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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林?輝(Feng-Huei Lin) | |
| dc.contributor.author | Yu-Chun Chen | en |
| dc.contributor.author | 陳郁君 | zh_TW |
| dc.date.accessioned | 2021-06-16T16:20:43Z | - |
| dc.date.available | 2018-03-06 | |
| dc.date.copyright | 2013-03-06 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-01-30 | |
| dc.identifier.citation | [1] Twomey LT, Taylor JR. Age changes in lumbar vertebrae and intervertebral discs. Clin Orthop 1987;224:97-104.
[2] Raj PP. Intervertebral disc: anatomy-physiology-pathophysiology-treatment. Pain Pract 2008;8:18-44. [3] Urban JPG, Roberts S, Ralphs JR. The Nucleus of the intervertebral disc from development to degeneration. American Zoologist 2000;40:53-061. [4] Walmsley R. The development and growth of the intervertebral disc. Edinburgh Med J 1953;60:341-64. [5] Roberts S. Disc morphology in health and disease. Biochem Soc Trans 2002;30:864-9. [6] Bogduk N. Clinical anatomy of the lumbar spine and sacrum: London: Elsevier Churchill Livingstone; 2005; p19-20. [7] Maldonado BA, Oegema TRJ. Initial characterization of the metabolism of intervertebral disc cells encapsulated in microspheres. J Orthop Res 1992;10:677-90. [8] Hunter CJ, Matyas JR, Duncan NA. The notochordal cell in the nucleus pulposus: a review in the context of tissue engineering. Tissue Eng 2003;9:667-77. [9] Maroudas A, Stockwell RA, Nachemson A, Urban J. Factors involved in the nutrition of the human lumbar intervertebral disc: cellularity and diffusion of glucose in vitro. J Anat 1975;120:113-30. [10] Lee CR, Sakai D, Nakai T, Toyama K, Mochida J, Alini M, et al. A phenotypic comparison of intervertebral disc and articular cartilage cells in the rat. Eur Spine J 2007;16:2174-85. [11] Risbud MV, Guttapalli A, Stokes DG, Hawkins D, Danielson KG, Schaer TP, et al. Nucleus pulposus cells express HIF-1alpha under normoxic culture conditions: a metabolic adaptation to the intervertebral disc microenvironment. Journal of cellular biochemistry 2006;98:152-9. [12] Fujita N, Miyamoto T, Imai J, Hosogane N, Suzuki T, Yagi M, et al. CD24 is expressed specifically in the nucleus pulposus of intervertebral discs. Biochem Biophys Res Commun 2005;338:1890-6. [13] Sztrolovics R, Grover J, Cs-Szabo G, Shi SL, Zhang Y, Mort JS, et al. The characterization of versican and its message in human articular cartilage and intervertebral disc. J Orthop Res 2002;20:257-66. [14] http://www.ilo.org/safework_bookshelf/english?content&nd=857170059. [15] http://www.ilo.org/safework_bookshelf/english?content&nd=857170059. [16] Rodkn L. Chemistry and Molecular Biology of the Intercellular Matrix: In Balazq, E. A. (ed.), London and New York, Academic Press; 1970; p. 797. [17] White A, Handler P, Smith EL. Principles of Biochemistry, 4th edn: New York: McGraw-Hiss; 1968:871-886. [18] Heinegård D, Sommarin Y. Proteoglycans: An overview. In: Leon WC, editor. Methods in Enzymology: Academic Press; 1987. p. 305-19. [19] Yang BL, Yang BB, Erwin M, Ang LC, Finkelstein J, Yee AAJ. Versican G3 domain enhances cellular adhesion and proliferation of bovine intervertebral disc cells cultured in vitro. Life Sciences 2003;73:3399-413. [20] Iozzo RV. The biology of the small leucine-rich proteoglycans. Functional network of interactive proteins. 1999;27:18843-6. [21] Wight TN HD, Hascall VC. Cel1 Biology of Extracellular Matrix. Second Edition: In Hay ED (ed), New York: Plenum Press; 1991, p 45-78. [22] Schonherr E, Witsch-Prehm P, Harrach B, Robenek H, Rauterberg J, Kresse H. Interaction of biglycan with type I collagen. J Biol Chem 1995;270:2776-83. [23] Reinboth B, Hanssen E, Cleary EG, Gibson MA. Molecular interactions of biglycan and decorin with elastic fiber components: biglycan forms a ternary complex with tropoelastin and microfibril-associated glycoprotein 1. J Biol Chem 2002;277:3950-7. [24] Chen XD, Allen MR, Bloomfield S, Xu T, Young M. Biglycan-deficient mice have delayed osteogenesis after marrow ablation. Calcif Tissue Int 2003;72:577-82. [25] Hildebrand A, Romaris M, Rasmussen LM, Heinegard D, Twardzik DR, Border WA, et al. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J 1994;302:527-34. [26] Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 1990;346:281-4. [27] De Luca A, Santra M, Baldi A, Giordano A, Iozzo RV. Decorin-induced growth suppression is associated with up-regulation of p21, an inhibitor of cyclin-dependent kinases. J Biol Chem 1996;271:18961-5. [28] Merle B, Durussel L, Delmas PD, Clezardin P. Decorin inhibits cell migration through a process requiring its glycosaminoglycan side chain. J Cell Biochem 1999;75:538-46. [29] Cs-Szabo G, Ragasa-San Juan D, Turumella V, Masuda K, Thonar EJ, An HS. Changes in mRNA and protein levels of proteoglycans of the anulus fibrosus and nucleus pulposus during intervertebral disc degeneration. Spine 2002;27:2212-9. [30] Sztrolovics R, Alini M, Mort JS, Roughley PJ. Age-related changes in fibromodulin and lumican in human intervertebral discs. Spine 1999;24:1765-71. [31] Melrose J, Ghosh P, Taylor TK. A comparative analysis of the differential spatial and temporal distributions of the large (aggrecan, versican) and small (decorin, biglycan, fibromodulin) proteoglycans of the intervertebral disc. J Anat 2001;198:3-15. [32] Roughley PJ. Biology of intervertebral disc aging and degeneration: involvement of the extracellular matrix. Spine 2004;29:2691-9. [33] Aigner T, Gresk-otter KR, Fairbank JC, J.C. F, K. vdM, Urban JP. Variation with age in the pattern of type X collagen expression in normal and scoliotic human intervertebral discs. Calcif Tissue Int 1998;63:263-8. [34] ROBERTS S, MENAGE J, DUANCE V, WOTTON S, AYAD S. 1991 Volvo Award in Basic Sciences: Collagen Types Around the Cells of the Intervertebral Disc and Cartilage End Plate: An Immunolocalization Study. Spine 1991;16:1030-8. [35] Oegema TR, Jr. Biochemistry of the intervertebral disc. Clin Sports Med 1993;13:419-39. [36] Allan JA, Docherty AJ, Barker PJ, Huskisson NS, Reynolds JJ, Murphy G. Binding of gelatinases A and B to type-I collagen and other matrix components. Biochem J 1995;309:299-306. [37] Aimes RT, Quigley JP. Matrix metalloproteinase-2 is an interstitial collagenase: inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4 and 1/4 length fragments. J Biol Chem 1995;270:5872-76. [38] Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, et al. Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 2001;28:261-5. [39] Suzuki K, Enghild JJ, Morodomi T, Salvesen G, Nagase H. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). Biochemistry 1990;29:10261-70. [40] Bressler HB, Keyes WJ, Rochon PA, Badley E. The prevalence of low back pain in the elderly. A systematic review of the literature. Spine 1999;24:1813-9. [41] Andersson GB. Epidemiological features of chronic low-back pain. Lancet 1999;354:581-5. [42] Luoma K, Riihimaki H, Luukkonen R, Raininko R, Viikari-Juntura E, Lamminen A. Low back pain in relation to lumbar disc degeneration. Spine 2000;25:487-92. [43] Maniadakis N, Gray A. The economic burden of back pain in the UK. Pain 2000;84:95-103. [44] Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. The Spine Journal 2008;8:8-20. [45] Martin BI, Deyo RA, Mirza SK, Turner JA, Comstock BA, Hollingworth W, et al. Expenditures and health status among adults with back and neck problems. J Am Med Assoc 2008;299:656-64. [46] Lyons G, Eisenstein SM, Sweet MBE. Biochemical changes in intervertebral disc degeneration. Biochim Biophys Acta 1981;673:443-53. [47] Johnson WE, Caterson B, Eisenstein SM, Hynds DL, Snow DM, Roberts S. Human intervertebral disc aggrecan inhibits nerve growth in vitro. Arthritis and rheumatism 2002;46:2658-64. [48] Bushel G, Ghosh P, Taylor TFK, Akeson WH. Proteoglycan Chemistry of the Intervertebral Disks. Clinical orthopaedics and related research 1977;129:115-23. [49] Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander AP, Poole RA, et al. The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest 1996;98:996-1003. [50] Lotz JC, Haughton V, Boden SD, An HS, Kang JD, Masuda K, et al. New Treatments and Imaging Strategies in Degenerative Disease of the Intervertebral Disks. Radiology 2012;264:6-19. [51] Johnson WE, Eisenstein SM, Roberts S. Cell cluster formation in degenerate lumbar intervertebral discs is associated with increased disc cell proliferation. Connet Tissue Res 2001;42:197-207. [52] Trout JJ, Buckwalter JA, Moore KC. Ultrastructure of the human intervertebral disc: II. Cells of the nucleus pulposus. Anat Rec 1982;204:307-14. [53] Gruber HE, Hanley EN, Jr. Analysis of aging and degeneration of the human intervertebral disc. Comparison of surgical specimens with normal controls. Spine 1998;23:751-7. [54] http://www.chirogeek.com/000_DDD_Page-1_Aging.htm. [55] Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine 2001;26:1873-8. [56] Qb B, Yuan HA. Prosthetic disc replacement: the future? Clinical Orthopedics and Related Research 2002;394:139-45. [57] Tibrewal SB, Pearcy MJ. Lumbar intervertebral disc heights in normal subjects and patients with disc herniation. Spine 1985;10:452-4. [58] Ray CD. Lumbar interbody threaded prosthesesprostheses:flexible, for an artif icial disc and rigid, for a fusion. In: Brock M, Mayer HM, Weigel K, eds. The art ificial disc. Berlin: Springer-Verlag; 1991:53-67. [59] Allen MJ, Schoonmaker JE, Bauer TW, Williams PF, Higham PA, Yuan HA. Preclinical evaluation of a poly (vinyl alcohol) hydrogel implant as a replacement for the nucleus pulposus. Spine 2004;29:515-23. [60] Di Martino A, Vaccaro AR, Lee JY, Denaro V, Lim MR. Nucleus pulposus replacement: basic science and indications for clinical use. Spine 2005;30:S16-22. [61] Ray CD. The PDN prosthetic disc-nucleus device. Eur Spine J 2002;11:S137-42. [62] Ahrens M, Tsantrizos A, Donkersloot P, Martens F, Lauweryns P, Le Huec JC, et al. Nucleus replacement with the DASCOR disc arthroplasty device: interim two-year efficacy and safety results from two prospective, non-randomized multicenter European studies. Spine 2009;34:1376-84. [63] Yoon ST, Patel NM. Molecular therapy of the intervertebral disc. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 2006;15 Suppl 3:S379-88. [64] Kandel R, Roberts S, Urban JP. Tissue engineering and the intervertebral disc: the challenges. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 2008;17 Suppl 4:480-91. [65] Roughley P, Hoemann C, DesRosiers E, Mwale F, Antoniou J, Alini M. The potential of chitosan-based gels containing intervertebral disc cells for nucleus pulposus supplementation. Biomaterials 2006;27:388-96. [66] Peroglio M, Grad S, Mortisen D, Sprecher CM, Illien-Junger S, Alini M. Injectable thermoreversible hyaluronan-based hydrogels for nucleus pulposus cell encapsulation. Eur Spine J 2012;21:839-49. [67] Sun J, Zheng Q, Wu Y, Liu Y, Guo X, Wu W. Culture of nucleus pulposus cells from intervertebral disc on self-assembling KLD-12 peptide hydrogel scaffold. Materials Science and Engineering: C 2010;30:975-80. [68] Reza AT, Nicoll SB. Characterization of novel photocrosslinked carboxymethylcellulose hydrogels for encapsulation of nucleus pulposus cells. Acta biomaterialia 2010;6:179-86. [69] Halloran DO, Grad S, Stoddart M, Dockery P, Alini M, Pandit AS. An injectable cross-linked scaffold for nucleus pulposus regeneration. Biomaterials 2008;29:438-47. [70] Fraser J, Laurent T, Laurent U. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 1997;242:27-33. [71] http://www.glycoforum.gr.jp/index.html. [72] Inkinen RI, Lammi MJ, Agren U, Tammi R, Puustjarvi K, Tammi MI. Hyaluronan distribution in the human and canine intervertebral disc and cartilage endplate. Histochem J 1999;31:579-87. [73] Slevin M, Krupinski J, Kumar S, Gaffney J. Angiogenic oligosaccharides of hyaluronan induce protein tyrosine kinase activity in endothelial cells and activate a cytoplasmic signal transduction pathway resulting in proliferation. Laboratory investigation; a journal of technical methods and pathology 1998;78:987-1003. [74] Campo GM, Avenoso A, Campo S, D'Ascola A, Nastasi G, Calatroni A. Small hyaluronan oligosaccharides induce inflammation by engaging both toll-like-4 and CD44 receptors in human chondrocytes. Biochemical pharmacology 2010;80:480-90. [75] Alaniz L, Garcia MG, Gallo-Rodriguez C, Agusti R, Sterin-Speziale N, Hajos SE, et al. Hyaluronan oligosaccharides induce cell death through PI3-K/Akt pathway independently of NF-kappaB transcription factor. Glycobiology 2006;16:359-67. [76] Goueffic Y, Guilluy C, Guerin P, Patra P, Pacaud P, Loirand G. Hyaluronan induces vascular smooth muscle cell migration through RHAMM-mediated PI3K-dependent Rac activation. Cardiovascular research 2006;72:339-48. [77] Chen WY, Abatangelo G. Functions of hyaluronan in wound repair. Wound Repair Regen 1999;7:79-89. [78] Day AJ, de la Motte CA. Hyaluronan cross-linking: a protective mechanism in inflammation? Trends Immunol 2005;26:637-43. [79] Delmage JM, Powars DR, Jaynes PK, Allerton SE. The selective suppression of immunogenicity by hyaluronic acid. Ann Clin Lab Sci 1986:303-10. [80] Yang SH, Chen PQ, Chen YF, Lin FH. Gelatin/chondroitin-6-sulfate copolymer scaffold for culturing human nucleus pulposus cells in vitro with production of extracellular matrix. J Biomed Mater Res B Appl Biomater 2005;74:488-94. [81] Kogan G, Soltes L, Stern R, Gemeiner P. Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications. Biotechnology letters 2007;29:17-25. [82] http://www.lsbu.ac.uk/water/hygel.html. [83] Balakrishnan B, Mohanty M, Umashankar PR, Jayakrishnan A. Evaluation of an in situ forming hydrogel wound dressing based on oxidized alginate and gelatin. Biomaterials 2005;26:6335-42. [84] Boedtker H, Doty P. A study of gelatin molecules, aggregates and gels. J Phys Chem Rec 1954;58:968-83. [85] Kwang YT, Lee MW. Collagen coupled with hyaluronic: synthesis and soft tissue filler application. BME 2010;22:401-7. [86] http://masterorganicchemistry.com/2011/10/21/reagent-friday-sodium-periodate/. [87] Kristiansen KA, Potthast A, Christensen BE. Periodate oxidation of polysaccharides for modification of chemical and physical properties. Carbohydrate research 2010;345:1264-71. [88] Anderson DG, Tannoury C. Molecular pathogenic factors in symptomatic disc degeneration. Spine J 2005;5:260S-6S. [89] Larson JWr, Levicoff EA, Gilbertson LG, Kang JD. Biologic modification of animal models of intervertebral disc degeneration. J Bone Joint Surg Am 2006;88 Suppl 2:83-7. [90] Thompson JP, Oegema TR, Jr., Bradford DS. Stimulation of mature canine intervertebral disc by growth factors. Spine 1991;16:253-60. [91] Bulpitt P, Aeschlimann D. New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J Biomed Mater Res 1999;47:152-69. [92] Organization IS. Biological evaluation of medical devices. Part 5. Test for cytotoxicity: in vitro methods. . ISO 10993-5 1992. [93] Wang JY, Baer AE, Kraus VB, Setton LA. Intervertebral disc cells exhibit differences in gene expression in alginate and monolayer culture. Spine 2001;26:1747-51. [94] Iatridis JC, Weidenbaum M, Setton LA, Mow VC. Is the nucleus pulposus a solid or a fluid? Mechanical behaviors of the nucleus pulposus of the human intervertebral disc. Spine 1996;21:1174-84. [95] Chen KS, Ku YA, Lin HR, Yan TR, Sheu DC, Chen TM, et al. Preparation and characterization of pH sensitive poly(N-vinyl-2-pyrrolidone/itaconic acid) copolymer hydrogels. Mater Chem Phys 2005;91:484-9. [96] Horner HA, Roberts S, Bielby RC, Menage J, Evans H, Urban JP. Cells from different regions of the intervertebral disc: effect of culture system on matrix expression and cell phenotype. Spine 2002;27:1018-28. [97] Kluba T, Niemeyer T, Gaissmaier C, Grunder T. Human anulus fibrosis and nucleus pulposus cells of the intervertebral disc: effect of degeneration and culture system on cell phenotype. Spine 2005;30:2743-8. [98] Mwale F, Iordanova M, Demers CN, Steffen T, Roughley P, Antoniou J. Biological evaluation of chitosan salts cross-linked to genipin as a cell scaffold for disk tissue engineering. Tissue Eng 2005;11:130-40. [99] Alini M, Li W, Markovic P, Aeb M, Spiro RC, Roughley PJ. The potential and limitations of a cell-seeded collagen/hyaluronan scaffold to engineer an intervertebral disc-like matrix. Spine 2003;28:446-54. [100] Rong Y, Sugumaran G, Silbert JE, Spector M. Proteoglycans synthesized by canine intervertebral disc cells grown in a type I collagen-glycosaminoglycan matrix. Tissue Eng 2002;8:1037-47. [101] De Smedt SC, Lauwers A, Demeester J, Van Steenbergen MJ, Hennink WE, Roefs SPFM. Characterization of the Network Structure of Dextran Glycidyl Methacrylate Hydrogels by Studying the Rheological and Swelling Behavior. Macromolecules 1995;28:5082-8. [102] Vervoort L, Vinckier I, Moldenaers P, Van den Mooter G, Augustijns P, Kinget R. Inulin hydrogels as carriers for colonic drug targeting. Rheological characterization of the hydrogel formation and the hydrogel network. J Pharm Sci 1999;88:209-14. [103] Bodine AJ, Ashany D, Hayes WC, White AA. Viscoelastic shear modulus of the human intervertebral disc. Transactions of the 28th annual meeting of the orthopaedic research society, vol 7 1982:237. [104] Setton LA, Mow VC, Howell DS. Mechanical behavior of articular cartilage in shear is altered by transection of the anterior cruciate ligament. J Orthop Res 1995;13:473-82. [105] Barbucci R, Lamponi S, Borzacchiello A, Ambrosio L, Fini M, Torricelli P, et al. Hyaluronic acid hydrogel in the treatment of osteoarthritis. Biomaterials 2002;23:4503-13. [106] Zhu W, Iatridis JC, Hlibczuk V, Ratcliffe A, Mow VC. Determination of collagen-proteoglycan interactions in vitro. Journal of biomechanics 1996;29:773-83. [107] Betre H, Setton LA, Meyer DE, Chilkoti A. Characterization of a genetically engineered elastin-like polypeptide for cartilaginous tissue repair. Bioamrcromolecules 2002;3:910-16. [108] Zhu W, Mow VC, Rosenberg LC, Tang LH. Determination of kinetic changes of aggrecan-hyaluronan interactions in solution from its rheological properties. J Biomech 1994;27:571-9. [109] Baier Leach J, Bivens KA, Patrick CW, Jr., Schmidt CE. Photocrosslinked hyaluronic acid hydrogels: natural, biodegradable tissue engineering scaffolds. Biotechnology and bioengineering 2003;82:578-89. [110] Nettles Dl, Vail TP, Morgan MT, Grinstaff MW, Setton LA. Photocrosslinkable hyaluronan as a scaffold for articular cartilage repair. Ann Biomed Eng 2004;32:391-7. [111] LeRoux MA, Guilak F, Setton LA. Compressive and shear properties of alginate gel: effects of sodium ions and alginate concentration. J Biomed Mater Res 1999;47:46-53. [112] Trabbic-Carlson K, Setton LA, Chilkoti A. Swelling and mechanical behaviors of chemically cross-linked hydrogels of elastin-like polypeptides. Biomacromolecules 2003;4:572-80. [113] Leone G, Torricelli P, Chiumiento A, Facchini A, Barbucci R. Amidic alginate hydrogel for nucleus pulposus replacement. J Biomed Mater Res A 2008;84:391-401. [114] Braund KG, Ghosh P, Taylor TK, Larsen LH. Morphological studies of the canine intervertebral disc. The assignment of the beagle to the achondroplastic classification. Res Vet Sci 1975;19:167-72. [115] Preradovic A, Kleinpeter G, Feichtinger H, Balaun E, Krugluger W. Quantitation of collagen I, collagen II and aggrecan mRNA and expression of the corresponding proteins in human nucleus pulposus cells in monolayer cultures. Cell Tissue Res 2005;321:459-64. [116] Weiler C, Nerlich AG, Zipperer J, Bachmeier BE, Boos N. 2002 SSE Award Competition in Basic Science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption. Eur Spine J 2002;11:308-20. [117] Knudson CB, Knudson W. Hyaluronan and CD44: modulators of chondrocyte metabolism. Clin Orthop Relat Res 2004;427 Suppl:S152-62. [118] Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: an information-rich system. Eur J Cell Biol 2006;85:699-715. [119] Noble PW, Lake FR, Henson PM, Riches DW. Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages. J Clin Invest 1993;91:2368-77. [120] National Centers for Health Statistics. Low back, migraine/severe headache, neck, and face pain. Health, United States, with chartbook on trends in the health of Americans. Hyattsville. MD: National Centers for Health Statistics 2006:72-4. [121] Hadjipavlou AG, Tzermiadianos MN, Bogduk N, Zindrick MR. The pathophysiology of disc degeneration: a critical review. J Bone Joint Surg Br 2008;90:1261-70. [122] Hohaus C, Ganey TM, Minkus Y, Meisel HJ. Cell transplantation in lumbar spine disc degeneration disease. Eur Spine J 2008;17 (Suppl 4):492-503. [123] Masuda K. Biological repair of the degenerated intervertebral disc by the injection of growth factors. Eur Spine J 2008;4:441-51. [124] Boyd LM, Carter AJ. Injectable biomaterials and vertebral endplate treatment for repair and regeneration of the intervertebral disc. Eur Spine J 2006;15:414-21. [125] Su WY, Chen YC, Lin FH. Injectable oxidized hyaluronic acid/adipic acid dihydrazide hydrogel for nucleus pulposus regeneration. Acta biomaterialia 2010;6:3044-55. [126] Girish KS, Kemparaju K. The magic glue hyaluronan and its eraser hyaluronidase: a biological overview. Life Sci 2007;80:1921-43. [127] Lokeshwar VB, Selzer MG. Differences in hyaluronic acid-mediated functions and signaling in arterial, microvessel, and vein-derived human endothelial cells. J Biol Chem 2000;275:27641-9. [128] Crawford JR, Jacobson BS. Extracellular calcium regulates HeLa cell morphology during adhesion to gelatin: role of translocation and phosphorylation of cytosolic phospholipase A2. Mol Biol Cell 1998;9:3429-43. [129] Lefebvre V, Huang W, Harley VR, Goodfellow PN, de Crombrugghe B. SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol 1997;17:2336-46. [130] Wiberg C, Klatt AR, Wagener R, Paulsson M, Bateman JF, Heinegard D, et al. Complexes of matrilin-1 and biglycan or decorin connect collagen VI microfibrils to both collagen II and aggrecan. J Biol Chem 2003;278:37698-704. [131] Schonherr E, Levkau B, Schaefer L, Kresse H, Walsh K. Decorin-mediated signal transduction in endothelial cells. Involvement of Akt/protein kinase B in up-regulation of p21(WAF1/CIP1) but not p27(KIP1). J Biol Chem 2001;276:40687-92. [132] Collin EC, Grad S, Zeugolis DI, Vinatier CS, Clouet JR, Guicheux JJ, et al. An injectable vehicle for nucleus pulposus cell-based therapy. Biomaterials 2011;32:2862-70. [133] Calderon L, Collin E, Velasco-Bayon D, Murphy M, O'Halloran D, Pandit A. Type II collagen-hyaluronan hydrogel - a step towards a scaffold for intervertebral disc tissue engineering. Eur Cell Mater 2010;20:134-48. [134] Chen YC, Su WY, Yang SH, Gefen A, Lin FH. In situ forming hydrogels composed of oxidized high molecular weight hyaluronic acid and gelatin for nucleus pulposus regeneration. Acta biomaterialia 2012;9:5181-93. [135] Vadalà G, Sowa G, Hubert M, Gilbertson LG, Denaro V, Kang JD. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med 2012;6:348-55. [136] Zhang H, La Marca F, Hollister SJ, Goldstein SA, Lin CY. Developing consistently reproducible intervertebral disc degeneration at rat caudal spine by using needle puncture. Journal of neurosurgery Spine 2009;10:522-30. [137] Keorochana G, Johnson JS, Taghavi CE, Liao JC, Lee KB, Yoo JH, et al. The effect of needle size inducing degeneration in the rat caudal disc: evaluation using radiograph, magnetic resonance imaging, histology, and immunohistochemistry. Spine J 2010;10:1014-23. [138] Gelse K, Ekici AB, Cipa F, Swoboda B, Carl HD, Olk A, et al. Molecular differentiation between osteophytic and articular cartilage--clues for a transient and permanent chondrocyte phenotype. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society 2012;20:162-71. [139] Weiss AP, Dorfman HD. S-100 protein in human cartilage lesions. J Bone Joint Surg Am 1986;68:521-6. [140] Martin F, Lehmann M, Schläger P, Sack U, Anderer U. Differentiation Capacity of Chondrocytes in Microtissues depends on TGF-β Subtype. J Biochip Tissue chip 2012;S2:1-11. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63058 | - |
| dc.description.abstract | 下背痛是病人求診骨科門診最常見的原因之一。儘管下背痛不會直接威脅到生命，但是該症狀會影響到個人的生活品質以及增加許多醫療及社會資源的支出。據統計，美國每年會有超過1000億美金的醫療支出花費在下背痛的治療上。大部的下背痛與末期的椎間盤退化(intervertebral disc degeneration)有關，老化、肥胖、抽菸、先天性基因變異或是從事體力勞動量較大的工作都是造成椎間盤退化的主要原因。服用止痛藥、進行椎間盤切除術或是脊椎融合手術是臨床上常見的治療方法，然而這些方法僅僅只能移除疼痛症狀而無法再生或是重建組織，因此如何有效地修復並重建椎間盤是目前醫學研究上一個重要的課題。
初期的椎間盤退化源於中心的髓核(nucleus pulposus)組織纖維化，而使得椎間盤失去減壓與吸震的能力。因此在本研究當中，我們嘗試開發出原位成型水膠以用於椎間盤髓核重建，實驗共分成三大部分。在第一部分的實驗，我們嘗試利用玻尿酸開發出原位成型水膠以用於椎間盤髓核之再生。玻尿酸先以高碘酸鈉進行氧化反應以獲得含有醛基的玻尿酸，稱之為氧化玻尿酸(oxidized hyaluronic acid)。該氧化玻尿酸可以進一步和已二酸二醯肼上的胺基反應交聯以形成具有黏彈特性的水膠。傅立葉轉換紅外線光譜分析儀和三硝基苯磺酸試劑用來分析氧化玻尿酸的結構以及氧化率。流變儀用來評估該水膠的操作性和黏彈特性。細胞的基因表現則是用即時聚合酶連鎖反應儀來分析。從實驗結果中可以發現該水膠注入體內後可於3分鐘內成膠，並可以維持膠態至少5周以上，而水膠的複變剪力模數數值較正常的髓核組織大一些。最重要的是該水膠有具良好的生物相容性，並且能協助椎間盤髓核細胞合成第二型膠原蛋白(COLII) 以及蛋白多醣 (AGG)。 第二部分的實驗，我們嘗試在先前的水膠系統內加入明膠以改善該水膠的細胞貼覆性以及黏彈特性。高分子量的玻尿酸(1900 kDa)先和不同濃度的明膠交聯，以形成玻尿酸-明膠高分子，之後再進行氧化反應以形成氧化玻尿酸-明膠高分子 (oxidized hyaluronic acid-gelatin)。最後，再將氧化玻尿酸-明膠高分子與已二酸二醯肼混和以形成氧化玻尿酸-明膠-已二酸二醯肼水膠。從流變實驗結果中可以發現該水膠的複變剪力模數(|G*|, complex shear modulus)數值(11~14 kPa)和正常椎間盤髓核組織(11.3 kPa)相似。螢光染色以及電子顯微鏡的結果中可以觀察到髓核細胞培養於不同明膠濃度的水膠內或是水膠上都具有貼附性，並且能以圓形的細胞型態存活。在含有高濃度明膠的水膠上，髓核細胞還能有顯著的增生表現。在細胞基質的修復上，我們發現了培養於水膠內的髓核細胞可以合成第二型膠原蛋白 (COLII) 以及蛋白多醣 (AGG)。此外，該細胞還能合成其他重要的信使核糖核酸像是SOX-9 以及缺氧誘導因子-1 (HIF-1α)。 為了要評估該水膠於臨床應用的可行性，實驗的最後一部分是動物實驗評估。大鼠的尾巴先以23號針頭於椎間盤中心處做穿刺以誘導椎間盤退化，並於誘導兩周後施打含有細胞之氧化玻尿酸水膠以及氧化玻尿酸-明膠水膠以重建退化的椎間盤。在給予水膠治療後的3周以及6周，利用核磁造影追蹤觀察椎間盤的退化及修復狀態，並於治療6周後犧牲動物以做後續的組織型態及染色分析。從核磁造影結果中可以發現有施打含細胞之水膠的椎間盤有較強的T2-weighted訊號，並呈現比較白的影像，而單純穿刺未給予任何治療的椎間盤則在穿刺8周後完全失去了訊號。從組織化學染色上也可以得到證實，單純穿刺的椎間盤在穿刺8周後完全退化，沒有任何的髓核組織存在，而原先外層整齊排列的纖維環嚴重坍塌並變得破碎。相較於退化的椎間盤，有施打含細胞之水膠的椎間盤，型態完整，中心髓核處具有許多細胞外基質以及髓核細胞，於髓核組織處亦能染到蛋白多醣(AGG)、第二型膠原蛋白 (COLII) 以及SOX-9。此外，在施打含細胞之氧化玻尿酸-明膠水膠的椎間盤髓核處還發現有均勻分布的緻密基質 (dense matrix)。從以上實驗結果中發現，含有細胞之氧化玻尿酸水膠以及氧化玻尿酸-明膠水膠具有再生椎間盤髓核的能力。 綜合以上所述，本研究結果顯示原位成型氧化玻尿酸水膠以及氧化玻尿酸-明膠水膠皆具有修復及再生椎間盤髓核之能力，因此該水膠應具備有相當的潛力應用在未來臨床治療上。 | zh_TW |
| dc.description.abstract | Low back pain (LBP) is one of the most common reasons for patients to visit or-thopedist. Although LBP is not life threatening, it affects the quality of life and contrib-utes to high medical expenditure. The total cost of LBP in the USA exceeds 100 billion dollars per year. It is believed most of the low back pain is associated with intervertebral disc degeneration. Aging, obesity, smoking, genetic or environmental factors are the major reason for intervertebral disc degeneration. Clinically, taking pain killer, discec-tomy and spinal fusion surgery are the most common treatments. These treatments can only relieve the symptoms, not repair the intervertebral disc. Therefore, how to repair the degenerated intervertebral disc is considered as an important issue.
Early stage of the degeneration originates from the fibrosis of nucleus pulposus (NP) which is located in the center of the intervertebral disc. Hence, in this study, we try to develop an in situ forming hydrogel for NP regeneration. The whole experiment di-vided into three parts, in the first part, we try to develop an in situ forming hydrogel for NP regeneration by hyaluronic acid. Hyaluronic acid was first oxidized by sodium pe-riodate to form oxidized hyaluronic acid (oxi-HA), and then the oxi-HA can be further crosslinked with the amino groups of adipic acid dihydrazide to form gel matrix. Fourier transform infrared spectrometry and trinitrobenzene sulfonate assay are used to char-acterize the oxi-HA, and evaluate the oxidation degree. Rheometer is use to evaluate the working ability and the viscoelastic properties of the hydrogel. Real-time PCR is used for gene expression analysis. Results showed the hydrogel can transform from liquid form into a gel matrix under physiological conditions within 3 minutes, and maintain its gel state for at least 5 weeks. The complex shear modulus of the hydrogel is slightly higher than that of native nucleus pulposus. Importantly, the hydrogel can assist in NP cell synthesis of type II collagen and aggrecan mRNA gene expression, and shows good biocompatibility based on cell viability and cytotoxicity assays. In the second stage of the study, we try to introduce gelatin into previous system to improve the cell attachment ability and the viscoelastic properties of the hydrogel. First, high molecular weight (1900 kDa) hyaluronic acid was crosslinked with various con-centrations of gelatin to form hyaluronic acid-gelatin (HAG) polymers. Sodium perio-date was then oxidized HAG polymer to form oxidized HAG (oxi-HAG) polymer. The oxi-HAG polymer can be further crosslinked by adipic acid dihydrazide (ADH) to form oxi-HAG-ADH hydrogel. Results showed that the viscoelastic properties of the hydro-gels were similar to native tissue, as reflected in the complex shear modulus (11~14 kPa for hydrogels, 11.3 kPa for native NP). Cultured NP cells not only attached to the hy-drogels but also survived and maintained their round morphology. Besides, NP cells can also proliferate on the high gelatin content oxi-HAG-ADH hydrogel. In the aspect of matrix repair, we found that the hydrogels increased NP cell expression of several crucial genes, such as type II collagen, aggrecan, SOX-9, and HIF-1A. In order to assess the feasibility of the hydrogel for future application, the last part of the experiment is the animal study. Rat coccygeal intervertebral disc was stabbed by 23-gauge needle in the center of the disc to create the intervertebral disc degeneration. After two weeks, intervertebral discs were treated with NP cell contained oxi-HAG-ADH and oxi-HA-ADH hydrogels to regenerate the intervertebral disc. Mag-netic resonance imaging scan was used to monitor the degeneration and regeneration of the intervertebral disc after treatment for 3 and 6 weeks. Animals were sacrificed at 6 weeks after treatment for subsequent histological analysis including hematoxylin and eosin staining, Alcian blue staining and immunohistochemistry of aggrecan, type II col-lagen, SOX-9, and S-100. Results showed the successful repair of the degenerated in-tervertebral disc on T2-weighted signal intensity in the hydrogel treatment intervertebral discs. In the stab-only group, no T2-weighted signal intensity can be detected at 8 weeks after needle-stab. Similar results can be found in histochemical staining. No nucleus pulposus cells can be found in the stab-only intervertebral disc and the outer annulus ring collapsed. For hydrogel treated intervertebral discs, lots of extracellular matrix and cells can be found in the nucleus pulposus. Immunohistochemistry also showed positive findings for aggrecan, type II collagen, and SOX-9. Besides, there are some well-distributed dense matrix can be found in the oxi-HAG-ADH hydrogel treated intervertebral disc. From the results of animal study, we found the cell contained oxi-HA-ADH and oxi-HAG-ADH hydrogel can assist NP regeneration in vivo. In conclusion, the developed in situ forming oxidized hyaluronic acid-based hy-drogel (including oxidized hyaluronic acid hydrogel and oxidized hyaluronic ac-id-gelatin hydrogel) has the potential to perform as a suitable material for the repair of nucleus pulposus. It should be a promising hydrogel for nucleus pulposus regeneration, especially, for the treatment of early stage intervertebral disc degeneration. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T16:20:43Z (GMT). No. of bitstreams: 1 ntu-102-F94548002-1.pdf: 8076292 bytes, checksum: 34fbf00d55dfa322afb76566395dcc42 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | TABLE OF CONTENT
謝誌………………………i 中文摘要…………………ii Abstract…………………v LIST OF TABLES……………xiii LIST OF FIGURES……………xiv Chapter 1 Introduction……………………………………….1 1.1 Structure of the Intervertebral Disc…………………2 1.1.1 Nucleus Pulposus…………………………………………3 1.1.2 Annulus Fibrosus…………………………………………5 1.2 Macromolecules of the Intervertebral Disc……………7 1.2.1 Glycosaminoglycan…………………………………………7 1.2.2 Proteoglycan………………………………………………8 1.2.3 Collagen………………………………………………………12 1.2.4 Enzyme………………………………………………………14 1.3. Intervertebral Disc Degeneration…………………………16 1.3.1 Symptoms and Risk Factors Associated with Disc Degeneration……………………16 1.3.2 Disc Degeneration at Molecular Levels…………………16 1.3.3 Disc Degeneration at Tissue and Cell Level…………18 1.3.4 Classification of Disc Degeneration by MRI…………20 1.4 Clinical Treatments for Symptomatic Disc Degeneration……22 1.5 Purpose of Study……………………………………………23 Chapter 2 Theoretical Basis………………………………24 2.1 Concept in Nucleus Pulposus Replacements……………25 2.1.1 Commercialized Preformed Nucleus Pulposus Replacements……25 2.1.2 Commercialized In Situ Forming Nucleus Pulposus Replacements……27 2.2 Biological Approach for Nucleus Pulposus Regeneration……………29 2.2.1 Growth Factor Injection………………………29 2.2.2 Gene Therapy………………………………………29 2.2.3 Cell Therapy………………………………………29 2.2.4 Injectable Hydrogel used in Disc Regeneration………………………30 2.2.5 Considerations for Injectable Hydrogel used in Disc Regeneration…31 2.3 Hyaluronic Acid …………………………………32 2.4 Gelatin……………………………………………35 2.5 Periodate Oxidation of Polysaccharide………37 Chapter 3 Oxidized Hyaluronic Acid/Adipic Acid Dihydrazide Hydrogel for Nucleus Pulposus Regeneration……………………39 3.1 Introduction………………………………………………………40 3.2 Experimental Materials……………………………………41 3.3 Experimental Methods…………………………………….…42 3.3.1 Oxi-HA Preparation and Characterization………….……42 3.3.2 Oxi-HA/ADH Hydrogel Preparation……………………43 3.3.3 Oxi-HA/ADH Hydrogel Degradation and Swelling Properties…43 3.3.4 Working Ability and Yield Stresss Evaluation…………………44 3.3.5 Viscoelastic Properties Evaluation…………………..……………45 3.3.6 Nucleus Pulposus Cell Isolation………….………………45 3.3.7 Biocompatibility Study…………………………………………………46 3.3.8 Fluorescent Staining……………………………………………………48 3.3.9 mRNA Gene Expression Analysis…………………………………48 3.3.10 Scanning Electron Microscopy Observation………………49 3.3.11 Statistical Analysis…………………………………………….………50 3.4 Result…………………………………………………………………….………50 3.4.1 Characterization of Oxi-HA/ADH Hydrogel…………….……50 3.4.2 Degradation and Swelling Ratio of Oxi-HA/ADH Hydrogel…53 3.4.3 Working Ability of Oxi-HA/ADH Hydrogel……………………54 3.4.4 Yield Stress of Oxi-HA/ADH Hydrogel…………………….……56 3.4.5 Viscoelastic Properties of Oxi-HA/ADH Hydrogel……..…56 3.4.6 Biocompatibility Studies of Oxi-HA/ADH Hydrogel…..…58 3.4.7 Fluorescent Staining of NP Cell……………………………..……61 3.4.8 Scanning Electron Microscopy Observation…………..……61 3.4.9 mRNA Gene Expression Analysis…………………………………62 3.5 Discussion……………………………………………………………………..63 3.6 Summary………………………………………………………………………70 Chapter 4 Oxidized Hyaluronic Acid-Gelatin-Adipic Acid Dihydrazide Hydrogels for Nucleus Pulposus Regeneration…71 4.1 Introduction…………………………………………………………………72 4.2 Experimental Material………………………………………………..74 4.3 Experimental Methods…………………………………………………74 4.3.1 HAG and Oxi-HAG Preparation and Characterization……74 4.3.2 Evaluation of the Viscoelastic Property…………….……76 4.3.3 Biocompatibility Study……………………………………………76 4.3.4 Fluorescent Staining of NP Cells Cultured on Hydrogels…77 4.3.5 Fluorescent Staining of Cells Encapsulated in Hydrogels……77 4.3.6 Scanning Electron Microscopy Observation………………78 4.3.7 mRNA Gene Expression Analysis……………………….………78 4.3.8 Statistical Analysis…………………………………………….………79 4.4 Result……………………………………………………………………..……80 4.4.1 Characterization of Oxi-HAG-ADH Hydrogel………………80 4.4.2 Viscoelastic properties of Oxi-HAG-ADH Hydrogel….…84 4.4.3 Biocompatibility Studies of Oxi-HAG-ADH Hydrogels….85 4.4.4 Fluorescent Staining of NP Cells Cultured on Hydrogels……87 4.4.5 Fluorescent Staining of NP Cells Encapsulated in Hydrogels……90 4.4.6 Scanning Electron Microscopy Observation………………93 4.4.7 mRNA Gene Expression Analysis………………………………94 4.5 Discussion…………………………………………………………………97 4.6 Summary…………………………………………………………………102 Chapter 5 Oxidized Hyaluronic Acid-based Hydrogel for Nucleus Pulposus Regeneration: An In Vivo Study……………103 5.1 Introduction……………………………………………………..………104 5.2 Experimental Animals……………………………………...………105 5.3 Experimental Methods………………………………….…………106 5.3.1 Animal Model of IVD Degeneration…………..…………106 5.3.2 Oxi-HAG-ADH Hydrogel and Oxi-HA-ADH Hydrogel Treatment……107 5.3.3 Magnetic Resonance Imaging Procedures………………108 5.3.4 Hematoxylin and Eosin Staining……………………..………108 5.3.5 Alcian Blue Staining…………………………………………..……108 5.3.6 Immunohistochemistry……………………………..……………109 5.4 Result………………………………………………………………..………110 5.4.1 Magnetic Resonance Imaging Assessment………..……110 5.4.2 Histological Changes………………………………………………112 5.4.3 Proteoglycan Analysis……………………………….……………114 5.4.4 Immunohistochemistry…………………………………..………115 5.5 Discussion…………………………………………………………………118 5.6 Summary………………………………………………….………………121 Chapter 6 Conclusion……………………………………...……………122 References………………………………………………………..…………124 Resume……………………………………………………………..…………136 | |
| dc.language.iso | en | |
| dc.subject | 玻尿酸 | zh_TW |
| dc.subject | 明膠 | zh_TW |
| dc.subject | 氧化反應 | zh_TW |
| dc.subject | 原位型水膠 | zh_TW |
| dc.subject | 椎間盤 | zh_TW |
| dc.subject | 髓核 | zh_TW |
| dc.subject | nucleus pulposus | en |
| dc.subject | hyaluronic acid | en |
| dc.subject | gelatin | en |
| dc.subject | oxidation | en |
| dc.subject | in situ hydrogel | en |
| dc.subject | intervertebral disc | en |
| dc.title | 原位成型氧化玻尿酸水膠於椎間盤髓核再生之應用 | zh_TW |
| dc.title | In Situ Forming Oxidized Hyaluronic Acid-Based Hydrogel for Nucleus Pulposus Regeneration | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王盈錦(Yng-JiinWang),朱一民(I-Ming Chu),邱英明(Ing Ming Chiu),陳克紹(Ko-Shao Chen),楊曙華(Shu-Hua Yang) | |
| dc.subject.keyword | 玻尿酸,明膠,氧化反應,原位型水膠,椎間盤,髓核, | zh_TW |
| dc.subject.keyword | hyaluronic acid,gelatin,oxidation,in situ hydrogel,intervertebral disc,nucleus pulposus, | en |
| dc.relation.page | 138 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-01-31 | |
| dc.contributor.author-college | 工學院 | zh_TW |
| dc.contributor.author-dept | 醫學工程學研究所 | zh_TW |
| 顯示於系所單位： | 醫學工程學研究所 | |
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