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研究生： 黃楚涵
Huang, Chu-Hann
論文名稱： 具一氧化氮緩釋功能之可注射仿貽貝黏覆蛋白新月形微球應用於腦創傷修復
Mussel-Inspired Injectable Self-Healing Microspheres Capable of Sustained Release of Nitrogen Oxide for Brain Traumatic Injury Repair
指導教授： 胡尚秀
Hu, Shang-Hsiu
口試委員: 黃玠誠
Huang, Chieh-Cheng
李亦淇
‪Lee, I-Chi
黃薇蓁
Huang, Wei-Chen
學位類別： 碩士
Master
系所名稱： 原子科學院 - 生醫工程與環境科學系
Department of Biomedical Engineering and Environmental Sciences
論文出版年： 2023
畢業學年度： 110
語文別： 中文
論文頁數： 108
中文關鍵詞： 微球 、微流道系統 、仿貽貝蛋白 、細胞黏附性水膠 、一氧化氮 、氣體治療 、腦創傷
外文關鍵詞： Microspheres, Micro-fluidic system, Mussel-inspired chemicals, Self-adhesive hydrogel, S-nitrosoglutathione (GSNO), gas therapy, TBI
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    • 受損性腦創傷(TBI)為一種由外力造成大腦產生異質性的大腦損傷。造成大腦成斑痕阻礙新生細胞的進入損傷區域進行組織修復。嚴重的免疫反應也會造成受損區域無法修復，新生血管及再生神經細胞難以進入受損區域，使受損區域的組織難以修復，且影響腦神經在受損區域的訊號傳遞。
    在組織工程中常以水膠進行填入腦受損區域，模擬細胞外間質以修復組織。傳統水膠形式雖具備高含水量、高生物相容性等優點卻缺少孔洞性以利細胞浸潤入受損區域造成修復效果受限。本研究將使用以PEGDA及Dextran為材料的水膠以微球形式填入腦損傷後造成的孔洞中進行組織修復。水膠由微流道系統製備以直徑約為150 μm 的微球形式注射入受損區空洞，具備雙層結構使微球具有裝載藥物及具備氣體協同治療的功能。微球雙層結構的內層中載入可釋放一氧化氮氣體之化合物，S-亞硝基穀胱甘肽(S-nitrosoglutathione, GSNO)。GSNO在雙層微球注入體內後會斷鍵並藉由微球的雙層結構緩釋出NO氣體，使受損區域免疫反應被抑制、促進受損組織血管新生。以PDA (Polydopamine) 修飾微球來改善PEGDA的高生物惰性使細胞無法貼附及增加材料黏附性。以兩步驟修飾微球，第一步在微流道晶片中載入外層水相使微球具備黏附性，第二步為通過微流道並以點光源照射行成微球後於表面塗布Polydopamine使其具有細胞黏附性。
    在細胞實驗中，證實經PDA改質並具備NO釋放之微球對於NIH-3T3及胚胎神經幹細胞 (Neural Stem Cells, NSCs)沒有細胞毒性。藉由和NIH-3T3細胞共培養後展現微球的高度細胞貼附能力，對於胚胎神經幹細胞具備刺激神經分化的能力。在體內動物實驗中，透過治療後7及60天的組織切片染色結果評斷PEGDA微球植入受損區域有益於降低短期的免疫反應，但缺少長期免疫反應抑制及血管新生或是促使神經分化的效果。相比於未經治療的控制組，經PDA改質及GSNO載入的最終治療組有較低的星狀膠質細胞的佔比面積。受損區域周邊的新生血管及神經細胞佔比面積也有最高的增加幅度。在動物行為實驗中，最終治療組也展示出最佳的四肢運用能力和靈活度。
    由以上實驗結果得知，本文所製作出經PDA改質的微球因具有球體間的黏覆性使其可形成更穩定的支架，降低長期免疫反應。在載入GSNO後可利用雙層結構緩是一氧化氮氣體並促進神經細胞分化及生長，提供一種有效的腦創傷治療方式。

    Traumatic brain injury (TBI) caused by external forces usually produce heterogeneous damage in the brain. The main reason for the deterioration of the injured area of the brain is that astrocytes accumulate to the injured area after brain injury, and then generate serious scars that would prevent cells from entering the injured area for tissue repair. Severe immune response leads to difficult revascularization and cellular infiltration, making the tissue in the injured area difficult to repair, and affecting the signal transmission of cranial nerves in the injured area.
    In tissue engineering, hydrogel is often used to fill the injured region of the brain to simulate extracellular matrix to repair the tissue. Although the traditional hydrogel has the advantages of high-water content and high biocompatibility, it lacks the porosity to facilitate the infiltration of cells into the damaged area, resulting in limited repair effect. In this study, we use PEGDA and Dextran as materials to fill in the cavity caused by brain injury in the form of microspheres for tissue repair. The hydrogel is prepared by micro-fluidic system and can be injected into the cavity in the form of microspheres (MPs) with a diameter of about 150 μm. S-nitrosoglutathione (GSNO) are loaded into the inner layer of the microsphere’s bilayer structure. GSNO breaks bonds and can slowly releases NO gas under room temperature due to the double-layer structure of microspheres. Local NO release can inhibit the immune response in the damaged region and promotes angiogenesis and neuro-regeneration. Modified microspheres with PDA (Polydopamine)will alter the PEGDA MPs’ characteristic from bio inertness to high cellular affinity. The microspheres are modified by PDA in two steps. The first step is loading polydopamine in the outer water phase of the micro-fluidic system to make microspheres possess self-healing ability. The second step is to coat a thin layer of polydopamine on the surface of microspheres, which can make microspheres cell-adhesive and can anchor neural growth factor on the outer side of MPs.

    中文摘要 I Abstract III Chapter 1 Introduction 0 Chapter 2 Literature review and theory 1 2.1 Introduction of traumatic brain injury 1 2.1.1Astrocytes in traumatic brain injury 3 2.1.2 Microglia in traumatic brain injury 6 2.1.3ROS release post traumatic brain injury 7 2.2 Hydrogel for tissue engineering 10 2.2.1Microfluidic system and Phase Separation 12 2.2.2 Injectable hydrogels 14 2.2.3 Hydrogels for wound healing 15 2.2.4 Materials Implantation for Central Nervous System repair 16 2.3 Adhesive hydrogel 19 2.3.1 Bio-inspired Self-healing Hydrogels 22 2.3.2 Mussel-inspired Catechol-Based Adhesion 24 2.4 Biofunction of polydopamine 24 2.4.1 Mussel-inspired Self-healing Hydrogel 27 2.4.2 Polydopamine for stem cell adhesion 30 2.4.3 Polydopamine for neuron stem cell proliferation 31 2.4.4 Polydopamine for neuroprotection 32 2.5 Introduction of gas therapy for tissue engineering 34 2.5.1 NO for neurotransmission 35 2.5.2 NO for wound healing 37 2.5.3 NO for NSCs proliferation 39 2.5.4 NO releasing microspheres 40 2.5.5 NO donor: S-nitrosoglutathione (GSNO) 41 Chapter 3 Experimental section 44 3.1 Materials 44 3.2 Apparatus 46 3.3 Methods 48 3.3.1 Fabrication of microfluidic chip 48 3.3.2 Fabrication of microspheres by microfluidic chips 49 3.3.3Fabrication of Polydopamine coating microspheres 50 3.3.4 Fabrication of GSNO loading microspheres 51 3.3.5 Rheology test 51 3.3.6 GSNO release study 52 3.3.7 In vitro cell culture 52 3.3.8 Cell viability 53 3.3.9 Co-culture of NIH-3T3 cell with microspheres 54 3.3.10 Inhibition of ROS level 54 3.3.11 Embryonic NSCs extraction experiment 55 3.3.12 Differentiation of NSCs experiment 55 3.3.13In vivo experiment 57 3.3.14Brain collection and immunofluorescence staining 58 3.3.15 In vivo degradation of microspheres 59 3.3.16Animal behavior experiment 59 Chapter 4 Results and discussions 61 4.1Characterization of microspheres 61 4.2Characterization of polydopamine coating microspheres 65 4.3 Self-healing property and rheology test for microspheres 69 4.4 Characterization of GSNO loading microspheres 71 4.5 In vitro Cytotoxicity of materials 73 4.6 In vitro co-culture of microspheres and cells 76 4.7 In vitro ROS reduction effect 77 4.8 In vitro NO detection 80 4.8 In vitro stimulate neuron differentiation 81 4.9 In vivo therapy and analysis 85 4.10 In vivo degradation of microspheres 95 4.11Animal behavior 97 Chapter 5 Conclusion 100 Reference 102

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