當臨床上進行手術或處理意外創傷時，如何快速有效的達到止血以及傷口癒合的目的，到目前為止對於醫生來說仍然是個十分棘手的問題。另一方面，對於慢性潰瘍或長久無法癒合的傷口，如何提供創傷部位足夠的新生血管亦是促進此類型傷口修復重要且必需的步驟。為了解決上述所提到的醫療問題，在此研究中，我們開發出功能化的自聚合胜肽水膠，分別由兩段具不同功能的奈米胜肽序列 RADA16-GGQQLK (QLK) 和 RADA16-GGLRKKLGKA (LRK) 所組成。具有功能性序列QLK修飾的胜肽水膠，其經由轉谷氨酰胺酶交聯後，能顯著提升水膠的機械性質；值得注意的是，轉谷氨酰胺酶同時也屬於一種內源性的酵素，可在止血階段促使纖維蛋白之交聯強化。我們預期可利用此一特性來交聯自聚合水膠，而不需額外添加交聯劑，是另一個潛在的優勢。另一方面，藉由功能性序列LRK和蛋白聚醣硫酸乙酰肝素之間良好的結合親和力，此自聚合胜肽水膠能緩效釋放出搭載包覆於其中的血管内皮生長因子和肝細胞生長因子。實驗結果顯示，此胜肽分子溶液能在接觸到生理環境時立即自組裝形成水膠，並且此自聚合水膠具有良好剪切恢復之特性，證明其屬於一種可注射式材料。經由酸鹼值之調整，自聚合水膠能產生連續緻密的奈米纖維纏繞，並建構出模仿細胞外間質微結構的三維立體網狀支架。透過將纖維母細胞包覆於水膠之中，我們證實水膠支架內的微結構能提供適合細胞生長存活的環境，並且藉由從水膠支架中釋放出的兩種生長因子，可經由協同作用進一步促進人類臍帶靜脈內皮細胞形成類血管狀的結構。在雞胚胎絨毛尿囊膜的實驗當中，我們發現搭載生長因子的水膠相較於單純水膠的組別，可以有效促進其周圍的血管以輻射狀向水膠處增生。總結整個研究，我們期望此功能化的自組裝胜肽水膠能成為一具有新穎及前瞻性的生醫材料應用於微創手術，並且對於缺血性疾病和慢性傷口的再生及修復能達到良好的治療效果。

How to efficiently stop bleeding and effectively facilitate wound healing is a critical challenge for surgical operation and emergency treatment in clinical settings. For ischemic diseases treatment, proper angiogenesis is potent and necessary via providing suitable vasculature supply to the injury sites. In view of these clinical unmet needs, we propose an applicable approach by designing functionalized self-assembling peptide (SAP) hydrogel with two sequences of RADA16-GGQQLK (QLK) and RADA16-GGLRKKLGKA (LRK) in this study. The SAP hydrogel conjugated with QLK functional motif can be cross-linked by endogenous transglutaminase, one of the intrinsic factors secreted during hemostasis process; thus, enhancing the mechanical property of the hydrogel without the need of external supply. On the other hand, the LRK sequence owns good binding affinity with heparan sulfate proteoglycan and can act as a cofactor by sustaining the release of embedded growth factors. The results show that this SAP solution undergoes self-assembling process in physiological environment, forms hydrogel in situ, and possesses good shear thinning property with injectability. After pH adjustment, the SAP develops densely-compacted fiber entanglements that closely mimics the three-dimensional fibrous framework of natural extracellular matrix. Such scaffold can not only support the survival of encapsulating cells but also promote the capillary-like tubular structure formation by dual angiogenic factors. The in vivo chicken chorioallantoic membrane assay demonstrates that the growth factor-loaded hydrogel promotes the growth of surrounding vessels in a spoke-wheel pattern compared to growth factor-free counterparts. In conclusion, we suggest that the designer bioinspired SAP hydrogel may be an attractive and promising therapeutic modality for non-invasive surgery and with niche for administration to ischemic tissue disorders and chronic wound healing.

Table of Contents
Abstract i
摘要 iii
Table of Contents iv
List of Figures viii
List of Tables x
Chapter 1. Introduction 1
1.1 The role of hemostasis 1
1.1.1 The importance of hemostasis 1
1.1.2 Hemostasis and factor XIII 2
1.1.3 Conventional and current strategies for hemostasis 3
1.2 The role of angiogenesis and vascularization 4
1.2.1 Important of angiogenesis 4
1.2.2 Angiogenesis mechanism 5
1.2.3 Angiogenic growth factor VEGF & HGF 6
1.3 Growth factors treatment for chronic wound healing 7
1.4 Development of self-assembling peptide materials 8
1.4.1 Introduction of self-assembling peptide 8
1.4.2 β-sheet and β-hairpin peptides 9
1.4.3 α-helical peptides and Lipid-like ultrashort peptides 10
1.4.4 Multidomain self-assembling peptide and Peptide amphiphile 12
1.4.5 Fluorenylmethoxycarbonyl (Fmoc) peptides 13
1.5 Motivation and objective of this study 15
Chapter 2. Literature Review 19
2.1 Experimental research for self-assembling hydrogel in tissue regeneration 19
2.1.1 First generation of self-assembling peptide 20
2.1.2 Second generation of self-assembling peptide 21
2.1.3 Future perspective of self-assembling peptide 24
2.2 Self-assembling peptide scaffold for bioactive therapeutics delivery 24
2.3 Induction of angiogenesis and vascularization via biological scaffolds 26
Chapter 3. Theoretical Basis 29
3.1 Proposed mechanism of RADA16 hydrogel formation 29
3.2 Novel crosslinking methods using transglutaminase enzyme 30
3.3 Effect of heparin binding consensus sequence, LRKKLGKA 32
3.4 Sustained growth factors release from glycosaminoglycan-assisted matrix 33
Chapter 4. Materials and Methods 36
4.1 Material list 36
4.2 Experimental design 37
4.3 Physiochemical characteristic analyses 37
4.3.1 Preparation of self-assembling peptide 37
4.3.2 Circular dichroism spectroscopy 38
4.3.3 MALDI-TOF mass spectrometry 38
4.3.4 Transmission electron microscopy and Atomic force microscopy 38
4.3.5 Rheological measurement 39
4.4 Formation and characterization of peptide hydrogel 39
4.4.1 Purification and activity quantification of microbial transglutaminase 39
4.4.2 Hydrogel formation and crosslinking process 39
4.4.3 In vitro disintegration profile of hydrogel 40
4.4.4 Isothermal Titration Calorimetry 40
4.4.5 Zeta Potential and Dynamic Light Scattering (DLS) Measurements 40
4.4.6 Growth factor encapsulating efficiency and release profile 41
4.5 In vitro studies 41
4.5.1 Culture of cells 41
4.5.2 3T3 cells cultured in three-dimensional peptide hydrogel scaffold 42
4.5.3 Cell viability assessment 42
4.5.4 Endothelial Tube-like Formation Assay 43
4.6 In vivo studies 43
4.6.1 Scanning electron microscopy 43
4.6.2 In vivo hemostasis efficacy 44
4.6.3 Incubation of fertilized eggs 44
4.6.4 In vivo chick chorioallantoic membrane (CAM) assay 45
4.6.5 Statistical analysis 45
Chapter 5. Results 46
5.1 Physiochemical and Structural Characteristics 46
5.1.1 Examination of β-sheet secondary structure 46
5.1.2 Observation of nano-fibrous microstructure 47
5.1.3 Investigation of rheological properties of hydrogel scaffold 48
5.1.4 Investigation of molecular weight by MALDI-TOF MS 49
5.2 Characterization of functionalized peptide hydrogel and the interaction between growth factors 50
5.2.1 In vitro disintegration profile of peptide hydrogel 50
5.2.2 Binding affinity of heparan sulfate and functionalized peptide sequence 51
5.2.3 Diameters and zeta potential of GF/HS complex 52
5.2.4 Release profiles of VEGF and HGF 53
5.3 In vitro studies 55
5.3.1 In vitro cytocompatibility of peptide hydrogel scaffold 55
5.3.2 In vitro regulation of tube-like formation by endothelial cells 57
5.4 In vivo studies 58
5.4.1 Hemostasis Efficacy 58
5.4.2 Angiogenic response in in vivo - chicken CAM assay 60
Chapter 6. Discussion 63
Chapter 7. Conclusion 68
References 69

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