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Multi-functionalization of Biomaterials Surfaces through Tyrosinase-mediated Reaction for Cardiovascular Therapy

초록/요약

Nowadays, the important role of implantable cardiovascular devices in the treatment of cardiovascular disease is undeniable. The functions of the implantable cardiovascular devices are not only about replacing or supporting the damaged part of the heart, but they also improve the heart functions. However, the implantation of the foreign biomaterials into human body always lead to series of damage and provoke a series of host responses at the implant-tissue interface such as infection, thrombus formation, and inflammation. These responses can cause the failure of implants, increased medical costs, and even life-threatening effect. Regulating the implant-associated tissue responses is one of the biggest challenges for the clinical application of the implantable devices. Therefore, the development of simple, safe and highly effective surface modifications to eliminate these responses is required. The objectives of this dissertation are to develop the multifunctional surfaces with enhanced anti-infection, anti-thrombosis, and anti-inflammation to improve the clinical performance of blood contacting devices, especially in treatment of CDVs, through tyrosinase-catalysed reaction. In chapter 2, graphene oxide (GO-)-immobilized titanium dioxide (TiO₂) was developed to efficiently carry and release antimicrobial drugs. Firstly, phenol-containing GO (GOTA) was immobilized onto the surfaces of TiO₂ through tyrosinase (Tyr)-catalyzed reaction (GOTA/TiO₂). Doxycycline hyclate (Dox) was then loaded onto GOTA/TiO₂ via non-covalent interactions between GO and Dox (Dox/GOTA/TiO₂), including electrostatic interaction, π-π stacking, hydrophobic interaction, and hydrogen bonds. The amount of loaded drug was able to be controlled, reaching a maximum of 36 µg/cm2. In vitro experiments revealed that the sustained release of Dox from the TiO₂ surfaces continued for over 30 days. Dox/GOTA/TiO₂ exhibited superior antibacterial activity against both gram-negative Escherichia coli and gram-positive Staphylococcus aureus bacteria, without affecting the viability of human dermal fibroblasts. The obtained results indicated that GO-immobilized TiO₂ is an effective carrier for antimicrobial drug delivery to reduce implant-associated infection through the synergistic antimicrobial effect of GO and the prescribed drugs. Chapter 3 described the development of the multifunctional surface with enhanced hemocompatibility and anti-inflammatory effects by combining the anticoagulant activity of heparin with the vasodilatory and anti-inflammatory properties of nitric oxide (NO). The co-immobilization of these two key molecules with distinct therapeutic effects is achieved by simultaneous conjugation of heparin (HT) and copper nanoparticles (Cu NPs), an NO-generating catalyst, via a simple tyrosinase (Tyr)-mediated reaction. The resulting immobilized surface showed long-term, stable and adjustable NO release. Importantly, the makeup of the material endows the surface with the ability to promote endothelialization and to inhibit coagulation, platelet activation, and smooth muscle cell proliferation. In addition, the HT/Cu NP co-immobilized surface-enhanced macrophage polarization towards the M2 phenotype in vitro, which can reduce the inflammatory response and improve the adaptation of implants in vivo. This study demonstrated a simple but efficient method of developing a multifunctional surface for blood-contacting devices. The obtained results demonstrated that tyrosinase-catalyzed reaction is an effective and facile method to functionalize the surface of various implantable devices. Besides, the synergistic effect of bioactive agents can significantly improve the achievement of the implantable medical devices

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목차

Chapter 1. General introduction 1
1. Cardiovascular disease (CVDs) 2
2. Implantable medical devices (IMDs) for treatment of CVDs 3
3. Interaction between cardiovascular IMDs and host 9
3.1. Cardiovascular IMDs - related infection 10
3.1.1. Formation of biofilm on the cardiovascular IMDs 10
3.1.2. Strategies for treatment and prevention of IMDs - related infection 11
3.2. Cardiovascular IMD - related thrombosis 14
3.2.1. Thrombosis on the cardiovascular IMDs 14
3.2.2. Strategies for treatment and prevention of IMD - related thrombosis 15
3.3. Cardiovascular IMD - related inflammation 18
3.3.1. Inflammation due to the implantation of cardiovascular IMDs 18
3.3.2. Strategies for treatment and prevention of IMD - related inflammation 19
4. Current surface modification strategies for cardiovascular IMDs 20
4.1. Overview of surface modification techniques 20
4.1.1. Physical modifications 20
4.1.2. Chemical modifications 24
4.2. Mussel-inspired surface modification techniques 27
4.2.1. Introduction about mussel-inspired chemistry 27
4.2.2. Tyrosinase-catalyzed surface modification 33
5. Overall objective 36
6. References 38
Chapter 2. Graphene oxide immobilized surfaces with sustained antibiotic release for infectious treatment in implantable cardiovascular devices 46
1. Introduction and objective 47
2. Experimental section 51
2.1. Materials 51
2.2. Synthesis and characterization of graphene oxide – tyramine (GOTA) 51
2.3. Immobilization of GOTA and loading of Dox onto TiO2 substrates 52
2.4. Characterization of immobilized substrates 53
2.5. Drug loading capacity and in vitro release kinetics of Dox 53
2.6. In vitro antimicrobial assays 54
2.7. In vitro cytotoxicity tests 55
2.8. Statistical analysis 56
3. Results and discussions 56
3.1. Synthesis and characterization of GOTA 56
3.2. Characterization of GOTA- and dox-immobilized TiO2 surfaces 58
3.3. Dox loading capacity and release kinetics from the immobilized surfaces 60
3.4. In vitro antibacterial activity of the immobilized surfaces 62
3.5. In vitro cytotoxicity of the immobilized surfaces 65
4. Conclusions 66
5. References 67
Chapter 3. Heparinized surface releasing nitric oxide sustainedly for enhanced anti-thrombogenesis and anti-inflammation of cardiovascular devices 71
1. Introduction and objective 72
2. Experimental section 77
2.1. Materials 77
2.2. Synthesis and characterization of heparin-tyramine (HT) polymer 78
2.3. Co-immobilization of HT and Cu NPs onto surface 79
2.4. Characterization of HT/Cu immobilized substrates 80
2.5. Measurement of Cu ions release from HT/Cu surfaces 81
2.6. Measurement of catalysis release of NO from HT/Cu surfaces 81
2.7. In vitro antiplatelet evaluation 82
2.8. In vitro anticoagulant evaluation 84
2.9. In vitro endothelial cells (HUVECs) proliferation and migration assay 84
2.10. In vitro smooth muscle cells (HUASMC) proliferation and cGMP synthesis assay 86
2.11. In vitro macrophage polarization assay 86
2.12. Statistical analysis 87
3. Results and discussions 88
3.1. Characterization of heparin-tyramine (HT) polymer 88
3.2. Characterization of HT/Cu immobilized surfaces 88
3.3. Controlled release of Cu ions for NO generation from HT/Cu surfaces 92
3.4. In vitro antiplatelet properties of HT/Cu surfaces 94
3.5. In vitro anticoagulant properties of HT/Cu surface 95
3.6. In vitro adhesion, proliferation and migration of HUVECs 97
3.7. In vitro adhesion, proliferation and cGMP synthesis of HUASMCs 100
3.8. In vitro macrophage polarization toward M2 phenotype 101
4. Conclusions 104
5. References 105
Chapter 4. Overall conclusions 108

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