請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34476完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林峰輝 | |
| dc.contributor.author | Ming-Hong Chen | en |
| dc.contributor.author | 陳敏弘 | zh_TW |
| dc.date.accessioned | 2021-06-13T06:10:32Z | - |
| dc.date.available | 2006-07-24 | |
| dc.date.copyright | 2006-07-24 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-04-12 | |
| dc.identifier.citation | REFERENCE
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34476 | - |
| dc.description.abstract | In this study, we focused on the development of artificial nerve guides that could offer sustained release of neurotrophic factors during the prolonged period of nerve regeneration. We used carbodiimide as a zero-length cross-linker to conjugate neurotrophic factors with gelatin-tricalcium phosphate composites (GTG). The bioactivity of neurotrophic factors after conjugation reaction, the release characteristics of neurotrophic factors grafted on GTG composites, and the in vitro biocompatibility of modified GTG composites were explored. With the immobilization of nerve growth factors (NGF) on GTG membranes, the releasing curve for NGF showing two distinctive parts with different slopes indicated that NGF was released from the composite in both diffusion-controlled mechanism and degradation-controlled mechanism. With the ELISA tests for β-NGF subunit, the biological activity of NGF molecules after the conjugation reaction could be confirmed. In addition, cultured PC12 cells also showed significant neurite outgrowth with NGF-grafted GTG membranes, which was statistically higher than GTG without NGF immobilization. Therefore, the technique used in the study is capable of immobilizing NGF on GTG membranes and retaining the bioactivity of NGF. Using the carbodiimide conjugation reaction, NGF, BDNF, and IGF-1 were then immobilized onto GTG membranes. Before the applications in animal studies, the in vitro biocompatibility of GTG membranes grafted with various neurotrophic factors was investigated. In PC12 cell culture, the total protein content and MTT assay indicated more cell attachment on the composites modified with growth factors. IGF-1 showed a higher survival promotion effect on PC12 cells than BDNF and NGF groups. On the other hand, NGF released from the composite showed the highest level of neurite outgrowth for PC12 cells. Cytotoxic effect was not induced by the conjugation reactions for the immobilization of neurotrophic factors.
In animal studies, we first evaluated the in vivo applications of GTG conduits for peripheral nerve repair. Six months after sciatic nerve repair with GTG conduits, the biocompatibility and effects on nerve regeneration of GTG conduits were evaluated. The GTG conduits that we implanted were well tolerated by the host tissue, elicited a mild foreign body reaction, and had an optimal degradation over 24 weeks. No inflammation, infection, nor allergic reaction was noticed. Sections taken at the midconduits demonstrated typical regenerated nerve cables. Electrophysiological examinations and walking tract analysis also showed better recovery of functions for nerves repaired with GTG conduits when compared with nerves repaired with silicone tubes. When nerve repair was conducted with GTG conduits modified with various neurotrophic factors, the conduits were also well tolerated by the host tissue. In the regenerated nerves, the number of regenerated axons per unit area, the average axon size, the density of nerve fiber were even more improved by incorporating neurotrophic factors with GTG conduits. In the assessment of compound muscle action potential, reinnervation of gastrocnemic muscles, and sciatic function index, conduits modified with various neurotrophic factors showed a more favourable outcome in compound muscle action potential. Conduits with BDNF had a better recovery of gastrocnemic muscle weight. Therefore, GTG nerve guidance conduit incorporated with neurotrophic factors can be a potential candidate for peripheral nerve repair. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T06:10:32Z (GMT). No. of bitstreams: 1 ntu-95-D91548007-1.pdf: 33652921 bytes, checksum: 2865d923e5dbd584f3f2403df7a404c8 (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | CONTENTS
CHAPTER 1 INTRODUCTION 1-1 Peripheral nerve injury ………………………………………………..............1 1-2 Strategies for peripheral nerve repair …………………………………............3 1-3 Development of artificial nerve grafts …………………….………………….5 1-3.1 Materials for nerve guidance channels …………….………………….6 1-3.2 Biomolecular signals ……………………………………………….…8 1-3.3 Cellular components …………………………………………………10 1-4 Objectives of this study ………………………………………………...……11 CHAPTER 2 THEORETICAL BASIS 2-1 The peripheral nervous system: structure and function ……………………..13 2-2 Peripheral nerve injury and regeneration ……………………………………17 2-3 Neurotrophic factors and peripheral nerve regeneration …………………….21 2-4 Selection of biomaterials for nerve guidance channels ……………………...24 2-5 Incorporation of neurotrophic factors onto nerve guidance channels ……….27 2-6 In vitro and in vivo evaluations for biomaterials releasing neurotrophic factors ……………………………………………………………………......31 2-6.1 In vitro evaluations …………………………………………………..31 2-6.2 In vivo evaluations …………………………………………………...32 CHAPTER 3 MATERIALS AND METHODS 3-1 Preparation of GTG membranes immobilized with neurotrophic factors …...35 3-1.1 Preparation of GTG membranes …………………...………………..35 3-1.2 Covalent immobilization of neurotrophic factors onto GTG membranes ………………………………………………………………......36 3-2 Evaluating the release characteristics and bioactivity of neurotrophic factors immobilized on GTG membranes using a nerve growth factor model …...…37 3-2.1 The amount of nerve growth factor immobilized on GTG membranes ......................................................................................................38 3-2.2 NGF releasing study………………………………………………….39 3-2.3 Evaluating the bioactivity of released NGF …………………………40 3-3 Evaluating the in vitro biocompatibility of GTG membranes grafted with neurotrophic factors ……………..…………………………………………..42 3-3.1 NGF, BDNF, and IGF-1 covalently immobilized onto GTG membranes …………………………………………………………………..42 3-3.2 Biocompatibility tests: cell viability, cell population and LDH leakage assays ………………………………………………………………………...42 3-3.2.1 MTT assay …………………………………………………...43 3-3.2.2 Total protein test …………………………………………….44 3-3.2.3 LDH leakage ………………………………………………...45 3-3.3 Bioactivity of the released neurotrophic factors: neurite outgrowth assay …………………………………………………………………………46 3-4 In vivo evaluations for biocompatibility and feasibility of GTG conduits in peripheral nerve repair ………………………………………………………47 3-4.1 Preparation of GTG conduits ………………………………………..48 3-4.2 Conduits implantation for sciatic nerve repair ………………………50 3-4.3 Electrophysiological study …………………………………………..52 3-4.4 Sciatic function index ………………………………………………..52 3-4.5 Histomorphometric assessment ……………………………………...55 3-5 Animal studies of GTG immobilized with various neurotrophic factors ……56 3-5.1 Preparation and implantation of GTG conduits grafted with NGF, BDNF, or IGF-1 for sciatic nerve repair …………………………………….58 3-5.2 Electrophysiological study …………………………………………..59 3-5.3 Functional and histomorphological assessment ……………………..59 3-5.3.1 Sciatic function index ...……………………………………...59 3-5.3.2 Pinch reflex test ……………………………………………..60 3-5.3.3 Weight ratios of gastrocnemic muscles …………………...…60 3-5.3.4 Histomorphological assessment ……………………………..61 CHAPTER 4 RESULTS AND DISCUSSION 4-1 The release characteristics and bioactivity of neurotrophic factors immobilized on GTG membranes …………………………………………………………62 4-1.1 The amount of NGF immobilized on GTG membranes …………….62 4-1.2 The amount and duration of NGF released from GTG membranes …………………………………………………………………..64 4-1.3 Bioactivity of NGF released from GTG membranes ………………..66 4-1.4 Discussion of NGF grafting and releasing study ……………………68 4-2 Biocompatibility of GTG grafted with various neurotrophic factors: in vitro study …………………………………………………………………………72 4-2.1 MTT assay …………………………………………………………...72 4-2.2 Total protein analysis ………………………………………………..73 4-2.3 LDH leakage analysis ……………………………………………….75 4-2.4 Measurement of neurite outgrowth of PC12 cells …………………...76 4-2.5 Discussion of biocompatibility tests of GTG membranes grafted with various neurotrophic factors …………………………………………………78 4-3 In vivo biocompatibility and feasibility of GTG conduits for peripheral nerve repair ………………………………………………………………………...80 4-3.1 Electrophysiological study …………………………………………..80 4-3.2 Sciatic function index ………………………………………………..82 4-3.3 Gross findings and histomorphometric assessment …………………85 4-3.4 Discussion of GTG conduits in peripheral nerve repair: in vivo biocompatibility and feasibility ……………………………………………...91 4-4 Animal study of GTG conduits grafted with various neurotrophic factors for peripheral nerve repair ………………………………………………………96 4-4.1 Electrophysiological study …………………………………………..96 4-4.2 Sciatic function index ………………………………………………..98 4-4.3 Nerve pinch reflex …………………………………………………...99 4-4.4 Weight ratios of gastrocnemic muscles ……………………………...99 4-4.5 Histomorphological evaluations ……………………………………100 4-4.6 Discussion of in vivo evaluations of GTG conduits grafted with various neurotrophic factors ……….……………………...………………………..112 CHAPTER 5 CONCLUSION AND FUTURE REFERENCE ……………………………………………………………………..118 FIGURE INDEX CHAPTER 1 Fig. 1.1. An illustration of nerve repair with a biological or artificial nerve graft ……4 Fig. 1.2. Considerations for the development of an artificial nerve guidance channel ………………………………………………………………………………..5 CHAPTER 2 Fig. 2.1. Unmyelinated axons ………...…………………………….……………….14 Fig. 2.2. A myelinated axon ...……………………………………….………………14 Fig. 2.3. Structure of a nerve ………………………………………….……………..15 Fig. 2.4. Node of Ranvier ……….…………………………………………………...16 Fig. 2.5. Nerve injury, degeneration, and regeneration ……………………………...20 Fig. 2.6. A gelatin tube bends and collapses during the repair of the sciatic nerve………………………………………………………………………………….26 Fig. 2.7. Steps of cross-linking with carbodiimide for covalent binding between the carboxyl groups of gelatin and the amine groups of neurotrophic factors …………..30 CHAPTER 3 Fig. 3.1. Flowchart of experiments ………………………………………………….34 Fig. 3.2. Preparation of GTG and immobilization of neurotrophic factors …………36 Fig. 3.3. Evaluating the release characteristics and bioactivity of GTG grafted with NGF ………………………………………………………………………………....37 Fig. 3.4. Sandwich ELISA method for NGF quantification ………………………...39 Fig. 3.5. MTT reaction…………………………………………………...…………..43 Fig. 3.6. Reaction for total protein test ……………………………………………...45 Fig. 3.7. Reaction for LDH leakage test …………………………………………….46 Fig. 3.8. In vivo tests for biocompatibility and feasibility of GTG membranes in peripheral nerve repair ………………………………………………………………48 Fig. 3.9. GTG conduits for sciatic nerve repair ……………………………………...49 Fig. 3.10. Repair of transected sciatic nerve with a GTG conduit …………………..51 Fig. 3.11. Intra-operative photograph of the sciatic nerve reconstructed with a GTG conduit ……………………………………………………………………………….51 Fig. 3.12. Sciatic function index was evaluated by walking tract analysis…...….…..54 Fig. 3.13. Parameters from footprints for sciatic function index …………...……….54 Fig. 3.14. Animal studies for GTG immobilized with various neurotrophic factors ………………………………………………………………………………………..57 CHAPTER 4 Fig. 4.1. The amount of NGF immoblized on GTG ………………………………...63 Fig. 4.2. The NGF releasing curve ………………………………………………….65 Fig. 4.3. Daily release of NGF from GEN membrane (ng/day) …………………….65 Fig. 4.4. Neurite-bearing cells in different groups …………………………………..67 Fig. 4.5. Neurite outgrowth assay …………………………………………………...67 Fig. 4.6. The MTT-tetrazolium assay ……………………………………………….73 Fig. 4.7. Total protein content (mg/ml) ……………………………………………..74 Fig. 4.8. LDH leakage test (U/dl) …………………………………………………...76 Fig. 4.9. Neurite-bearing cells in different groups …………………………………..77 Fig. 4.10. Neurite outgrowth assay ………………………………………………….77 Fig. 4.11. Compound muscle action potential: unoperated side …………...………..80 Fig. 4.12. Compound muscle action potential: 24 weeks after silicone tube repair ………………………………………………………………………………………..81 Fig. 4.13. Compound muscle action potential: 24 weeks after GTG tube repair ………………………………………………………………………………………..81 Fig. 4.14. Recovery index of CMAP amplitude 24 weeks after conduit bridging repair ………………………………………..………………………………………………82 Fig. 4.15. Graph showing change in the SFI as a funtion of time ………..……………………………………………………………………………....83 Fig. 4.16. Walking tract analysis with footprints in GTG group at 6 and 24 weeks after nerve repair ………………………………………………….…………………84 Fig. 4.17. Intraoperative view of silicone conduit …………………………………...86 Fig. 4.18. Intraoperative view of the GTG conduit during harvesting …………...….86 Fig. 4.19. A GTG conduit harvested 24 weeks after implantation …………………..87 Fig. 4.20. Regenerated nerve with small diameter in the silicone conduit ...………..87 Fig. 4.21. Regeneration of nerve and degradation of conduit in GTG group (low power field) …….……………………………………………………………………88 Fig. 4.22. Nerve regenerated in the GTG conduit (high power field) ……………….89 Fig. 4.23. Total nerve area at the mid portion of the conduits …………...………….90 Fig. 4.24. Compound muscle action potential: NGF group 16 weeks after repair ………………………………………………………………………………...96 Fig. 4.25. Compound muscle action potential: BDNF group 16 weeks after repair ………………..…………………………………………...………………………….97 Fig. 4.26. Compound muscle action potential: IGF-1 group 16 weeks after repair …………………..……………………………………………………………………97 Fig. 4.27. Recovery index of CMAP amplitude 16 weeks after conduit bridging repair …...……………………………………………………………………………98 Fig. 4.28. Sciatic function index (SFI) …………….………………………………...99 Fig. 4.29. Weight ratios of the gastrocnemic muscle …………….………………...100 Fig. 4.30. Gross findings during the harvest of GTG conduits modified with neurotrophic factors ………………………………….…………………………….102 Fig. 4.31. Macrographs of the GTG grafted with neurotrophic factors and 16 weeks after implantation …………………………………………………………………..103 Fig. 4.32. Micrograph of GTG conduits grafted with neurotrophic factors 16 weeks after implantation ………………………………..…………………………………104 Fig. 4.33. Light micrograph of regenerated nerve cross-section in the blank GTG conduit ……………………………………………………………………………...105 Fig. 4.34. Light micrograph of regenerated nerve cross-section in the GTG conduit immobilized with NGF ……………………………………..……………………...106 Fig. 4.35. Light micrograph of regenerated nerve cross-section in the GTG conduit immobilized with BDNF ……………………………………………………..…….107 Fig. 4.36. Light micrograph of regenerated nerve cross-section in the GTG conduit immobilized with IGF-1 ……………………………………………………………108 Fig. 4.37. Number of axons per unit area calculated from sections at the midconduits at 16 weeks ………………………………………………………………………....109 Fig. 4.38. Nerve fiber density calculated from sections at the midconduits (sum of axon area/image area) at 16 weeks …………………………………………..……..110 Fig. 4.39. Average axon area (μm2) calculated from sections at the midconduits at 16 weeks …………………………………………………………………...…………..111 TABLE INDEX CHAPTER 2 Table 2.1. Seddon and Sunderland peripheral nerve injury grading system …….….18 CHAPTER 4 Table 4.1. Results of MTT assay ……………...…………………………………….72 Table 4.2. Results of total protein analysis …………...…………………………..…74 Table 4.3. Results of LDH leakage analysis ………………………...……………....75 | |
| dc.language.iso | en | |
| dc.subject | 體外 | zh_TW |
| dc.subject | 神經導管 | zh_TW |
| dc.subject | 持續釋放 | zh_TW |
| dc.subject | 體內 | zh_TW |
| dc.subject | 生物相容性 | zh_TW |
| dc.subject | 生物可分解性 | zh_TW |
| dc.subject | 神經滋養因子 | zh_TW |
| dc.subject | 神經再生 | zh_TW |
| dc.subject | nerve regeneration | en |
| dc.subject | nerve guidance channels | en |
| dc.subject | neurotrophic factors | en |
| dc.subject | biodegradable | en |
| dc.subject | sustained release | en |
| dc.subject | in vitro | en |
| dc.subject | in vivo | en |
| dc.subject | biocompatibility | en |
| dc.title | 可持續釋放神經滋養因子之生物可分解性神經導管於周邊神經再生之研發與應用 | zh_TW |
| dc.title | Development and Applications of Biodegradable Nerve Guidance Channels with Sustained Release of Neurotrophic Factors in Peripheral Nerve Regeneration | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 林瑞明,邱英明,孫瑞昇,姚俊旭,陳悅生,史杜賓斯基(Leszek Stobinski) | |
| dc.subject.keyword | 神經導管,神經滋養因子,生物可分解性,持續釋放,體外,體內,生物相容性,神經再生, | zh_TW |
| dc.subject.keyword | nerve guidance channels,neurotrophic factors,biodegradable,sustained release,in vitro,in vivo,biocompatibility,nerve regeneration, | en |
| dc.relation.page | 138 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2006-04-13 | |
| 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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