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研究生： 程子芸
Cheng, Tzu Yun
論文名稱： 具自我聚合能力的功能性奈米胜肽材料於再生醫學上的應用
Characterization of Functionalized Self-Assembling Nano-peptides for Regenerative Medicine Applications
指導教授： 王子威
Wang, Tzu-Wei
口試委員: 張晃猷
Chang, Hwan-You
陳敏弘
Chen, Ming-Hong
學位類別： 碩士
Master
系所名稱： 工學院 - 材料科學工程學系
Materials Science and Engineering
論文出版年： 2012
畢業學年度： 100
語文別： 英文
論文頁數： 63
中文關鍵詞： 奈米材料 、功能性 、胜肽 、水膠 、神經幹細胞 、組織再生 、創傷性腦損傷 、止血
外文關鍵詞： Nanomaterial, Functionalized, Peptide, Hydrogel, Neural Stem Cells, Tissue Regeneration, Traumatic Brain Injury, Hemostasis
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    • 本研究致力於發展具自我聚合能力的功能性奈米胜肽材料(SAPs)於再生醫學上的應用。自我聚合能力的奈米胜肽材料(SAPs)具有在人體環境成膠的特質並且擁有以胺基酸作為材料的特點; 此外，奈米胜肽材料(SAPs)除了本身可作為三維立體網狀支架外，亦可當作包覆幹細胞或基因藥物的載體，，未來可望在生物醫學方面有廣泛的應用價值，極具發展潛力。藉由特殊的序列設計，在RADA16 的碳端延伸功能性的序列，如: GRGDS, YIGSR 以及IKVAV，我們發展出具自我聚合能力並且能分別提供促進細胞貼附、肝組織的再生與修復，以及促進神經幹細胞的成熟分化與突觸外生等額外效果的奈米胜肽材料。本研究期望能將此具自我聚合能力的功能性奈米胜肽材料應用於止血、肝組織再生與修復以及腦組織的重建。
    本研究的第一部分為物化性質以及成膠性值的探討。透過建立滴定取線求得各胜肽的酸解離常數(pKa)以及等電點(pI)，利用圓二色光譜分析胜肽的旋光性質，證實各胜肽皆具有beta-sheet折板二級結構，藉由原子力顯微鏡觀測得到胜肽排列堆疊形成直徑約25奈米的纖維網狀結構，最後藉由流變性質的分析探討機械強度與成膠行為。
    第二部分為止血及肝組織再生與修復的應用。我們在大鼠的肝臟製造穿刺大量流血的傷口模式，當胜肽材料注射入傷口時迅速成膠並形成奈米纖維屏障，進而達到快速止血的效果，大幅降低止血所需的時間到約只需8秒左右。進一步的組織分析結果可看出末端接上GRGDS, YIGSR特殊序列的胜肽，在2週之後肝臟組織的修復方面皆有較良好的表現。
    第三部分為中樞神經系統腦組織創傷重建的應用。我們特別將水膠包覆神經幹細胞，期望達到神經細胞再生的效果，並且進一步促進腦組織修復與重建。首先透過體外的分析，探討被包覆在三維水膠內進行培養的神經幹細胞行為表現。經由Live/Dead的染色分析及MTS定量分析，證實細胞具有良好的活性以及增生現象。此外，透過免疫染色分析，顯示被包覆的幹細胞能具有可塑性，並且驗證了末端接上IKVAV特殊序列的胜肽具有促進神經幹細胞誘導分化成神經細胞的效果。總結體外細胞培養的結果，驗證此胜肽水膠在成膠過程中，不會對神經幹細胞造成過度的傷害，具有良好的生物相容性。進一步的動物實驗，我們建立創傷性腦損傷大鼠模式，並且植入包覆有神經幹細胞的水膠，為了追蹤植入的細胞，在規劃的其中一些組別，我們特地將幹細胞進行螢光蛋白轉染標定。組織收集後的外觀結果，可證實胜肽水膠能夠很完整地填滿傷口缺陷處； 在組織切片圖分析中，證實植入的神經幹細胞存活良好並且只有觀測到短期的輕微發炎反應，末端接上IKVAV特殊序列的胜肽在神經細胞的再生及腦組織重建方面也有良好的表現。
    本研究成功發展出具自我聚合能力的功能性奈米胜肽材料應用於止血、肝組織再生與修復以及腦組織的重建。透過在RADA16 的末端延伸特殊功能序列以及包覆神經幹細胞，提升了自我聚合能力的奈米胜肽的應用價值。根據體外分析實驗，證實了此胜肽水膠具有良好的物化性質、生物相容性、以及自我成膠的特性，並且可以做為一個幹細胞培養基材。動物實驗結果顯示所開發出來的功能性奈米胜肽材料可有效促進止血以及肝臟與腦神經組織的再生。總結本研究所發展的具自我聚合能力的功能性奈米胜肽為一個具有前瞻性的新穎材料，可望在生醫領域上有相當大的應用價值及發展潛力。

    With the property of sol-gel transition in physiological condition and numerous advantages from peptide-based material, self assembling peptide (SAP) has been regarded as a promising 3D hydrogel scaffold or cell/gene (drug) carrier for the applications in tissue engineering and drug delivery system. The additional functional motifs with various modification ratios and multi-extended diversity can be conjugated and extended at the terminal residue sequence of specific-designed SAPs to enrich SAP possessing therapeutic functionality for different biopharmaceutical applications and serve as medical disease treatment modality. In this study, we specifically enriched RADA16, one of the widely used SAPs, with different functional motifs and evaluated the medical applications of the functionalized SAPs in hemostasis, liver tissue regeneration and brain neural tissue repair in the central nervous system.
    In the first part of this study, the physiochemical properties and gelation mechanism of SAPs were in detail investigated. The pKa1, pKa2, and isoelectric point (pI) was obtained by pH titration curve. The peptide showed net-charged at neutral pH value. The protein secondary structure of β-sheet arrangement was confirmed by circular dichroism (CD) spectroscopy. The morphology of nanofibers about 25nm diameter was observed by atomic force microscopy (AFM). The gelation behavior in terms of mechanical property of hydrogel was determined by oscillatory rheology test. As for in vitro experiments, the relative low cytotoxicity of peptide hydrogel was examined by Live/Dead assay and the high cell proliferation ability was shown in 3D hydrogel culture by MTS assay. The results demonstrated that the encapsulated neural stem cells well survived with 3D culture in SAP hydrogel. We also found that even with extended motifs, the gelation behavior, physical and chemical properties of functionalized SAPs were still preserved. It is believed that the functionalized SAPs can be a promising material for follow-up tissue engineering applications.
    In hemostasis and liver tissue regeneration study, specifically extended fragments of functional motifs derived from fibronectin and laminin, GRGDS and YIGSR, was designed to evaluate the capability of these functional SAPs in the effect of immediate hemostasis and accelerative liver tissue regeneration. The results showed that hemostasis can be achieved within 10 seconds and the histological analyses demonstrated by H/E stain and immunohistochemistry revealed that SAPs with these extended functional motifs significantly enhanced liver tissue regeneration in rat liver wound model. It is reported that SAPs enriched with the extended functional motifs not only maintained their spontaneous self-assembly property but also extensively advanced the potential therapeutic effect in hemostasis and liver tissue regeneration.
    In the study of brain neural tissue repair in the central nervous system, the functionalized RADA16-IKVAV peptide hydrogel was used to encapsulate neural stem cells (NSCs) for investigation of the effectiveness in brain tissue regeneration. The results showed that after 6 weeks transplantation, the regenerative extracellular matrix (ECM) of brain neural tissue was noticed. The specific neuronal protein markers, such as βIII tubulin, MAP2, NF-H were positively stained in the region of wound defect area, suggesting regenerative process of neuronal cells in the brain cerebral cortex.
    In summary, we have successfully developed functionalized SAPs with multiple extended motifs, including RADA16-GRGDS, RADA16-YIGSR and RADA16-IKVAV, and their physiochemical properties were also carefully evaluated for the comparison with RADA16 nanopeptides. These functionalized SAPs can not only be used alone as 3D nanoscale scaffold for immediate hemostasis and accelerative liver tissue wound healing, but also be incorporated with neural stem cells for the improvement of brain tissue repair in the central nervous system.

    Abstract I 摘要 III Table of Content V List of Figure........................................................................................................................................VII List of Figure.........................................................................................................................................IX Chapter 1. Introduction 1 1.1 Tissue Engineering and Extracellular Matrix-Like Scaffold 1 1.2 Self-Assembling Peptide 3 1.2.1 Introduction of Self-Assembling Peptide 3 1.2.2 Self-Assembling β-Sheet Peptide 4 1.2.3 Lipid-Like Self-Assembling Peptides 6 1.2.4 Self-Assembling α Helical Peptide 9 1.3 RADA16 11 1.3.1 Introduction of RADA16 11 1.3.2 Proposed Mechanism of Hydrogel Formation of RADA16 12 1.4 Functional Peptide Motif as Conjugated Signal 16 1.5 Hemostasis : Conventional Methods and Current Biomedical Materials for Hemostasis 17 1.6 Brain Tissue Regeneration 17 1.6.1 Traumatic Brain Injury (TBI) 17 1.6.2 Conventional Methods and Current Biomedical Materials for Brain Tissue Regeneration 18 1.6.3 Cell Therapy for Traumatic Brain Injury 18 Chapter2.Materials and Methods 20 2.1 Mechanism Study and Characteristic Analysis 20 2.1.1 Preparation of SAP Solution 20 2.1.2 Measurement of Apparent pk1, pk2, and Isoelectric Point (pI) 20 2.1.3 CD for Secondary Structure 20 2.1.4 AFM for Morphology 20 2.1.5 Rheology for Gelation Behavior Analysis 21 2.1.6 Statistical Analysis 21 2.2 Immediate Hemostasis and Rat Liver Tissue Regeneration 21 2.2.1 Hemostasis Experiment 21 2.2.2 Histological and Immunohistochemical Analysis 23 2.3 Brain Neural Tissue Repair in the Central Nervous System 23 2.3.1 Culture of Neural Stem Cells 23 2.3.2 SAPs Scaffold Preparation and Cell Seeding in 3D Hydrogel 23 2.3.3 Cell Viability and Proliferation Assay 24 2.3.4 In vitro Immunocytochemistry 24 2.3.5 Quantitative PCR 25 2.3.6 Transduction of Neural Stem Cells with Green Florescence Protein 25 2.3.7 Surgical Procedures 25 2.3.8 In vivo Immunohistochemistry Analysis 27 Chapter3. Results 28 3.1 Mechanism Study and Characteristic Analysis 28 3.1.1 Measurement of Apparent pk1, pk2, and Isoelectric Point (pI) 28 3.1.2 β-Sheet Structure 29 3.1.3 Nanofiber Structure 30 3.1.4 Gelation Behavior 31 3.2 Immediate Hemostasis and Rat Liver Tissue Regeneration 34 3.2.1 Hemostasis Efficacy 34 3.2.2 Histology Analysis 34 3.3 Brain Neural Tissue Repair in The Central Nervous System 39 3.3.1 Cell Viability and Proliferation Rate in 3D Peptide Culture 39 3.3.2 Adhesive Gene Expression Analysis in 3D Peptide Hydrogel 40 3.3.3 NSCs Differentiation in 3D Peptide Hydrogel 41 3.3.4 Morphology Examination and H/E Stain of Regenerative Brain Tissue. 44 3.3.5 Survival and Distribution of Donor NSCs 48 3.3.6 In vivo Immunohistochemistry Staining of Differentiated NSCs and Regenerative Brain Neural Tissue 49 Chapter4. Discussion 52 4.1 Mechanism and Physiochemical Properties Study 52 4.2 Hemostasis and Liver Tissue Regeneration 53 4.3 Brain Neural Tissue Repair in the Central Nervous System 55 Chapter5. Conclusion 58 Reference 59

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