在臨床治療中，針對腦受損的議題，大多數的治療方針著重在如何避免受損後的腦組織持續流失，但鮮少治療方式能有效地促進受損腦組織的再生修復，達到腦細胞外基質及神經網絡的重建效果。近年來，根據許多研究顯示，若能促進腦部受損區域的血管再生，改善血流供應情形，不僅能避免受損區域的缺血性壞死，減少併發症產生。
有鑑於促進血管再生對於腦組織修復效率的提升以及極具潛力的組織再生支架的治療策略，本研究欲利用奈米胜肽分子開發一具有生物相容性以及促進血管再生能力的功能化自主裝奈米胜肽水膠支架，來促進受損區域的再生效果。此功能化奈米胜肽分子－RADA16－SVVYGLR能在水溶液中透過胜肽分子間的靜電吸引力以及疏水作用力進行自我聚合，形成奈米纖維，並且藉由奈米纖維的相互纏繞、聚集堆疊，構築出模仿細胞外間質、相互聯通並且富含水分的三維立體的網狀支架。為了賦予奈米胜肽水膠具有促進血管再生的能力，在自我聚合胜肽的末端延伸出源於骨橋蛋白並具有促進血管再生的功能性胜肽－SVVYGLR。該功能性序列在修飾於RADA16後，不僅仍保有本身促進血管再生的能力，且賦予自我聚合胜肽水膠調控人類臍帶靜脈內皮細胞的生長以及形成管狀結構的生物活性。透過將神經幹細胞包覆在胜肽水膠支架中，更進一步證實支架內的結構能提供細胞適宜生存環境並且利於生長。另外，該自我聚合胜肽分子的二級結構、奈米微結構、水膠支架的機械性質可以藉由調控水溶液的酸鹼值以及鹽類加入與否，進行調控。此依據不同的環境變化而導致的物化性質‭ (‬結構上、機械性等‭)‬轉變，能廣泛應用於不同的應用範疇。藉由斑馬魚幼魚毒性測試，該功能性自我聚合胜肽水膠具有高度的生物相容性；在幼魚生長發育的過程中，不會造成魚隻的畸形異變、血管生長異常甚至死亡等負面影響。藉由斑馬魚成魚的腦創傷模式實驗，透過功能性自我聚合胜肽水膠的植入治療，提升了該腦組織中的內皮細胞、外被細胞、放射狀膠細胞以及星狀細胞在腦部受損區域以及水膠注入位置的表現量，進而證明該水膠具有促進受損組織周邊血管再生的潛力，並且輔助腦受損組織的神經再生。
藉由結合自我聚合胜肽以及促進血管再生功能序列，本研究成功發展出能自我聚合並且具有促進血管再生的胜肽材料，進而提升了自我聚合奈米胜肽的應用價值。根據諸多實驗分析，證明該功能性胜肽水膠具有可調變的物化特性、良好的生物相容性，以及促進血管再生、提升神經組織再生並且促進受損區域功能性回復的能力。結合水膠的促進血管再生特性以及包覆幹細胞、治療性藥物的應用，本研究期望該功能性自我聚合胜肽水膠能成為一具有前瞻性的新穎材料，可望能應用於生醫領域中，提升受損組織的再生修復，解決腦受損的健康議題。

Brain disease may lead to irreparable neurological insults due to the limited regeneration capacity of the organ. Current therapeutic strategies for such health issue aim mainly at preventing tissue loss, but no clinical treatment has been used to reconstruct formed cavities. Nowadays, more and more evidences have shown that if the blood circulation in damaged brain area can be improved, that can not only prevent diseased area from being worse but also improve damaged tissue repair.
The tissue-engineered scaffold-based strategy has shown a promising potential as therapeutics for brain injury. In this study, functionalized self-assembling peptides have been employed to fabricate a biocompatible angiogenic hydrogel scaffold. Self-assembling peptide, RADA16, was exploited to form nanofibers through self-organizing process; via peptide nanofibers entanglement and aggregate, they further construct an ECM-mimicking scaffold. Herein, through cell encapsulation within peptide scaffold, such scaffold could support neural stem cells survival and proliferation. By the adjustment of pH condition and salt addition, the physicochemical properties of peptide material were tunable, which is beneficial to develop scaffolds meeting the various requirements in tissue engineering. To regulate the angiogenesis around injured site, the osteopontin-derived angiogenic peptide, SVVYGLR, was used to enrich RADA16 hydrogel as an angiogenic scaffold. Such functionalized hydrogel displayed the ability to regulate human umbilical vein endothelial cells growth and enhance the tube-like structure formation. Through zebrafish embryo toxicity test, the angiogenic peptide hydrogel was highly biocompatible and did not interrupt the development of zebrafish embryo and blood vessels. By the assessment of damaged brain wound healing, implanted angiogenic hydrogel could regulate the growth of cells involved in angiogenesis and neurogenesis, which have the potential in promotion of neuronal tissue regeneration as well as in the enhancement of brain functional recovery.
In summary, we have successfully developed functionalized self-assembling peptide with angiogenic motif, RADA16-SVVYGLR. Such peptide hydrogel can not only be used alone as an angiogenic scaffold but also be incorporated with drugs or cells in the tissue regeneration medicine. We expect this functionalized peptide hydrogel could support neural tissue regeneration and be a potential therapeutic application in the injured brain diseases.

Chapter 1. Introduction 13
1. 1 Brain injury 13
1. 2 Neurogenesis 14
1. 3 Angiogenesis in brain 16
1. 4 Clinical treatments for brain injury 18
1. 5 Self-assembling peptide biomaterials for tissue regeneration 20
1.5.1 α-helix self-assembling peptide 20
1.5.2 β-sheet self-assembling peptide 22
1.5.3 Lipid-like self-assembling peptide 23
1.5.4 Multidomain self-assembling peptide 25
1. 6 Motivation and objective of this study 27
Chapter 2. Literature reviews 29
2. 1 State of art in injured brain tissue regeneration 29
2. 1. 1 Cell-based strategy 29
2. 1. 2 Drug/ Biologics-based strategy 30
2.2 Experimental researches of novel scaffold-based strategy for injured brain tissue reconstruction 32
2. 2. 1 Biologic scaffolds 32
2. 2. 2 Synthetic biologic scaffolds 33
2. 3 Strategies for functionalizing scaffolds 35
2. 3. 1 Encapsulation of cells, drugs, or growth factors 35
2. 3. 2 Functional peptide motif as conjugated signal 37
Chapter 3. Theoretical basis 40
3. 1 Self-assembling mechanism of peptide, RADA16 40
3. 2 Effect of inducing angiogenesis by angiogenic peptide sequence, SVVYGLR 41
3. 3 Angiogenesis in the brain organ 44
Chapter 4. Materials and Methods 46
4. 1 Materials list 46
4. 2 Physiochemical characteristics analyses 47
4.2.1 Preparation of self-assembling peptide 47
4.2.2 Circular dichroism spectroscopy 48
4.2.3 Transmission electron microscopy 49
4.2.4 Rheological measurement 49
4. 3 In vitro examination of cytocompatibility and effect of tube-like structure formation 51
4.3.1 Culture of neural stem cell and human umbilical vein endothelial cell 51
4.3.2 NSCs cultured in the 3D peptide hydrogel scaffold 51
4.3.3 Live/Dead assay 52
4.3.4 MTS assay 52
4.3.5 In vitro angiogenesis assay 53
4.3.6 Statistical analysis 54
4. 4 In vivo biocompatibility of peptide hydrogel and efficacy 54
of improving wound healing 54
4.4.1 In vivo zebrafish embryo toxicity test (zFET) 54
4.4.2 In vivo brain disease model of adult zebrafish 55
4.4.3 Immunohistochemistry stain 56
4.4.4 Zebrafish optomotor response (OMR) 57
Chapter 5. Results 59
5. 1 Physiochemical characteristics analyses 59
5.1.1 Examination of β-sheet secondary structure of RADA16 and RADA16-SVVYGLR 59
5.1.2 Observation of fibrillar assembling in RADA16 and RADA16-SVVYGLR 62
5.1.3 Investigation of rheological properties of RADA16 and RADA16-SVVYGLR hydrogel scaffold 65
5. 2 In vitro cytocompatibility in neural stem cell and regulation of endothelial cells tube-like structure formation 68
5.2.1 Neural stem cell viability and proliferation in 3D peptide hydrogel 68
5.2.2 Tube-like structure formation by cultured endothelial cells 70
5. 3 In vivo biocompatibility of peptide hydrogel and efficacy of improving wound healing 72
5.3.1 Genetic and cytocompatibility of peptide hydrogel using zebrafish embryo toxicity test 72
5.3.2 In vivo zebrafish brain disease model for efficacy assessment of angiogenesis, neurogenesis, and wound healing 74
5.3.3 In vivo zebrafish brain functional recovery assessment by the examination of optomotor response (OMR) 79
Chapter 6. Discussion 81
6.1 Physicochemical properties of self-assembling peptide hydrogel 81
6.1.1 Peptides conformational change under various pH conditions 81
6.1.2 Peptide nanostructure transformation induced by various environmental factors 83
6.1.3 Peptide hydrogel stiffness with pH dependency 85
6.2 In vitro study for examination of peptide hydrogel biocompatibility and the effect of regulating tube-like structure formation 87
6.2.1 Peptide hydrogel with biocompatible microenvironment for encapsulated cells 87
6.2.2 Enhanced in vitro angiogenesis regulated by angiogenic self-assembling peptide hydrogel 89
6.3 In vivo study for examination of peptide hydrogel toxicity and effect on improving damaged brain tissue regeneration by zebrafish animal model 90
6.3.1 Non-developmental toxicity of peptide hydrogel for the growth of fish embryos and blood vessels 90
6.3.2 Induction of angiogenesis, improved neurogenesis, wound healing and brain functional recovery after peptide hydrogel treatment 91
Chapter 7. Conclusion 93
References 95

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