在現今的日常生活中，許多原因可能造成腦創傷(TBI)，例如車禍，激烈的運動，或是來自外界的直接重挫都有可能造成腦創傷，程度較輕的腦創傷會造成頭痛，暈眩，四肢不協調等，嚴重的情形則是會造成語言困難，四肢癱瘓，甚至是造成死亡。腦創傷的症狀只會不斷地變嚴重，不會自然的好轉，原因是因為在創傷的邊界會形成一個膠質疤痕，這疤痕會阻擋神經祖細胞進入創傷處分化成新生的神經細胞。在本研究中，我們製備出可注射的水膠球，可以注入腦創傷區使星狀膠細胞不會聚集於創傷邊界並且成為一個細胞支架，使新生細胞能隨著支架中的空隙生長，另外我們結合了可以應用於外部磁場以控制釋放藥物的多孔性金奈米粒子，透過電子顯微鏡(SEM)的觀察，可以看到奈米金粒子的外觀有如大腦一樣，其表面有著交錯的條狀結構，提供奈米金多孔的特性，這多孔的特性使奈米金具有攜帶藥物的能力，並在藉由外界高週波的刺激，瞬間的相反電場可使藥物釋放，達到治療的效果。在本研究中，我們使用的藥物為普羅布考(probucol)，此藥物原為用於降血脂的功能，於近期發現，此藥物可以抗氧化並且使細胞的能量消耗降低，以達到保護神經細胞的效果。經過表面電荷分析，改質後的金表面電荷為+12mV，可以由靜電吸引力吸附於表面電荷為-8mV的水膠球上，另外，測得普羅布考的電荷為負電，因此，除了可藉由金的多孔性吸附於孔洞中，亦可經由其靜電吸引力吸附。在本研究中發現，使細胞與水膠球共培養7天後，再以共軛焦顯微鏡拍攝，可以看到細胞能攀附在水膠球上，並且能將水膠球固定於基底上。在動物實驗中，我們以電鑽磨開老鼠的頭蓋骨，並再以生物穿孔器，於老鼠的大腦挖出一個直徑2mm，深度2mm的創傷，並以抗沾黏膜覆蓋住，再將傷口縫起來，於4天後再將傷口打開，填入水膠球於傷口中，並於3天後犧牲並將大腦切片。我們以GFAP來染色星狀膠細胞，以觀察疤痕的厚度以及其傷口周圍的螢光強度，可以發現疤痕的厚度由原本的200μm，經過水膠填入後，可以使疤痕的厚度幾乎消失，Iba-1用以微染膠質細胞，以觀察傷口處附近的免疫反應情形，以NeuN作為神經細胞的標靶，觀察藥物對於神經細胞保護的情形，最後再以BrdU染色新生的細胞，觀察傷口周圍是否有新生細胞的產生，最後以螢光強度分析，此水膠球與奈米金和藥物的結合，對於治療腦創傷有著不錯的治療潛力。

In today's daily life, many causes may cause trauma brain injury (TBI). For example, car accidents, intense sports, or direct heavy losses from the outside world can cause brain trauma. Lesser degree of brain trauma can cause headaches, dizziness, incompatibility of limbs, etc. In severe cases, it can cause language difficulties, limb paralysis, and even death. The symptoms of brain trauma will only continue to become severe and will not naturally improve, because a glial scar is formed at the boundary of the wound, which will block the neural progenitor cells from entering the wound and differentiate into new nerve cells. In this study, we prepared an injectable microgel ball that can be injected into the brain wound area so that the astrocyte does not accumulate at the wound boundary and becomes a cell scaffold, allowing the new cells to grow on the microgel scaffold. In addition, we combined porous gold nanoparticles that can be applied to an external magnetic field to control the release of drugs. Through observation by electron microscopy (SEM), it can be seen that the appearance of nano-gold particles is like the brain, and the surface has staggered strips. The structure provides the porous nature of nanogold. This porous property makes nanogold have the ability to carry drugs, and by the external high-frequency stimulation, the instantaneous opposite electric field can release the drug to achieve the therapeutic effect. In this study, the drug we used was probucol, which was originally used to lower blood fat. It was recently discovered that the drug can resist oxidation and reduce the energy consumption of cells to protect nerve cells. After zeta poential analysis, the modified gold surface charge is +12mV, which can be adsorbed on the water gel ball with a surface charge of -8mV by electrostatic attraction. In addition, the charge of probucol is negative, so probucol could be adsorbed in the pores and can also be adsorbed via its electrostatic attraction. In the present study, it was found that after the cells were co-cultured with the water-gel ball for 7 days, and then photographed with a conjugated focus microscope, it was observed that the cells could adhere to the microgel ball and the ball could be fixed on the substrate. In vivo experiment, we used the electric drill to open the skull of the mouse, and then used a biopunch to dig a wound with a diameter of 2 mm and a depth of 2 mm in the brain of the mouse, and covered it with anti-adhesion film, and then stitched the wound. The wound was opened 4 days later, filled with a water gel ball in the wound, and sacrificed 3 days later and the brain was sliced. We stained astrocyte cells with GFAP to observe the thickness of the scar and the intensity of the fluorescence around the wound. We observed that after filling in the microgel, the thickness of glial scar would be from 200μm to almost disappeared. Iba-1 was used to stain microglia cells to observe the immune response near the wound. Using NeuN as a label of nerve cells to observe the drug protection for nerve cells, and finally staining the newborn cells with BrdU, observed whether there were new born cells around the wound, and finally analyze the fluorescence intensity, the combination of the microgel ball and nano gold and drugs. It has a good therapeutic potential for the treatment of brain trauma.

中文摘要 III
Abstract V
Chapter 1 Literature review and theory 1
1.1 Introduction of traumatic brain injury 1
1.2 Introduction of astrocyte and microglia 5
1.3 Introduction of injectable materials 8
1.4 Nowadays tactic of nanoparticle 11
1.4.1 Composition 11
1.4.2 Surface Modification 14
1.4.3 Size 14
1.4.4 Surface charge 14
1.5 Functions of probucol 15
Chapter 2. Experiment section 17
2.1 Materials 17
2.2 Apparatus 18
2.3 Methods 19
2.3.1 Composite of porous gold nanoparticles (GNB) 19
2.3.2 Modification of GNB 19
2.3.3 Synthesis of GelMA 19
2.3.4 Microfluidic chip manufacturing 20
2.3.5 Using microfluidic chip to fabricate microgels 21
2.3.6 Loading probucol in GNB and combine gelma microporous hydrogel with GNB 21
2.3.7 Cell culture 21
2.3.8 Cell viability assay 22
2.3.9 Cellular uptake of GNB, GNB-probucol, GNB-HFMF and GNB-probucol-HFMF 23
2.3.10 In vivo experiments 23
Chapter 3. Results and Discussions 25
3.1 Composite and characterization of GNB 25
3.2 The characterization of microgel and probucol 26
3.3 Cell uptake and cytotoxicity 30
3.4 Cells cultured on microgel 35
3.5 In vivo therapy and analysis 36
Chapter 4. Conclusion 47

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