博碩士論文 107827605 詳細資訊




以作者查詢圖書館館藏 以作者查詢臺灣博碩士 以作者查詢全國書目 勘誤回報 、線上人數:19 、訪客IP:3.235.139.152
姓名 吳氏蘭香(Ngo Thi Lan Huong)  查詢紙本館藏   畢業系所 生醫科學與工程學系
論文名稱 開發可生物降解的完全磷酸膽鹼水凝膠
(Development of Biodegradable Complete Phosphorylcholine Hydrogel)
檔案 [Endnote RIS 格式]    [Bibtex 格式]    [相關文章]   [文章引用]   [完整記錄]   [館藏目錄]   至系統瀏覽論文 ( 永不開放)
摘要(中) 水凝膠是一種三維聚合物結構,具有高含水量、柔軟性、柔韌性、與生物相容性等特殊性質,因此水凝膠成為一種有潛力的生醫材料。水凝膠適合應用於藥物傳遞系統、生醫感測器、組織工程支架、生物膜、人工器官、傷口癒合敷料、隱形眼鏡等。[1] 其中,在控制釋放藥物系統及植入式醫療器材的應用中,水凝膠的生物降解能力是一項重要的性質。[3] 因此,我們展示一項新型生物可降解的雙離子交聯劑,藉由合成2-[2-{2-(methacryloyloxy)ethyldimethylammonium}ethyl phosphate] 2-ethyl disulfide (MPCSS),以提供可經由還原而降解的雙硫鍵結。經由結合2-甲基丙烯酰氧基乙基磷酰膽鹼(MPC)及MPCSS交聯劑,以形成完全磷酸膽鹼的雙離子水凝膠,而此水凝膠展現生物可相容及生物可降解的特性。我們深入探討完全磷酸膽鹼的雙離子水凝膠,了解其機械性質、生物相容性及抗汙貼附的能力。此外,我們探討MPCSS交聯劑水凝膠的重量損失,以衡量其可降解的特性。在這項研究中,我們初步探討了磷酸膽鹼水凝膠的注射應用.
摘要(英) Hydrogel, a three-dimensional polymer structure, has been discovered as a good biomaterial with specific properties, such as high water content, softness, flexibility, and biocompatibility. The hydrogels are great candidates for drug delivery systems, biosensors, tissue engineering scaffolds, physiological membranes, artificial organs, wound healing dress, and contact lenses. [1] Moreover, with applications for control drug delivery or implantable medical devices, the biodegradable property is in high demand. Hence, a novel zwitterionic degradable crosslinker, 2-[2-{2-(methacryloyloxy)ethyldimethylammonium}ethyl phosphate] 2-ethyl disulfide (MPCSS) was synthesized to provide a disulfide linkage for degradation via reduction. A full zwitterionic phosphorylcholine (PC) hydrogel, which is phospholipid-inspired, biocompatible and biodegradable, was created by combining zwitterionic monomer 2-Methacryloyloxyethyl phosphorylcholine (MPC) and MPCSS crosslinker. Herein, the mechanical, biocompatible and antifouling properties of the full zwitterionic PC hydrogels were investigated. Besides, the degradation characteristic of MPCSS-crosslinked hydrogel was evaluated through their weight loss. In this research, the injectable application of PC hydrogel is preliminarily explored.
關鍵字(中) ★ 雙離子交聯劑
★ 磷酸膽鹼
★ 水凝膠
★ 可降解
關鍵字(英) ★ Zwitterionic crosslinker
★ phosphorylcholine
★ hydrogel
★ degradable
論文目次 ABSTRACT v
Acknowledgment vii
Table of contents vii
List of figures xi
List of tables xiii
List of Abbreviations xiv
Chapter 1: Literature Review 1
1.1. Overview of hydrogel. 1
1.2. Formation of hydrogels 1
1.3.1 Polymer for hydrogels. 1
1.3.2. Crosslinking of hydrogels 3
1.3. Zwitterionic hydrogel 4
1.4. Biodegradable hydrogel systems 6
1.4.1. Hydrolytically degraded hydrogels 6
1.4.2. Cell-mediated degradation in hydrogel systems 7
1.4.3. Degradable hydrogels based on natural polymers 9
1.4.4. Photodegradable hydrogels 10
1.5. Review of MPC 13
1.5.1. Biological Phosphorylcholine (PC) structure 13
1.5.2. Poly(phosphorylcholine) 14
1.5.3. Applications of 2-methacryloyloxyethyl phosphorylcholine (MPC) 16
Chapter 2: Research Objectives 19
Chapter 3: Materials and Methods 21
3.1. Materials 21
3.2. Methods 22
3.2.1. Synthesis of biodegradable MPCSS crosslinker 22
3.2.1.1. 2-Chloro-1,3,2-dioxaphospholane (CP) 22
3.2.1.2. 2-Chloro-2-oxo-1,3,2-dioxaphospholane (COP) 22
3.2.1.3. 2-[2-2-(Methacryloyloxy)ethyldimethylammonium}ethyl -phosphate]ethyl disulfide (MPCSS) 23
3.2.1.4. 2-(2-oxo-1,3,2-dioxaphospholane-2-yloxy)ethyl disulphide (OOPES) 23
3.2.2. Degradable property of the crosslinker 24
3.2.3 The cytotoxicity of MPCSS crosslinker. 24
3.2.4. MPC/MPCSS hydrogel preparation 24
3.2.5. The swelling ratio and mechanical characterization of the hydrogel 25
3.2.6. Protein fouling test by enzyme-linked immunosorbent assay (ELISA) 25
3.2.7. Degradability of PC hydrogels 26
3.2.8. The cytotoxicity of PC hydrogels 26
3.2.9. Cell adhesion on PC hydrogels 27
3.2.10. The cytotoxicity of degraded PC hydrogels 27
3.2.11. Injectable process of PC hydrogels 28
3.3. Characterization 28
Chapter 4: Results and Discussion 29
4.1. Synthesis MPC crosslinker. 29
4.2. Degradable property of MPCSS crosslinker 32
4.3. Evaluation of the cytotoxicity of MPCSS crosslinker 34
4.4. Complete Phosphorylcholine Hydrogel 35
4.3.1. The swelling ratio of PC Hydrogels 35
4.3.2. Mechanical properties of PC hydrogels 36
4.3.3. Degradability of PC hydrogels 38
4.3.4. Protein absorption on the PC hydrogels 39
4.3.5. Evaluation of in vitro biocompatibility of PC hydrogels 41
4.3.6. Assessment of Cell resistance of PC hydrogels in vitro 42
4.3.7. The cytotoxicity of degraded PC hydrogels 43
4.3.8. Injectable PC hydrogels 44
Chapter 5: Conclusions and Future works 46
BIBLIOGRAPHY 47
參考文獻 1. Caló, E. and V.V. Khutoryanskiy, Biomedical applications of hydrogels: A review of patents and commercial products. European Polymer Journal, 2015. 65: p. 252-267.
2. George, J., et al., Neural tissue engineering with structured hydrogels in CNS models and therapies. Biotechnology advances, 2019.
3. Ahmed, E.M., Hydrogel: Preparation, characterization, and applications: A review. Journal of advanced research, 2015. 6(2): p. 105-121.
4. Catoira, M.C., et al., Overview of natural hydrogels for regenerative medicine applications. Journal of Materials Science: Materials in Medicine, 2019. 30(10): p. 115.
5. Hong, W., et al., A theory of coupled diffusion and large deformation in polymeric gels. Journal of the Mechanics and Physics of Solids, 2008. 56(5): p. 1779-1793.
6. Hoffman, A.S., Hydrogels for biomedical applications. Advanced drug delivery reviews, 2012. 64: p. 18-23.
7. Hoare, T.R. and D.S. Kohane, Hydrogels in drug delivery: Progress and challenges. Polymer, 2008. 49(8): p. 1993-2007.
8. Lee, D., et al., Ocular drug delivery through pHEMA-Hydrogel contact lenses co-loaded with lipophilic vitamins. Scientific Reports, 2016. 6: p. 34194.
9. Parente, M., et al., Bioadhesive hydrogels for cosmetic applications. International journal of cosmetic science, 2015. 37(5): p. 511-518.
10. Perera, M.M. and N. Ayres, Dynamic covalent bonds in self-healing, shape memory, and controllable stiffness hydrogels. Polymer Chemistry, 2020. 11(8): p. 1410-1423.
11. Tsou, Y.-H., et al., Hydrogel as a bioactive material to regulate stem cell fate. Bioactive Materials, 2016. 1(1): p. 39-55.
12. Kim, S. and K.E. Healy, Synthesis and characterization of injectable poly (N-isopropylacrylamide-co-acrylic acid) hydrogels with proteolytically degradable cross-links. Biomacromolecules, 2003. 4(5): p. 1214-1223.
13. Ko, H.-F., C. Sfeir, and P.N. Kumta, Novel synthesis strategies for natural polymer and composite biomaterials as potential scaffolds for tissue engineering. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 2010. 368(1917): p. 1981-1997.
14. Liang, Y., et al., Fabrication and characters of a corneal endothelial cells scaffold based on chitosan. Journal of Materials Science: Materials in Medicine, 2011. 22(1): p. 175-183.
15. Talebian, S., et al., Self‐Healing Hydrogels: The Next Paradigm Shift in Tissue Engineering? Advanced Science, 2019. 6(16): p. 1801664.
16. Lu, D., C. Xiao, and S. Xu, Starch-based completely biodegradable polymer materials. Express polymer letters, 2009. 3(6): p. 366-375.
17. Sadr, N., et al., Enhancing the biological performance of synthetic polymeric materials by decoration with engineered, decellularized extracellular matrix. Biomaterials, 2012. 33(20): p. 5085-5093.
18. Billiet, T., et al., A review of trends and limitations in hydrogel-rapid prototyping for tissue engineering. Biomaterials, 2012. 33(26): p. 6020-6041.
19. Koetting, M.C., et al., pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery. Journal of Controlled Release, 2016. 221: p. 18-25.
20. Yu, X., et al., Triplet–triplet annihilation upconversion from rationally designed polymeric emitters with tunable inter-chromophore distances. Chemical Communications, 2015. 51(3): p. 588-591.
21. Zhu, Z., et al., Au@ Pt nanoparticle encapsulated target‐responsive hydrogel with volumetric bar‐chart chip readout for quantitative point‐of‐care testing. Angewandte Chemie International Edition, 2014. 53(46): p. 12503-12507.
22. Bailon, P. and W. Berthold, Polyethylene glycol-conjugated pharmaceutical proteins. Pharmaceutical Science & Technology Today, 1998. 1(8): p. 352-356.
23. Ronda, L., et al., Ligand reactivity and allosteric regulation of hemoglobin-based oxygen carriers. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, 2008. 1784(10): p. 1365-1377.
24. Hu, W., et al., Advances in crosslinking strategies of biomedical hydrogels. Biomaterials science, 2019. 7(3): p. 843-855.
25. Sung, H.-W., et al., In vitro evaluation of cytotoxicity of a naturally occurring cross-linking reagent for biological tissue fixation. Journal of Biomaterials Science, Polymer Edition, 1999. 10(1): p. 63-78.
26. Lee, J.H., Injectable hydrogels delivering therapeutic agents for disease treatment and tissue engineering. Biomaterials research, 2018. 22(1): p. 1-14.
27. Chung, H.J., Y. Lee, and T.G. Park, Thermo-sensitive and biodegradable hydrogels based on stereocomplexed Pluronic multi-block copolymers for controlled protein delivery. Journal of controlled release, 2008. 127(1): p. 22-30.
28. Xu, J., et al., The role of chemical and physical crosslinking in different deformation stages of hybrid hydrogels. European Polymer Journal, 2018. 100: p. 86-95.
29. Jiang, S.Y. and Z.Q. Cao, Ultralow-Fouling, Functionalizable, and Hydrolyzable Zwitterionic Materials and Their Derivatives for Biological Applications. Advanced Materials, 2010. 22(9): p. 920-932.
30. Beltrán-Osuna, A.n.A., et al., New antifouling silica hydrogel. Langmuir, 2012. 28(25): p. 9700-9706.
31. Dundua, A., S. Franzka, and M. Ulbricht, Improved antifouling properties of polydimethylsiloxane films via formation of polysiloxane/polyzwitterion interpenetrating networks. Macromolecular rapid communications, 2016. 37(24): p. 2030-2036.
32. Hu, G. and T. Emrick, Functional choline phosphate polymers. Journal of the American Chemical Society, 2016. 138(6): p. 1828-1831.
33. Diao, W., et al., Highly stretchable, ionic conductive and self‐recoverable zwitterionic polyelectrolyte‐based hydrogels by introducing multiple supramolecular sacrificial bonds in double network. Journal of Applied Polymer Science, 2019. 136(29): p. 47783.
34. He, H., et al., Simple Thermal Pretreatment Strategy to Tune Mechanical and Antifouling Properties of Zwitterionic Hydrogels. Langmuir, 2018. 35(5): p. 1828-1836.
35. Erathodiyil, N., et al., Zwitterionic polymers and hydrogels for antibiofouling applications in implantable devices. Materials Today, 2020.
36. Hawkins, A.M., et al., Tuning biodegradable hydrogel properties via synthesis procedure. Polymer, 2013. 54(17): p. 4422-4426.
37. Ozcelik, B., Degradable hydrogel systems for biomedical applications, in Biosynthetic Polymers for Medical Applications. 2016, Elsevier. p. 173-188.
38. Hamid, Z.A., et al., Epoxy-amine synthesised hydrogel scaffolds for soft-tissue engineering. Biomaterials, 2010. 31(25): p. 6454-6467.
39. Wachiralarpphaithoon, C., Y. Iwasaki, and K. Akiyoshi, Enzyme-degradable phosphorylcholine porous hydrogels cross-linked with polyphosphoesters for cell matrices. Biomaterials, 2007. 28(6): p. 984-993.
40. West, J.L. and J.A. Hubbell, Polymeric biomaterials with degradation sites for proteases involved in cell migration. Macromolecules, 1999. 32(1): p. 241-244.
41. Almany, L. and D. Seliktar, Biosynthetic hydrogel scaffolds made from fibrinogen and polyethylene glycol for 3D cell cultures. Biomaterials, 2005. 26(15): p. 2467-2477.
42. Ahearne, M., Introduction to cell–hydrogel mechanosensing. Interface focus, 2014. 4(2): p. 20130038.
43. Banerjee, A., K. Chatterjee, and G. Madras, Enzymatic degradation of polymers: a brief review. Materials Science and Technology, 2014. 30(5): p. 567-573.
44. Zhu, J. and R.E. Marchant, Design properties of hydrogel tissue-engineering scaffolds. Expert review of medical devices, 2011. 8(5): p. 607-626.
45. Nicodemus, G.D. and S.J. Bryant, Cell encapsulation in biodegradable hydrogels for tissue engineering applications. Tissue Engineering Part B: Reviews, 2008. 14(2): p. 149-165.
46. Liu, J., et al., Fast-degradable microbeads encapsulating human umbilical cord stem cells in alginate for muscle tissue engineering. Tissue Engineering Part A, 2012. 18(21-22): p. 2303-2314.
47. Giraud, M.N., et al., Hydrogel‐based engineered skeletal muscle grafts normalize heart function early after myocardial infarction. Artificial organs, 2008. 32(9): p. 692-700.
48. Boontheekul, T., H.-J. Kong, and D.J. Mooney, Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution. Biomaterials, 2005. 26(15): p. 2455-2465.
49. Chatterjee, S. and P.C.-l. Hui, Stimuli-Responsive Hydrogels: An Interdisciplinary Overview, in Hydrogels-Smart Materials for Biomedical Applications. 2018, IntechOpen.
50. Kloxin, A.M., et al., Tunable hydrogels for external manipulation of cellular microenvironments through controlled photodegradation. Advanced materials, 2010. 22(1): p. 61-66.
51. Tibbitt, M.W., et al., Controlled two-photon photodegradation of PEG hydrogels to study and manipulate subcellular interactions on soft materials. Soft matter, 2010. 6(20): p. 5100-5108.
52. Brown, T.E., I.A. Marozas, and K.S. Anseth, Amplified Photodegradation of Cell‐Laden Hydrogels via an Addition–Fragmentation Chain Transfer Reaction. Advanced Materials, 2017. 29(11): p. 1605001.
53. Kirschner, C.M., et al., Clickable, photodegradable hydrogels to dynamically modulate valvular interstitial cell phenotype. Advanced healthcare materials, 2014. 3(5): p. 649-657.
54. GRIFFIN, D.R., et al., Synthesis of Photodegradable Macromers for Conjugation and Release of Bioactive Molecules. Biomacromolecules, 2013. 14(4): p. 1199-1207.
55. Ooi, H., et al., Hydrogels that listen to cells: a review of cell-responsive strategies in biomaterial design for tissue regeneration. Materials Horizons, 2017. 4(6): p. 1020-1040.
56. Houk, J. and G.M. Whitesides, Structure-reactivity relations for thiol-disulfide interchange. Journal of the American Chemical Society, 1987. 109(22): p. 6825-6836.
57. Lees, W.J. and G.M. Whitesides, Equilibrium constants for thiol-disulfide interchange reactions: a coherent, corrected set. The Journal of organic chemistry, 1993. 58(3): p. 642-647.
58. Kar, M., et al., Poly (ethylene glycol) hydrogels with cell cleavable groups for autonomous cell delivery. Biomaterials, 2016. 77: p. 186-197.
59. Singer, S. and G.L. Nicolson, The fluid mosaic model of the structure of cell membranes. Membranes and Viruses in Immunopathology; Day, SB, Good, RA, Eds, 1972: p. 7-47.
60. Ishihara, K., Phospholipid polymers. Encyclopedia of Polymer Science and Technology. 2012, New York (NY): John Wiley & Sons, Inc.
61. Zwaal, R., P. Comfurius, and L. Van Deenen, Membrane asymmetry and blood coagulation. 1977.
62. Daemen, F., et al., Activity of Synthetic Phospholipid in Blood Coagulation. Thrombosis et diathesis haemorrhagica, 1965. 13: p. 194.
63. Jiang, S. and Z. Cao, Ultralow‐fouling, functionalizable, and hydrolyzable zwitterionic materials and their derivatives for biological applications. Advanced Materials, 2010. 22(9): p. 920-932.
64. Zwaal, R. and H.C. Hemker, Blood cell membranes and haemostasis. Pathophysiology of Haemostasis and Thrombosis, 1982. 11(1): p. 12-39.
65. Ishihara, K., et al., Modification of polysulfone with phospholipid polymer for improvement of the blood compatibility. Part 2. Protein adsorption and platelet adhesion. Biomaterials, 1999. 20(17): p. 1553-1559.
66. Kojima, M., et al., Interaction between phospholipids and biocompatible polymers containing a phosphorylcholine moiety. Biomaterials, 1991. 12(2): p. 121-124.
67. Wu, L., et al., Synthesis of a zwitterionic silane and its application in the surface modification of silicon-based material surfaces for improved hemocompatibility. ACS applied materials & interfaces, 2010. 2(10): p. 2781-2788.
68. Ishihara, K., T. Ueda, and N. Nakabayashi, Preparation of phospholipid polymers and their properties as polymer hydrogel membranes. Polym J, 1990. 22(5): p. 355-360.
69. Kadoma, Y., et al., Synthesis and hemolysis test of polymer containing phosphorylcholine groups. Kobunshi Ronbunshu, 1978. 35(7): p. 423-427.
70. Iwasaki, Y., et al., Behavior of blood cells in contact with water‐soluble phospholipid polymer. Journal of biomedical materials research, 1999. 46(3): p. 360-367.
71. Nakaya, T., H. Toyoda, and M. Imoto, Polymeric Phospholipid Analogues XIII. Synthesis and Properties of Vinyl Polymers Containing Phosphatidyl Choline Groups. Polymer journal, 1986. 18(11): p. 881-885.
72. Lewis, A.L. and A.W. Lloyd, Biomedical Applications of Biomimetic Polymers: The Phosphorylcholine‐Containing Polymers. Biomimetic, Bioresponsive, and Bioactive Materials: An Introduction to Integrating Materials with Tissues, 2012: p. 95-140.
73. Tsuruta, T., Biomedical applications of polymeric materials. 1993: CRC.
74. Ishihara, K., Revolutionary advances in 2‐methacryloyloxyethyl phosphorylcholine polymers as biomaterials. Journal of Biomedical Materials Research Part A, 2019. 107(5): p. 933-943.
75. Ishiyama, N., et al., Reduction of Peritendinous adhesions by hydrogel containing biocompatible phospholipid polymer MPC for tendon repair. JBJS, 2011. 93(2): p. 142-149.
76. Islam, M.M., et al., Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications. Acta biomaterialia, 2015. 12: p. 70-80.
77. Liu, X., J.M. Holzwarth, and P.X. Ma, Functionalized synthetic biodegradable polymer scaffolds for tissue engineering. Macromolecular bioscience, 2012. 12(7): p. 911-919.
78. Freed, L.E., et al., Biodegradable polymer scaffolds for tissue engineering. Bio/technology, 1994. 12(7): p. 689-693.
79. Hutmacher, D.W., Scaffold design and fabrication technologies for engineering tissues—state of the art and future perspectives. Journal of Biomaterials Science, Polymer Edition, 2001. 12(1): p. 107-124.
80. Becker, G. and F.R. Wurm, Breathing air as oxidant: Optimization of 2-chloro-2-oxo-1, 3, 2-dioxaphospholane synthesis as a precursor for phosphoryl choline derivatives and cyclic phosphate monomers. Tetrahedron, 2017. 73(25): p. 3536-3540.
81. Patai, S. and Z. Rappoport, The Chemistry of The Thiol Group. Handbook of Chemistry and Pysics, 1972.
82. Sorensen, H., et al., Chromatography and capillary electrophoresis in food analysis. 2007: Royal Society of Chemistry.
83. Yoshii, E., Cytotoxic effects of acrylates and methacrylates: relationships of monomer structures and cytotoxicity. Journal of Biomedical Materials Research: An Official Journal of The Society for Biomaterials and The Japanese Society for Biomaterials, 1997. 37(4): p. 517-524.
84. Zhou, Y., et al., A super-stretchable, self-healing and injectable supramolecular hydrogel constructed by a host–guest crosslinker. Biomaterials Science, 2020.
85. Yang, J., et al., Simple one pot preparation of chemical hydrogels from cellulose dissolved in cold LiOH/Urea. Polymers, 2020. 12(2): p. 373.
86. Kowalski, G., et al., Synthesis and effect of structure on swelling properties of hydrogels based on high methylated pectin and acrylic polymers. Polymers, 2019. 11(1): p. 114.
87. Kryscio, D.R. and N.A. Peppas, Surface imprinted thin polymer film systems with selective recognition for bovine serum albumin. Analytica chimica acta, 2012. 718: p. 109-115.
88. Ishihara, K., et al., Why do phospholipid polymers reduce protein adsorption? Journal of Biomedical Materials Research: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and the Australian Society for Biomaterials, 1998. 39(2): p. 323-330.
89. Kuo, Z.K., et al., Hydrophilic films: How hydrophilicity affects blood compatibility and cellular compatibility. Advances in Polymer Technology, 2018. 37(6): p. 1635-1642.
90. Kwon, D.H., et al., Glutathione induced immune-stimulatory activity by promoting M1-like macrophages polarization via potential ROS scavenging capacity. Antioxidants, 2019. 8(9): p. 413.
91. Wang, Y., et al., PHEMA hydrogel films crosslinked with dynamic disulfide bonds: synthesis, swelling-induced mechanical instability and self-healing. Polymer Chemistry, 2019. 10(35): p. 4844-4851.
指導教授 李宇翔 黃俊仁(Lee,Yu-Hsiang Huang,Chun-Jen) 審核日期 2021-1-18
推文 facebook   plurk   twitter   funp   google   live   udn   HD   myshare   reddit   netvibes   friend   youpush   delicious   baidu   
網路書籤 Google bookmarks   del.icio.us   hemidemi   myshare   

若有論文相關問題,請聯絡國立中央大學圖書館推廣服務組 TEL:(03)422-7151轉57407,或E-mail聯絡  - 隱私權政策聲明