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Title Page

Abstract

Contents

Nomenclature 9

Chapter 1: Introduction 17

1.1. Objective 17

1.2. Outline of the thesis 23

Chapter 2: Theoretical overviews 24

2.1. Electroporation 24

2.2. Electrochemotherapy 32

2.2.1. Anti-cancer agent 35

2.2.2. Pre-clinical trials of electrochemotherapy 37

2.2.3. Clinical trials of electrochemotherapy 38

2.2.4. Electrode configurations 42

2.3. Irreversible electroporation 44

Chapter 3: Cell-based in vitro ECT testing device with two-electrode format 48

3.1. Introduction 48

3.2. Experimental 49

3.2.1. Design and fabrication 49

3.2.2. Cell culture and seeding 51

3.2.3. Electroporation procedure 53

3.2.4. Electroporation with propidium iodide 55

3.2.5. Electrochemotherapeutic assay with bleomycin 57

3.3. Results and discussion 58

3.3.1. Thermal distribution during electroporation 58

3.3.2. Effect of electric pulses on the neighboring electroporation sites 60

3.3.3. Cell viability and apoptotic assays after electroporation 62

3.3.4. Electroporation rate of propidium iodide 64

3.3.5. Electrochemotherapy with bleomycin 66

3.4. Conclusion 72

Chapter 4: Cell-based in vitro ECT testing device with six-electrode format 75

4.1. Introduction 75

4.2. Experimental 76

4.2.1. Design and fabrication 77

4.2.2. Cell culture and seeding 80

4.2.3. Electroporation procedure 80

4.2.4. Electroporation with propidium iodide 83

4.2.5. Electrochemotherapeutic assay with bleomycin 84

4.3. Results and discussion 84

4.3.1. Thermal distribution during electroporation 84

4.3.2. Cell viability and apoptotic assays after electroporation 88

4.3.3. Results of electroporation with propidium iodide 88

4.3.4. Electrochemotherapy with bleomycin 92

4.4. Conclusion 98

Chapter 5: Tissue-based IRE testing device 100

5.1. Introduction 100

5.2. Experimental 101

5.2.1. Design and fabrication 101

5.2.2. Procedure of irreversible electroporation 103

5.3. Results and discussion 106

5.3.1. Electric current change during the pulse application 106

5.3.2. Histological changes after irreversible electroporation 106

5.4. Conclusion 112

Chapter 6: Conclusions 115

Summary in Korean 118

References 123

Acknowledgement 144

Curriculum Vitae 146

Publications 147

List of Tables

Table 1.1. Previous researches on microfabricated electroporation devices. 21

Table 2.1. Clinical response to electrochemotherapy before and in the ESOPE clinical trials: PD (progressive disease) if tumors increase in size; NC (no change) if tumors reduce in size by less than 50%; PR (partial response) if the... 40

Table 3.1. Composition of iso-osmolar electroporation buffer (Eppendorf, Hamburg, Germany). 54

Table 3.2. Electric field strength in the center of the EP site of two-electrode ECT testing device. 56

Table 4.1. Electric field strength in the center of the EP site of six-electrode ECT testing device. 82

List of Figures

Fig. 2.1. Electroporation on a cell membrane; (a) Initial cell membrane. (b) Electropermeabilized state. (c) Resealing of pores. (Electron microscopic images are taken from http://www.genetronics.com). 25

Fig. 2.2. Cell under a uniform electric field between two parallel plate electrodes. and the corresponding electric potential drop. 27

Fig. 2.3. Schematic relationship between electric field strength and pulse length applicable to the electroporation of cells. 30

Fig. 2.4. Principle of electrochemotherapy. 34

Fig. 2.5. Different types of electrodes used in electrochemotherapy; (a) Two-needle array. (b) Circular array of six-needle electrodes. (c) Circular array of six-needle electrodes with extra needle placed in the center of the circle. (d)... 43

Fig. 3.1. Comparison of conventional clinical electroporator (a) with the microfabricated ECT testing device (b~f). (a) A clinical ECT electroporator. (b) Schematics of the ECT testing device in this study. (c) Installation drawing. (d)... 50

Fig. 3.2. Simulation results of electric field strength. (a) Clinical electroporator. (b) ECT testing device. 52

Fig. 3.3. Computational model for the simulation of thermal distribution. 59

Fig. 3.4. Simulation results of thermal distribution. (a) Maximum thermal distribution on the electrode surface. (b) Time history of temperature at the electrode tip (the arrow-marked point in Fig. 3.4 (a)). 61

Fig. 3.5. Effect of electric pulses on the neighboring electroporation sites; simulation result and the fluorescence images of electroporated cells with PI. 63

Fig. 3.6. (a) Electroporation rate of PI with electric field strength. Each data point represents the mean ± standard deviation derived from at least four experiments. (b) Fluorescence images of total cells and electroporated cells.... 65

Fig. 3.7. (a) Cell proliferation after 48 h of ECT with 5×10-7 M bleomycin. Each data point represents the mean ± standard deviation derived from at least four experiments. (b) Fluorescence images of initial cells and final live cells...(이미지참조) 67

Fig. 3.8. Cell proliferation after 48 h of ECT with bleomycin concentration. Each data point represents the mean ± standard deviation derived from at least four experiments. 69

Fig. 3.9. (a) Fluorescence image of final live cell distribution after 48 h of ECT with the condition of 1 kV/cm pulses and 5×10-6 M bleomycin, and (b) The corresponding electric field strength. Dashed boundaries are the iso-electric...(이미지참조) 70

Fig. 3.10. Correlation of the fluorescence area and the corresponding number of cells. 73

Fig. 4.1. Comparison of conventional clinical electroporator (a) with the microfabricated ECT testing device (b~f). (a) A clinical ECT electroporator. (b) Schematics of the ECT testing device in this study. (c) Installation drawing. (d)... 78

Fig. 4.2. Simulation results of electric field strength. (a) Clinical electroporator. (b) ECT testing device. 79

Fig. 4.3. (a) Electric pulse sequence of six-electrode mode, and (b) electrical interconnecting jig for the six-electrode ECT testing device. 81

Fig. 4.4. Computational model for the simulation of thermal distribution. 85

Fig. 4.5. Simulation results of thermal distribution. (a) Maximum thermal distribution on the electrode surface. (b) Time history of temperature at the electrode tip (the arrow-marked point in Fig. 4.5 (a)). 87

Fig. 4.6. (a) Electroporation rate of PI with electric field strength. Each data point represents the mean ± standard deviation derived from at least four experiments. (b) Fluorescence images of total cells and electroporated cells... 89

Fig. 4.7. Average fluorescence intensity of PI of electroporated cells. Each data point represents the mean ± standard deviation derived from at least four experiments. 91

Fig. 4.8. (a) Cell proliferation after 48 h of ECT with 5×10-7 M bleomycin. Each data point represents the mean ± standard deviation derived from at least four experiments. (b) Fluorescence images of initial cells and final live cells...(이미지참조) 93

Fig. 4.9. (a) Cell proliferation after 48 h of ECT with bleomycin concentration. Each data point represents the mean ± standard deviation derived from at least four experiments. (b) Fluorescence images of final live cells distribution after 48... 95

Fig. 4.10. Cell proliferation after 48 h of ECT with 5×10-6 M bleomycin. Each data point represents the mean ± standard deviation derived from at least four experiments.(이미지참조) 97

Fig. 5.1. Comparison of conventional clinical electroporator (a) with the miniaturized IRE testing device (b). 102

Fig. 5.2. Fabrication process (a~e) and the photograph of the fabricated IRE testing device (f). 104

Fig. 5.3. Electric current change during the pulse application of (a) 140 V, and (b) 280 V voltage amplitude. 107

Fig. 5.4. Microscopic images of pulsed liver tissues. (a, c) TUNEL assays after 1 h and 3 h of in vivo IRE, respectively. (b, d) H&E stainings corresponding to (a) and (c), respectively. Arrows indicate the positions of electrodes. 109

Fig. 5.5. Microscopic images of pulsed liver tissues after 3 h of in vivo IRE. (a, b) TUNEL assays. (c, d) H&E stainings. 110

Fig. 5.6. Microscopic images of discrete boundary between the IRE treated and untreated zones after 3 h of in vivo IRE. 111

Fig. 5.7. Microscopic images of blood vessels in the IRE (a) treated, and (b) untreated zone after 3 h of in vivo IRE. 113

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