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標題: | 自癒合水膠於神經組織工程之應用 Application of self-healing hydrogels in neural tissue engineering |
作者: | 鄭堃志 Kun-Chih Cheng |
指導教授: | 徐善慧 Shan-hui Hsu |
關鍵字: | 幾丁聚醣,自癒合水凝膠,可注射水凝膠,聚胺脂,生物3D列印,神經系統修復,犧牲水凝膠,血管化結構,葡萄糖敏感, chitosan,self-healing hydrogel,injectable hydrogel,polyurethane,bioprinting,nervous system repair,sacrificial hydrogel,vascularized structures,glucose-sensitive, |
出版年 : | 2024 |
學位: | 博士 |
摘要: | 神經系統的意外損傷及退化所造成的疾病,是大多數現代人可能面臨到的問題。在過去的治療方式,例如植入神經導管、植入含有神經幹細胞的支架或是直接注射幹細胞等。然而每個受傷的部位都不相同,且受傷的傷口大小也不一樣,過去的治療方式顯然存在一些限制。因此,本論文將探討幾丁聚醣自癒合水凝膠的性質,並搭配生物3D列印,應用於神經修復系統。同時,將犧牲材料引入用作製造神經系統周邊之血管化結構,使整體的神經系統更加完整。在第一部分中,將非常微量的纖維素奈米纖維嵌入幾丁聚醣自癒合水凝膠中,形成具有可調整自癒合性質之幾丁聚醣複合水凝膠。神經幹細胞於幾丁聚醣複合水凝膠中有較高的氧代謝與神經分化的現象。在斑馬魚腦損傷模型中,幾丁聚醣複合水凝膠比傳統幾丁聚醣自癒合水凝膠,具有更好的治療效果。此可調整自癒合性質之新型自癒合水凝膠,為具有神經組織潛力的水凝膠提供了設計的改念。在第二部分中,利用新製備之水性三元軟鏈段之溫敏性聚胺酯與幾丁聚醣自癒合水凝膠互相結合,開發了一系列雙網絡之聚胺脂-幾丁聚醣複合水凝膠。該水凝膠具有自癒合特性和生物3D列印性,可以客製化不同的損傷模型。複合水凝膠可以增強生物3D列印時的穩定性,且生物3D列印後的複合水凝膠具有較好的細胞增殖率與神經幹細胞的分化效果。第三部分中,為了讓整個神經修復系統更加完整,藉此引入的犧牲水凝膠作為犧牲材料,用來構建神經周圍的血管化通道。此犧牲水凝膠主要是以二硫蘇糖醇與硼砂製備而成,因此具有葡萄糖敏感的特性。同時,因為犧牲水凝膠內部鍵結相互競爭效應,使其還具有自癒合、可注射、和3D列印性能。將內皮細胞嵌入犧牲水凝膠中透過生物3D列印至載有神經乾細胞的非犧牲水凝膠中,在一段時間後,可以觀察到毛細血管的結構與血管化通道的形成。以上的研究提出了針對完整神經系統修復之自癒合水凝膠系統與改進之策略方式。 The diseases resulting from unexpected injuries and neurodegeneration present significant challenges for the majority of modern individuals. Previous treatment modalities, such as nerve conduit implantation, scaffolds incorporating neural stem cells, or direct stem cell injections, have limitations due to the heterogeneous nature and varying sizes of different injuries. Thus, the objective of this research is to investigate the properties of chitosan-based self-healing hydrogels and their potential application in neural repair systems, particularly in conjunction with bio-3D printing technology. Additionally, the introduction of sacrificial materials aims to create vascularized structures in the vicinity of the nervous system, thereby enhancing its overall integrity. In the first part of this study, a small quantity of cellulose nanofibers was incorporated into a chitosan-based self-healing hydrogel to develop a chitosan-based composite hydrogel with adjustable self-healing properties. Within this composite hydrogel, neural stem cells exhibited improved oxygen metabolism and neural differentiation phenomena. When tested in a zebrafish brain injury model, the chitosan composite hydrogel demonstrated superior therapeutic effects compared to pristine chitosan-based self-healing hydrogel. This innovative self-healing hydrogel, with its adjustable properties, holds promise for tissue engineering applications in neural repair. The second part of this study focused on the development of a series of double-network polyurethane-chitosan composite hydrogels. The composite hydrogels were accomplished by combining an aqueous ternary soft segment polyurethane that possesses temperature-sensitive properties with a chitosan self-healing hydrogel. These hydrogels possess self-healing properties and can be used for bioprinting, allowing customization for different injury models. The composite hydrogel enhances the stability during bioprinting, and the bioprinted composite hydrogel exhibits improved cell proliferation rates and effective differentiation of neural stem cells. In the third part, a sacrificial hydrogel was introduced to create vascularized channels surrounding the nerves, contributing to a more comprehensive neural repair system. This sacrificial hydrogel, primarily prepared using dithiothreitol and borax, demonstrated glucose-sensitive characteristics. Furthermore, it displayed self-healing, injectability, and 3D printing capabilities, facilitated by competitive chemical bonding within the hydrogel structure. Endothelial cells were embedded within the sacrificial hydrogel and bioprinted into the non-sacrificial hydrogel loaded with neural stem cells. Over time, the formation of capillary-like structures and vascularized tunnels could be observed. This study introduces self-healing hydrogel systems and innovative strategies tailored specifically for the repair of the entire neural system. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92000 |
DOI: | 10.6342/NTU202400464 |
全文授權: | 同意授權(限校園內公開) |
顯示於系所單位: | 高分子科學與工程學研究所 |
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