혈관 스텐트계 적용을 위한 폴리우레탄의 새로운 표면개질에 관한 연구
Novel surface modification of polyurethane for intravascular stent applications
- 주제(키워드) 폴리우레탄 , 스텐트 , PEG , Thiol-ene reaction
- 발행기관 아주대학교 대학원
- 지도교수 박기동
- 발행년도 2008
- 학위수여년월 2008. 8
- 학위명 박사
- 학과 및 전공 일반대학원 분자과학기술학과
- 본문언어 영어
초록/요약
Stent is a medical device, with a cylinder body, used to induce or maintain patency within a human lumen. Based on their indications for use, the stents are devided into vascular and non-vascular stent. This thesis is related with the preparation of the intravascular stent. This thesis includes 4 chapters. In chapter 1, polyurethane (PU) as a polymeric biomaterial was introduced. PU has been widely used in stent coating material. Also, thiol-ene polymerization and strategy for immobilization of bioactive molecules to improve the biocompatibility are summarized. A stent is briefly reviewed and finally the overall objectives of this study are presented. In chapter 2, a new surface modification that facilitates the grafting of poly (ethylene glycol) methacrylate (PEGMA) on the polyurethane (PU) surface was developed using a thiol-ene reaction. The thiolated PU surface for grafting of PEGMA was created by fabricating allylated PU through an allophanate reaction, which was then modified with tetra-thiols to increase the functionality of the PU surface. The amount of the thiol groups increased with increasing irradiation time, and its concentration was almost equilibrated after irradiation for 30 min. The irradiation time-dependent increase in surface wettability of poly(PEGMA)-g-PU was confirmed by water contact angle measurement. These surface characteristics support that poly(PEGMA)-g-PU was prepared successfully using a thiol-ene reaction. It was also confirmed that poly(PEGMA)-g-PU could show reduced fibrinogen adsorption and smooth muscle cell proliferation. This surface modification of PU using a thiol-ene polymerization can be used to improve the blood compatibility of PU-based blood-contacting devices. In chapter 3, an endothelial cell (EC) active PU surface which can promote endothelialization using the peptides and poly (ethylene glycol) (PEG) spacer was prepared and the modified PU surfaces were characterized in vitro. The density of grafted PEG on PU surface was measured by acid-base back titration and the successful immobilization of peptides was confirmed by amino acid analysis, following hydrolysis. Uniform distribution of peptides on the surface was observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). To evaluate EC adhesive property, cell viability test using HUVEC (human umbilical vein endothelial cell) was investigated in vitro and enhanced endothelialization was characterized as a result of introduction of cell adhesive peptides, GRGDS and YIGSR, and PEG spacer. Therefore, GRGDS and YIGSR co-immobilized PU surfaces can be applied to an EC-specific vascular graft with long-term patency by endothelialization. In chapter 4, four different coronary stents were developed. The stents had S shape of main cells and bridges which connected main cells. The number of the main cells in circumference was fixed at nine. Co-Cr alloy was used as the stent material. The finite element method (FEM) was performed to investigate the deformation and stress distribution at both crimped state and expanded state. Radial force, flexibility, foreshortening, recoil of the stents were measured and then were compared to the simulated results. It was possible to confirm the dependency of the characteristics of the stent on the position and shape of the main cell and bridge. The bio-inert PU-PEG surfaces described in chapter 2 and the bio-active PU-RGD/YIGSR surfaces of chapter 3 can be used for the coating materials of the stent platforms described in chapter 4. These surfaces are promising to serve as vascular medical devices due to PEG effects such as anti-thrombosis, anti-bacterial adhesion, anti-calcification.
more초록/요약
스텐트란 인체내 혈관 또는 비혈관 내강이 암이나 종양등에 의하여 폐쇄되거나 협착이 발생했을 겨우, 좁아지거나 막힌 내강의 개통을 목적으로 설치되어지는 의료기의 총칭을 말한다. 스텐트는 적용부위에 따라 혈관용과 비혈관용스텐트로 구분된다. 본 연구는 혈관용 스텐트에 관한 논문으로서 크게 4 장으로 구성되어 있다. 제 1 장에서는 생체재료, 생체적합성, 의료용 폴리우레탄, thiol-ene polymerization 그리고 스텐트에 대하여 요약하였고, 전반적인 연구의 목적이 제시되었다. 제 2 장에서는 스텐트의 코팅재료등 혈액과 접촉하는 의료기기에 적용할 수 있는, 혈액적합성이 개선된 우레탄 표면을 개발하였다. 우레탄에 allyl 기를 도입하고, UV 를 이용하여 thiol-ene polymerization 을 통해 thiol 기를 대량 도입시킨후, poly(ethylene glycol) methacrylate 를 그래프트시켜 표면을 친수화시켰다. 우레탄 표면의 thiol 기의 함량은 UV 조사시간에 비례하여 증가하였고, 조사시간이 약 30 분이 되면 평형상태에 도달함을 확인하는 등 표면분석이 수행되었다. 체외실험에서 혈장단백질의 부착이 감소함을 확인하였고, 토끼대동맥 혈관내피 세포의 증식을 억제하는 등 혈액적합성이 개선되었음을 확인하였다. 제 3 장에서는 혈관내피세포를 유도하는 펩타이드로 알려진 RGD 와 YISGR 를 폴리우레탄 표면에 화학적으로 결합시켜 혈관의 재내피화를 촉진시키고자 하였다. 친수성 고리로서 PEG 를 사용하여 HMDI-PEG-HMDI 를 제조후, 우레탄 표면에 화학결합시켰다. 이후, 말단을 아민으로 치환시킨후, EDC/NHS 를 이용하여 RGD 와 YISER 을 도입하였고, 물리화학적 표면분석이 수행되었다. 체외에서 혈관내피세포의 증식실험 결과 RGD 와 YISER 도입된 우레탄 표면에서 두드러린 재피세포의 증식이 관찰되었다. 또한, 혈장단백질 피브리노겐과 혈소판 부착시험결과, 우레탄 필름에 비해 친수성 고리인 PEG 의 영향으로 단백질과 혈소판의 부착이 감소되었다. 제 4 장에서는 관상동맥용 스텐트 구조물을 개발하였다. S 자 형태의 주셀과 주셀을 연결해주는 연결셀로 이루어진 스텐트를 디자인 했고, 원주방향으로 주셀의 수는 9 개로 고정하였다. 주셀의 모양과 연결셀의 모양을 변화시켜 4 개의 모델을 개발하였다. 유한요소해석을 통해 각 모델별 스텐트가 풍선카테터에 장창되었을 때와, 팽창되었을 경우를 가상하여 변형과 응력분포를 조사하였다. 또한, 코발트-크롬 합금으로 스텐트를 제작하여 팽창력, 유연성, 리코일, 팽창전후의 스텐트 길이변화폭을 측정하였고, 유한요소측정법으로 예측한 값과 비교하였다. 제 2 장의 생체불활성(Bio-inert) 특성을 갖는 PU-PEG 표면과 제 3 장의 생체활성(Bio-active) 특성을 갖는 PU-RGD/YIGSR 표면은 제 4 장에서 개발된 혈관용 스텐트의 코팅재료로 유용하게 사용될 수 있다. 또한, 항혈전성, 항박테리아성, 항석회화 성질을 갖는 PEG 효과를 통해서 심장밸브, 카테터등 다른 혈관용 의료기기로의 적용이 기대된다.
more목차
Chapter1. General Introduction = 1
1. Biomaterials = 2
1.1 Biocompatibility of biomaterials = 2
1.2 Polyurethane (PU) = 6
1.3 Surface modifications of PU for improved biocompatibility = 10
2. Thiol-ene polymerization = 14
3. Immobilization of bioactive molecules = 16
3.1 Heparin = 16
3.2 Cell adhesive peptides (RGD, YIGSR) = 18
4. Stent = 22
4.1 Types of metallic stent = 24
4.2 Stent procedure = 29
4.3 Performance tests of the stent = 30
5. Overall Objectives = 37
6. References = 40
Chapter2. Poly(ethylene glycol) modified PU surfaces via thiol-ene reaction = 51
1. Introduction = 52
2. Materials and methods = 54
2.1 Materials = 54
2.2 Preparation of poly(PEGMA)-grafted PU = 54
2.3 Surface characterization = 56
2.4 In vitro adsorption and RASMC proliferation = 56
3. Results and discussion = 57
4. Summary = 66
5. References = 67
Chapter3. Endothelial cell-specific PU surfaces by immobilizing with GRGDS and YIGSR = 70
1. Introduction = 71
2. Materials and methods = 73
2.1 Materials = 73
2.2 Preparation of aminated PU surfaces = 73
2.3 Surface immobilization of cell adhesive peptides = 74
2.4 Surface characteristics and amino acid analysis = 75
2.5 In vitro cell culture = 76
2.6 Fibrinogen adsorption test = 77
2.7 Platelet adhesion assay = 77
3. Results and discussion = 78
4. Summary = 87
5. References = 88
Chapter4. Coronary Stent Platform = 94
1. Introduction = 95
2. Materials and methods = 97
2.1 Stent design = 97
2.2 Preparation of the stent = 98
2.3 Finite element model = 98
2.4 Performance evaluations = 99
3. Results and discussion = 102
3.1 Stent design = 102
3.2 Stent crimping = 106
3.3 Stent expansion = 112
3.4 Performance evaluations = 118
4. Summary = 123
5. References = 124
국문요약 = 126
