肥胖是一場健康災難，可能會導致許多種慢性疾病，其中包括了心血管疾病、糖尿病……等。這篇論文提出了將壓電材料鈦酸鋇（BaTiO3, BT）與辣椒素（Capsaicin, Cap）以化學反應接枝，使用最能被患者接受的口服方式給藥，模擬一自供電胃電刺激器，以非侵入自供電方式電刺激迷走神經控制體重。將此自產電BT@Cap粒子系統以管餵投遞方式遞送至飲食誘導肥胖（Diet-Induced Obese, DIO）小鼠之胃中，BT@Cap粒子會靶向胃粘膜內對Cap敏感的感覺神經末梢，粒子於胃蠕動時被施予壓力，自發性地產生溫和的電脈衝，將此訊號通過迷走神經傳遞訊號至腦部下視丘位置影響食慾與新陳代謝。BT@Cap粒子被胃中capsaicin酵素分解脫落於胃神經末梢之前，迷走神經的刺激約90分鐘左右。經過3週的每日兩劑管餵治療，BT@Cap治療之DIO小鼠組其食物攝取量及體重相對於對照組小鼠明顯減少，有效改善了他們的肥胖和肥胖相關的代謝功能障礙。期望此BT@Cap粒子系統可作為一新穎的治療方法，通過口服無創自產電腸腦神經刺激，應用於肥胖的臨床治療。





關鍵字：肥胖、控制體重、壓電材料、辣椒素、迷走神經刺激

Obesity is a health disaster that may causing numerous chronic diseases, including cardiovascular disease, diabetes, etc. This thesis proposes a piezoelectric material BaTiO3 (BT) that are chemical conjugated with capsaicin (Cap). Simulate a self-powered gastric electrical stimulator to electrically stimulate the vagus nerve for weight control by a noninvasively self-powered manner. Following oral administration in diet-induced obese (DIO) mice, self-powered BT@Cap particles system target the Cap-sensitive sensory nerve endings within the gastric mucosa. In response to gastric movement, the BT@Cap particles spontaneously generate mild electric pulses, which are transmitted to the hypothalamus of brain via vagal afferents to affect the appetite and metabolism. The stimulation of the vagus nerve lasts for about 90 min before the BT@Cap particles decompose by capsaicin enzyme of stomach and escape from the gastric surface. After three weeks daily two doses treatment, BT@Cap-treated DIO mice exhibit significant reductions in food intake and body weight relative to control mice, effectively improving their obesity and obesity-associated metabolic dysfunction. These findings suggest that the as-proposed BT@Cap particles may serve as a novel class of therapeutic regimens, through their noninvasive oral gut-to-brain neurostimulation by oral administration, for the clinical treatment of obesity.
Keywords: obesity, weight control, piezoelectric material, capsaicin, vagus nerve stimulation

摘要-----i
Abstract-----ii
目錄-----iii
圖錄-----iv
第一章 緒論-----1
1.1 肥胖與糖尿病-----1
1.2 迷走神經刺激-----2
1.3 壓電材料與辣椒素-----3
1.4 研究動機與實驗設計-----5
1.5 實驗架構-----6
第二章 材料與方法-----8
2.1 材料-----8
2.2 粒子合成與分析-----8
2.3 BT於模擬胃腸道下其物理穩定性測試-----11
2.4 粒子壓電之性能測試-----11
2.5 BT@Cap粒子於細胞之毒性測試-----11
2.6 實驗動物-----12
2.7 BT@Cap粒子之生物分佈-----12
2.8 迷走神經訊號之紀錄測試-----12
2.9 BT@Cap粒子管餵治療之療效-----13
2.10 統計分析-----15
第三章 結果與討論-----16
3.1 BT和BT@Cap粒子的分析 16
3.2 BT@Cap粒子對腸上皮細胞之毒性測試-----21
3.3 管餵BT@Cap粒子的體內生物分佈及其對小鼠迷走神經傳入的壓電響應-----21
3.4 管餵BT@Cap粒子作為VNS刺激劑對DIO小鼠的抗肥胖作用-----23
3.5 BT@Cap介導的DIO小鼠VNS治療的抗肥胖機制與代謝指標-----27
3.6 BT@Cap對於DIO小鼠之生物安全性分析-----30
第四章 結論-----32
參考文獻-----33

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