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研究生: 薛元毓
Hsueh, Yuan-Yu
論文名稱: 合併使用甲殼素塗佈之神經導管以及脂肪幹細胞所誘導之神經球細胞來促進大鼠坐骨神經再生與功能性恢復
Functional recoveries of sciatic nerve regeneration by combining chitosan-coated conduit and neurosphere cells induced from adipose-derived stem cells
指導教授: 吳佳慶
Wu, Chia-Ching
林聖哲
Lin, Sheng-Che
學位類別: 博士
Doctor
系所名稱: 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年: 2015
畢業學年度: 103
語文別: 英文
論文頁數: 69
中文關鍵詞: 甲殼素週邊神經受損坐骨神經神經導管脂肪幹細胞球狀體神經球細胞
外文關鍵詞: Chitosan, Peripheral nerve injury, Sciatic nerve, Nerve conduit, Adipose-derived stem cell, Spheroid, Neurosphere
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  • 週邊神經受損是影響失能重大的來源之一。雖然遵守一些已完整建立之基本原則來評估進而治療週邊神經受損可使得結果最佳化,但是週邊神經受損之臨床恢復效果通常不甚理想。源自脂肪幹細胞而來之神經前驅細胞所提供之幹細胞療法可說為週邊神經受損帶來希望,特別是在臨床可用組織短缺的情形之下格外重要。將脂肪幹細胞跨胚層分化為神經前驅細胞可以藉由使用各式各樣的神經營養因子或是改變其力學微環境來達成,例如使用甲殼素表面塗佈之技術。就我們所知,甲殼素已被廣泛的應用於藥物釋放以及在組織再生上擔任立體之細胞支架。並且由於其具有生物可分解以及生物相容性,也常被拿來當作神經導管來幫助神經再生。在作者先前的研究中,我們使用甲殼素表面塗佈技術以提供立體的細胞支架,並成功使得脂肪幹細胞跨胚層分化為神經前驅細胞。再者考量到神經再生之緩慢性,合併使用內含神經前驅細胞之甲殼素導管將有可能持續提供脂肪幹細胞誘導為神經前驅細胞之力學微環境。
    在本研究中我們使用S-D大鼠的週邊神經再生模式,在其坐骨神經製造一個10 mm的神經缺損後,使用帶有甲殼素塗佈的神經導管以及合併使用自脂肪幹細胞所誘導而成的神經前驅細胞來重建此一神經缺損並研究其神經再生的效果。在單純使用矽膠導管來重建神經的組別中,可以見到神經髓鞘的退化以及膠質疤痕的增生。而若是單獨只使用甲殼素神經導管或是神經前驅細胞,在六週後可見坐骨神經有部分再生。唯有在合併使用甲殼素神經導管以及神經前驅細胞的組別中,神經有更進一步的再生情形,此再生之進步可表現於髓鞘化神經軸突密度以及髓鞘厚度的增加、腓腸肌肌肉的重量增加以及肌肉纖維增厚、以及在步態分析中步伐與步距的進步。在作用機制的分析上,我們發現在使用矽膠導管的組別中,再生的神經內疤痕中有大量表現介白素1β以及白三烯B4受體,而此兩種發炎訊號在甲殼素導管中會被大量抑制。因此在此研究中我們發現甲殼素塗佈表面具有多重的功能,除了可以誘使脂肪幹細胞形成神經前驅細胞外,更可以與該神經前驅細胞結合成一細胞輔助之神經導管,用以合併來促進週邊神經之再生。

    Peripheral nerve injuries are a significant source of disability. Although adherence to well-established basic principles of evaluation and repair can optimize results, clinical outcomes of peripheral nerve injuries are often suboptimal. The stem cell therapy of neural progenitor cell (NPC) from adipose-derived stem cell (ASC) may bring hope to peripheral nerve injury, especially in the clinical reality of tissue shortage. Transdifferentiation can be induced from ASC to NPC by adding numerous neurotrophic factors, or by mechanical microenvironment such as chitosan surface coating. To our knowledge, chitosan has widely been used for drug release and 3-dimentional scaffold for tissue engineering. And owning to the characteristics of biodegradable and biocompatible in nature, it also applies as nerve conduit to guide nerve regeneration. In author’s previous study, transdifferentiation of ASC into NPC can be achieved by using chitosan surface coating as the 3-D scaffold. Under the consideration of slow nature of nerve regeneration, continued maintenance of the microenvironment for the NPC seems possible to achieve by combined use of the chitosan conduit with induced NPC from ASC.
    The purpose of this study is to use the in vivo rat model of sciatic nerve transection to survey the therapeutic benefit of chitosan coated conduit containing with induced NPC from ASC. For the analysis of functional recoveries, we will focus on the improvement of the walking track analysis, relative gastrocnemius muscle weight measurement, and the ratio of regenerated myelinated axons. For the exploration of underlying mechanism, we will try to investigate the survival of functional cells after treatment, including the inflammatory profile.

    Chinese Abstract I-II English Abstract III-IV Acknowledgement V Table of Contents VI-VIII List of Tables IX List of Figures X Abbreviations XI-XII Chapter 1 Introduction 1 1.1 Peripheral nerve injury and regeneration 1 1.1.1 Peripheral nerve injury 1 1.1.2 Wallerian degeneration 4 1.1.3 Cells and molecules involved in WD in peripheral nerve 5 1.1.4 Difficulties in peripheral nerve regeneration 7 1.2 Treatment of peripheral nerve injuries 8 1.2.1 Primary nerve repair and grafting 8 1.2.2 Autogenous nerve conduit 9 1.2.3 Synthetic nerve conduit 11 1.3 Stem cell therapy for peripheral nerve regeneration by ASC 12 1.3.1 Stem cell therapies for peripheral nerve injuries 12 1.3.2 Plasticity and multipotency of ASC 14 1.3.3 ASC as stem cell therapy for nerve injuries 15 1.4 3-Dimensional culture for stem cells to form spheroid by chitosan surface 16 1.4.1 3-D cell culture concept 16 1.4.2 Chitosan biomaterial 18 1.4.3 Use of chitosan to induce spheroid formation 19 1.5 Hypothesis and Specific Aims 21 Chapter 2 Materials and Methods 22 2.1 Preparation of the chitosan-coated plate and conduit 22 2.2 ASC culture and spheroid formation 23 2.3 Sciatic nerve transection and treatments 24 2.4 Examination of myelin sheath 25 2.5 Histologic assessments 27 2.6 Innervated muscle weight and remodeling of muscle fibers 29 2.7 Gait analysis 30 2.8 Statistics 31 Chapter 3 Results 32 3.1 Improvement of nerve regeneration by using various conduits and cell therapies 32 3.1.1 Chitosan conduit enhances axon regeneration and re-myelination 34 3.1.2 Chitosan conduit or cell therapy reduces glial scar formation 36 3.2 Prevention of effector muscle atrophy and maintenance of muscle fibers 38 3.3 Chitosan conduit and neurosphere cells improve motor function 41 3.4 Anti-inflammation signal mechanisms for improving nerve regeneration 43 Chapter 4 Discussion 46 Chapter 5 Future Works 53 Chapter 6 Conclusion 54 Reference 55 Thesis related publication 64 Non-thesis related publication 65 Grants 66 Author's Curriculum Vitae 67

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