首先研究螢光奈米鑽石對不同細胞株的細胞毒性,結果顯示螢光奈米鑽石在3T3-L1, 489-2.1 細胞株內生物相容性好; 進一步研究顯示, 細胞藉由網格蛋白輔助 (clathrin mediated) 吞噬螢光奈米鑽石; 細胞倍增時間 (cell doubling time)實驗中, 約百分之十的螢光奈米鑽石在短期及長時間內被細胞排出 ,除了螢光之外 , 散射光亦是細胞分選的重要參數,本實驗證明螢光奈米鑽石亦可做細胞分選的探針, 與常用的有機染料CFSE具有相似功能 ; 螢光奈米鑽石亦展現活體影像的應用潛力 , 注射入老鼠的螢光奈米鑽石累積於輔助淋巴結中 , 並由本實驗發展的方法進行組織及器官內螢光奈米鑽石的定量。最後,螢光奈米鑽石亦被證實可做為活體幹細胞追蹤的螢光標籤。總結,螢光奈米鑽石為生物應用的理想材料。
1. Fluorescent Nanodiamonds 1
1.1 Introduction 1
1.2 Classification of Diamonds 1
1.3 Synthesis of HPHT Diamond 2
1.4 Vacancy related defect centers 4
1.5 Preparation of fluorescent nanodiamonds 5
1.6 Optical characterization 6
1.7 References 10
2. Nanodiamonds-Literature review 13
2.1 Introduction 13
2.2 Biocompatibility 15
2.3 Surface modification 17
2.4 Photoluminescence 21
2.5 Conclusion 27
2.6 Future perspective 27
2.7 References 28
3. Cytotoxicity studies of FNDs 35
3.1 Introduction 36
3.2 Experimental Methods 37
3.3 Results and Discussion 41
3.4 Summary 53
3.5 References 53
4. Cellular uptake mechanism of FNDs 55
4.1 Introduction 56
4.2 Experimental methods 57
4.3 Results and Discussion 59
4.4 Summary 66
4.5 References 67
5. Exocytosis and in vitro applications of FND 68
5.1. Introduction 69
5.2 Experimental Section 71
5.3 Results and Discussion 76
5.4 Summary 94
5.5 References 94
6. Fluorescent nanodiamonds in mouse and rat models:Optical imaging and histopathological analysis 97
6.1 Introduction 98
6.2 Experimental Section 100
6.3 Results and discussion 103
6.4 Summary 111
6.5 References 111
7. Fluorescent Nanodiamonds for in vivo tracking 113
7.1 Introduction 114
7.2 Experimental section 115
7.3 Results and discussion 119
7.4 Summary 125

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