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研究生:陳邑佳
研究生(外文):Yi-Chia Chen
論文名稱:利用交聯反應治療角膜病變之研究
論文名稱(外文):The Research of Healing Cornea Lesion with Cross-linking Reaction
指導教授:楊台鴻
指導教授(外文):Tai-Horng Young
口試日期:2017-07-11
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學工程學研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:43
中文關鍵詞:圓錐角膜核黃素/紫外線交聯術化學交聯劑生物機械性質酵素消化紅外線光譜
外文關鍵詞:Keratoconusriboflavin/UVA crosslinkingchemical cross-linkerbiomechanical strengthenzyme digestioninfrared spectroscopy
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核黃素/紫外線膠原蛋白交聯術已普遍得到認可是治療圓錐角膜及其他角膜異位症安全又有效的療法。核黃素於其中扮演光敏劑的角色,對於波長370nm的光能具最大吸收峰值,當其受到波長370nm的紫外光照射、激發時,核黃素會因而產生自由基導致組織中的膠原纖維進行物理交聯,因而使逐漸變薄和弱化的角膜基質被硬化。然而,有鑑於紫外線照射的傷害力,此種光交聯法仍有許多潛在風險。因此,許多研究團隊開始改用化學交聯劑,作為光交聯的替代方案,以提高角膜的機械性質及硬度。在本研究中,我們選擇了三種不同的化學交聯劑,旨在比較這些化學交聯法和核黃素/紫外線交聯法對牛角膜的生物物理、生物化學、生物力學和光譜學性質的影響。研究結果顯示,無論我們使用哪種交聯方法,牛角膜的機械強度都有顯著的變化,對於酵素酶的消化抵抗力也有增加,但是對於角膜的含水行為來講並無太大的改變,此外,從傅立葉轉換紅外光譜的分析結果看來,角膜交聯後力學強度的提升及對酵素酶消化抵抗力的提升很有可能是因為多了碳氫鍵的生成。
Riboflavin/UVA collagen cross-linking has already been recognized as a safe and effective therapy for the progressive keratoconus and other corneal ectatic disorders. The thinning and weakening corneal stroma can be stiffened when the photosensitizer riboflavin excited by UVA at its absorption peak of 370 nm creates free radicals resulting in cross-linking of collagen fibers. However, there are still some potential risks for the corneal and the ocular tissues with UVA irradiation. Therefore, searching other chemical cross-linking alternatives have become emergent to enhance biomechanical properties and stiffness of cornea in addition to riboflavin/UVA collagen cross-linking. In this research, we chose three different chemical cross-linkers and aimed to compare their safety and effectiveness caused by these chemical cross-linking and riboflavin/UVA collagen cross-linking on the biophysical, biochemical, biomechanical and spectroscopy properties of bovine cornea. Our results suggest that there are significant change in the mechanical strength of bovine cornea and its resistance against enzyme digestion in all of the cross-linking methods. However, there is no difference of the hydration behavior of cornea after cross-linking treated among them except the group cross-linked by BDDE. In addition, from the FT-IR spectrum that the enhancement of biomechanical property of cornea and the resistance to enzyme digestion are possibly due to the formation of carbon-oxygen linkage between collagen and cross-linker.
誌謝 i
中文摘要 ii
ABSTRACT iii
CONTENTS iv
LIST OF FIGURES vi
LIST OF TABLES vii
Chapter 1 Introduction 1
1.1 Keratoconus 1
1.2 Corneal structures 1
1.3 Corneal collagen cross-linking 3
1.3.1 Collagen structure maturation and degradation 3
1.3.2 Collagen Cross-linking protocols in clinical practice 4
1.4 Chemical cross-links and potential applications in ophthalmology 6
1.5 Evaluating corneal properties using cross-linking strategies 8
1.5.1 Biomechanical properties 8
1.5.2 Biophysical properties 9
1.5.3 Biochemistry properties 11
1.6 The Aim 13
Chapter 2 Materials and methods 14
2.1 Materials 14
2.2 Methods 14
2.2.1 Human corneal epithelial cell (HCEC) culture 14
2.2.2 Isolation of bovine corneal fibroblasts (BCfb) and bovine corneal endothelium cell (BCED) 15
2.2.3 Cell viability 16
2.2.4 Crosslinking procedures 16
.2.2.4.1 Photo-induced cross-linking 17
.2.2.4.2 Chemical cross-linking 17
2.2.5 Hydration behavior 18
2.2.6 Enzymatic digestion 18
2.2.7 Biomechanical measurements 18
2.2.8 Fourier-transformed infrared spectroscopy(FT-IR) 19
2.2.9 Statistical analysis 19
Chapter 3 Results 20
3.1 Cell viability 20
3.2 Hydration behavior 21
3.3 Enzymatic digestion 21
3.4 Biomechanical measurements 22
3.5 Fourier-transformed infrared spectroscopy 23
Chapter 4 Discussion 25
Chapter 5 Conclusion and perspective 30
FIGURES 31
Tables 36
REFERENCES 38

LIST OF FIGURES
Figure 1 Cross section through the cornea 3
Figure 2 Collagen lamellae in the corneal stroma 3
Figure 3 Hyperelastic behaviour of sclera tissue governed by the un-crimpling of buckled collagen fibres 9
Figure 4 Collagen-Proteoglycan arrangement in the corneal stroma 10
Figure 5 Experiment framework 13
Figure 6 Cross-linkers 26
Figure 7 The possible locations where cross-links occur after cross-linking 27
Figure 8 Cell Viability 31
Figure 9 Bovine Corneal Hydration Behavior 32
Figure 10 Bovine Cornea Enzyme Digestion 33
Figure 11 Bovine Cornea Young’s Modulus 34
Figure 12 FT-IR Spectrum of Bovine Cornea 35

LIST OF TABLES
Table 1 Weight of Bovine Cornea before/after immersion (n = 3) 36
Table 2 Young’s Modulus of Bovine cornea after cross-linking (control group:n=12; experiment groups: n = 6) 36
Table 3 Under curve area of cross-linked cornea FT-IR spectrum (n=4, p value : compare to control group) 37
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