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Engineering medical device surfaces with zwitterionic polymer and chitosan/dexamethasone to improve anti-adhesion and anti-bacterial/anti-inflammatory properties

  • 권호준 (Kwon, Ho Joon, 아주대학교 일반대학원)

초록/요약

With the gradual development of medical technology, various biomaterials capable of supporting or replacing the damaged tissue have been developed and utilized. However, implantation of biomaterials into the body cannot always be free from side effects such as thrombosis, infection, and foreign body reaction, which may cause discomfort and even threaten the patient’s life. Since all of these side effects occur due to the interaction between the surface of the implantation material and the host's internal environment, the need for surface modification technology to ensure safer implantation of the biomaterial is emerging. The main purpose of this dissertation is to introduce various bio-functionalities to biomaterial surface via dopamine-derived surface grafting methods that can modify the material surface regardless of the type of biomaterial. In chapter 2, poly(sulfobetaine-co-tyramine), a tyramine-conjugated sulfobetaine polymer, was synthesized and simply grafted onto the surface of polyurethane via a tyrosinase-mediated reaction. Surface characterization by water contact angle measurements, X-ray photoelectron spectroscopy and atomic force microscopy demonstrated that the zwitterionic polymer was successfully introduced onto the surface of polyurethane and remained stable for 7 days. In vitro studies revealed that poly(sulfobetaine-co-tyramine)-coated surfaces dramatically reduced the adhesion of fibrinogen, platelets, fibroblasts, and S. aureus by over 90% in comparison with bare surfaces. These results proved that polyurethane surfaces grafted with poly(sulfobetaine-co-tyramine) via a tyrosinase-catalyzed reaction could be promising candidates for an implantable medical device with excellent bioinert abilities. In chapter 3, Chitosan immobilized and dexamethasone loaded surface that can solve both inflammation and infection problems was developed. Also, when it used in proper concentrations, dexamethasone can promote osseointegration by differentiating stem cells into osteoblasts. To fabricate funtional surface, phenylboronic acid-modified chitosan was immobilized through polydopamine assisted reaction. Then, dexamethasone-loaded β-cyclodextrin was treated to generate the phenylboronic ester bond between chitosan-phenylboronic acid and cyclodextrin. Scanning electron microscope and energy dispersive X-ray spectroscopy confirmed the successful conjugation of chitosan derivative and β-cyclodextrin onto surface. The anti-inflammatory effect of surface was evaluated by macrophage polarization test. Immunofluorescent staining of CD 163 and increased amount of TGF-β which are the markers of M2 macrophage, indicating anti-inflammatory effect of dexamethasone-loaded surface. Antibacterial assay also showed the significant bactericidal effect of chitosan immobilized surface against gram negative and gram positive strain, E. coli and S. aureus. Also, assays using ARS and ALP demonstrated the osteogenic effect of modified surface. The results indicated that chitosan/dexamethasone surface modification could serve as potential antibacterial/anti-inflammatory implant surface modification methods.

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목차

I. General introduction 1
1. Biocompatibility, biofouling and surface modification of biomaterials 2
2. Interactions between host and biomedical surface 5
2.1. Biomaterial surface related inflammation responses 5
2.2. Biomaterial surface related infection 7
2.3. Biomaterial surface related thrombosis 9
3. Surface modification of biomaterials 10
3.1. Bioactive and bioinert surface modifications 10
3.2. Physical and chemical modifications 11
3.3. Biological modifications using polymers and biomolecules 14
3.3.1. Bioactive surface modifications using natural polymers 15
3.3.2. Bioinert surface modifications using synthetic polymers 16
3.4. Mussel-inspired surface modifications 19
4. Overall objectives 20
5. References 21
II. Zwitterionic sulfobetaine polymer-immobilized surface by simple tyrosinase-mediated grafting for enhanced antifouling property 32
1. Introduction 33
2. Experimental section 36
2.1. Materials 36
2.2. Synthesis and characterizations of poly(sulfobetaine-co-tyramine) 37
2.3. Synthesis and characterizations of poly(sulfobetaine) and poly(methacrylic-acid) 38
2.4. Preparation of PU substrate 39
2.5. Preparation of pSBTA-grafted PU substrate 39
2.6. Surface characterizations 39
2.7. Coating stability 40
2.8. Fibrinogen adsorption test 40
2.9. Platelet adhesion assay 40
2.10. Cell adhesion test 41
2.11. Bacteria adhesion assay 42
2.12. Statistical analyses 43
3. Results and discussions 43
3.1. Synthesis and characterizations of pSBTA polymer 43
3.2. Characterization of poly(sulfobetaine), poly(sulfobetaine-co-methacrylic acid) and poly(methacylic acid) 45
3.3. Preparation of pSBTA-grafted PU substrate 45
3.4. Surface characterizaitons 48
3.5. Coating stability 51
3.6. Antifouling assays 54
4. Conclusions 60
5. References 61

III. Chitosan/β-cyclodextrin-dexamethasone modified surface for enhanced anti-inflammatory and antibacterial properties 69
1. Introduction 70
2. Experimental section 72
2.1. Materials 72
2.2. Synthesis and characterization of CPBA 73
2.3. Preparation of DEX-loaded CPBA immobilized PVC surface 73
2.4. Surface characterizations 74
2.5. Release profile of DEX-loaded surface 74
2.6. In vitro macrophage polarization assay 74
2.7. In vitro bacterial colony forming assay 76
2.8. In vitro bone-marrow stem cell differentiation 77
2.9. Statistical analyses 79
3. Results and discussions 79
3.1. Synthesis and characterization of CPBA 79
3.2. Preparation and characterizations of PDA/CPBA/βCD-DEX surface 81
3.3. In vitro anti-inflammation properties of PDA/CPBA/βCD-DEX surface 85
3.4. In vitro antibacterial properties of PDA/CPBA/βCD-DEX surface 88
3.5. In vitro osteogenic properties of PDA/CPBA/βCD-DEX surface 90
4. Conclusions 92
5. References 93
IV. Overall conclusions 105

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