아주대학교

목차

CHAPTER 1. General introduction 1
1.1. Drug delivery systems 2
1.2. Hydrogels 4
1.3. Biomaterials 4
1.4. Natural materials 5
1.5. Synthetic materials 6
1.6. Strategy of this work 6

CHAPTER 2. Preparation and in vivo evaluation of an injectable crosslinked cartilage acellular matrix-PEG hydrogel scaffold derived from porcine cartilage 9
2.1. Introduction 10
2.2. Experimental section 14
2.2.1. Materials 14
2.2.2. Preparation of a CAM powder 15
2.2.3. Determination of Double Strand DNA of CAM Before and After Decellularization 16
2.2.4. Preparation of a Near Infrared (NIR) tagged CAM powder 17
2.2.5. Synthesis of COOH-PEG-400-COOH 17
2.2.6. Synthesis of NHS-PEG-400-NHS (PEG crosslinker) 18
2.2.7. Preparation of crosslinked CAM using PEG cross-linker 19
2.2.8. Preparation of CAM suspensions 20
2.2.9. Hydrophilicity test of CAM films and CAM hydrogel 21
2.2.10. Rheological properties of CAM hydrogels 22
2.2.11. Injectability test of CAM hydrogels 22
2.2.12. Animal experiment 23
2.2.13. In vivo biodegradation and biocompatibility experiments of NIR-labeled CAM, 0.6-CAM-GA, 0.6-CAM-PEG, 1-CAM-PEG, 3-CAM-PEG and 5-CAM-PEG hydrogels 24
2.2.14. In vivo implantation of CAM, 0.6-CAM-GA, and 0.6-CAM-PEG 24
2.2.15. Histological assay of CAM, 0.6-CAM-GA, and 0.6-CAM-PEG hydrogels 25
2.2.16. Statistical analysis 27
2.3. Results and Discussion 28
2.3.1. Preparation of CAM powder 28
2.3.2. Synthesis of COOH-PEG-400-COOH and NHS-PEG-400-NHS 31
2.3.3. Preparation of CAM, 0.6-CAM-GA, 0,6-CAM-PEG films 33
2.3.4. Preparation and characterization of CAM-PEG Powders 38
2.3.5. Hydrophilicity test of CAM, 0.6-CAM-GA, 0.6-CAM-PEG, 1-CAM-PEG, 3-CAM-PEG, and 5-CAM-PEG films 41
2.3.6. Rheological properties of CAM hydrogels 46
2.3.7. Injectability test of CAM hydrogels 49
2.3.8. In vivo biodegradation of NIR-labeled CAM, 0.6-CAM-GA, 0.6-CAM-PEG, 1-CAM-PEG, 3-CAM-PEG, and 5-CAM-PEG hydrogels 52
2.3.9. In vivo biodegradation of CAM, 0.6-CAM-GA, 0.6-CAM-PEG hydrogels 56
2.3.10. In vivo biocompatibility of CAM, 0.6-CAM-GA, 0.6-CAM-PEG hydrogels 58
2.4. Conclusion 62

CHAPTER 3. Anti-cancer activity of intratumorally injectable in-situ forming hyaluronic acid hydrogel 63
3.1. Introduction 64
3.2. Experimental section 69
3.2.1. Materials 69
3.2.2. Preparation of HA-Tet and HA-TCO hydrogels 69
3.2.3. Preparation of near-infrared (NIR) fluorescence-labeled HA-Tet (HA-Tet-NIR), HA-TCO (HA-TCO-NIR) and HA (HA-NIR) hydrogels 70
3.2.4. Preparation of HA-Dox Cx-HA-Dox, HA-NIR-Dox and Cx-HA-NIR-Dox formulation 71
3.2.5. Zeta potential of HA, HA-TCO, HA-Tet, Dox, HA-Dox, HA-TCO-Dox and HA-Tet-Dox 72
3.2.6. Rheological properties of hydrogels 72
3.2.7. Injectability test of hydrogels 73
3.2.8. In vitro release of Dox from HA and Cx-HA hydrogels 74
3.2.9. In vitro degradation of NIR tagged HA and Cx-HA hydrogels and Dox release from HA and Cx-HA hydrogels 75
3.2.10. In vitro anti-tumor activity 76
3.2.11. Inhibitiory effects 77
3.2.12. Animal study 77
3.2.13. Ex vivo fluorescent images of remained Dox and NIR labeled Cx-HA hydrogel within tumors and organs 78
3.2.14. Distribution of Dox in tumors after intratumoral injection 79
3.2.15. Histological assay 79
3.2.16. Statistical analysis 82
3.3. Result and discussion 83
3.3.1. Preparation and charaterization of Cx-HA hydrogel 83
3.3.2. Zeta potential of HA hydrogel formulations 86
3.3.3. Rheological properties and injectability of Cx-HA-Dox hydrogel formulation 90
3.3.4. In vitro Dox release and in vitro degradation of HA and Cx-HA hydrogels 95
3.3.5. In vivo Dox release and in vivo degradation of HA and Cx-HA hydrogels 99
3.3.6. In vivo anti-tumor effect of Dox of formulation 102
3.3.7. In vivo fluorescent images of remained Dox and NIR labelled Cx-HA hydrogel 105
3.3.8. Distribution of Dox in tumors after intra-tumoral injection 109
3.3.9. Histological assay 111
3.4. Discussion 117
3.5. Conclusion 121

CHAPTER 4. Overall conclusion 122