관능기를 갖는 생분해성 폴리 에스테르의 제조 및 응용
Preparation and application of biodegradable functional polyester
초록/요약
Polyesters have been widely used as implantable implants and drug delivery systems. However, since the polyesters made up of aliphatic esters are composed of hydrophobic chains that can't give the functional group to a main chain, it is difficult to control the biodegradation period and mechanical properties and to give a more varied and functional role. Therefore, it is necessary to develop polyesters having a functional group by introducing functional groups to aliphatic esters to solve this problem. The purpose of this study is to synthesize polyesters with functional groups with various decomposition periods and physical properties and then to evaluate the possibility of the activation of the functional groups. First, a functional polyester composed of functional L-lactide(fLA) containing ε-caprolactone(CL), L-lactide(LA) and a functional group was produced, and an antithrombotic functional group was incorporated to confirm the functionality of the functional group as implants. The antithrombotic functional polyester featured biodegradability, blood stability and antithrombotic properties, so that it showed the possibility of cardiovascular transplantation. In addition, functional polyesters made up of functional L-lactide(fLA) containing ε-caprolactone(CL) and functional groups were produced as a drug transporter, and ionic functional groups were incorporated thereto. Polyesters with ionic functional groups have been formulated for the delivery of hydrogel drug to treat rheumatoid arthritis (RA), and the efficacy of RA treatment was verified by the sustained release of drug through electrostatic attraction using counter-ion drug. In conclusion, according to the results of the study, functional polyesters were made by polymerizing aliphatic esters that functional groups were given, and the granted functional groups roles were well performed. This presents a new strategy for the development of biomaterials by suggesting and then verifying a strategy for producing more functional and customized polyesters that are currently used as biodegradable biomaterials in regenerative medicine.
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CHAPTER 1. General introduction 1
1.1. Background of the research 1
1.2. Polyester 6
1.3. Functional polyester 7
1.4. Strategy of this works 8
CHAPTER 2. Preparation of biodegradable and elastic poly(ε-caprolactone-co-lactide) copolymers and evaluation as a localized and sustained drug delivery carrier 11
2.1. Introduction 11
2.2. Experimental section 14
2.2.1. Materials 14
2.2.2. Characterization 14
2.2.3. Synthesis of PCxLyA copolymers 15
2.2.4. Synthesis of PCxLyA copolymer with fluorescein-isothiocyanate (FITC) (PC5L5A-FITC). 16
2.2.5. Preparation of PCxLyA films 17
2.2.6. Mechanical testing of PCxLyA films 17
2.2.7. In vitro degradation test 18
2.2.8. In vivo implantation 18
2.2.9. Histological analysis 19
2.2.10. Preparation of drug-loaded polymer films 20
2.2.11. In vitro release 21
2.2.12. In vivo release 21
2.2.13. In vivo fluorescence imaging 22
2.2.14. In vivo near infrared (NIR) imaging 22
2.2.15. Statistical analysis 22
2.3. Results and Discussion 24
2.3.1. Preparation of PCxLyA copolymers 24
2.3.2. Thermal properties of PCxLyA copolymers 27
2.3.3. Mechanical properties of PCxLyA copolymers 30
2.3.4. In vitro and in vivo degradation of PCxLyA copolymers 32
2.3.5. In vivo fluorescence imaging 37
2.3.6. Histological analysis 39
2.3.7. Drug release from drug-loaded PCxLyA copolymers 42
2.4. Conclusion 46
CHAPTER 3. Preparation of an anti-thrombotic biodegradable polymer and evaluation of its in vitro hemocompatibility 47
3.1. Introduction 47
3.2. Experimental section 52
3.2.1. Materials 52
3.2.2. Characterization 52
3.2.3. Synthesis of (PCL-ran-PLA) (PCLA) copolymer 53
3.2.4. Synthesis of (PCL-ran-PLA-ran-PfLA) copolymer (PCfLA-Bz) 53
3.2.5. Synthesis of PCfLA-OH copolymer 54
3.2.6. Synthesis of PCfLA-COOH copolymer 54
3.2.7. Synthesis of PCfLA-MPEG copolymer 55
3.2.8. Synthesis of PCfLA-NH2 copolymer 55
3.2.9. Synthesis of PCfLA-heparin copolymer 56
3.2.10. Preparation of PCLA and PCfLA films 57
3.2.11. In vitro degradation test 57
3.2.12. Mechanical testing of PCfLA copolymer films 58
3.2.13. Hemolysis analysis 58
3.2.14. Anti-platelet adhesion 59
3.2.15. Toluidine blue assay 59
3.2.16. Thrombin deactivation analysis 60
3.2.17. Statistical analysis 60
3.3. Results and Discussion 61
3.3.1. Preparation of PCfLA copolymer 61
3.3.2. In vitro degradation of PCLA and PCfLA copolymers 63
3.3.3. Mechanical properties of PCLA and PCfLA copolymers 65
3.3.4. Hemocompatibility test of PCLA and PCfLA copolymers 67
3.3.5. Platelet adhesion of PCLA and PCfLA copolymers 69
3.3.6. Toluidine blue assay of PCfLA-heparin copolymer 71
3.3.7. Thrombin inactivation properties of PCLA and PCfLA-heparin copolymers 73
3.4. Conclusion 75
CHAPTER 4. An injectable, electrostatically interacting drug depot for the treatment of rheumatoid arthritis 76
4.1. Introduction 76
4.2. Experimental section 80
4.2.1. Materials 80
4.2.2. Synthesis of MPEG-b-(PCL-ran-PLA) diblock copolymer (MCL) 81
4.2.3. Synthesis of MPEG-b-(PCL-ran-PfLA) diblock copolymer (MCfL-Bz) 81
4.2.4. Synthesis of MCfL-OH 82
4.2.5. Synthesis of MCfL-COOH (MCfL-C) 82
4.2.6. Synthesis of MCfL-NH2 (MCfL-N) 83
4.2.7 Zeta potential 84
4.2.8. Determination of sol-to-gel phase-transition times 84
4.2.9. Viscosity measurements 85
4.2.10. In vitro drug release 85
4.2.11. Inflammatory tests using RAW 264.7 and synovial cells 86
4.2.12. Treatment of RA rats 87
4.2.13. Articular index score and ankle diameter measurements of RA rats 88
4.2.14. Histology 88
4.2.15. TNF-α and IL-1β expression of RA rats 89
4.2.16. Statistical analysis 91
4.3. Results and Discussion 92
4.3.1. Preparation and characterization of injectable MCL, MCfL-C and MCfL-N diblock copolymers 92
4.3.2. Thermogelling properties of injectable MCL, MCfL-C and MCfL-N hydrogels 96
4.3.3. Electrostatic properties of injectable MCL, MCfL-C and MCfL-N hydrogels 98
4.3.4. Thermogelling properties of drug-loaded MCL, MCfL-C and MCfL-N hydrogels 102
4.3.5. In vitro release of drug-loaded MCL and MCfL-C hydrogels 106
4.3.6. In vitro cell viability on drug-loaded MCL and MCfL-C hydrogels 108
4.3.7. Evaluation of RA repair via imaging of the paws, ankle diameter, and articular index 111
4.3.8. Histology 113
4.3.9. Evaluation of RA repair by TNF-α and IL-1β expression 119
4.4. Conclusion 121
CONCLUSION 122
REFERENCES 124
LIST OF PUBLICATIONS 137
LIST OF PRESENTATIONS 140
LIST OF PATENTS 141
ABSTRACT IN KOREAN 142
