神經相關疾病通常肇因於特定腦區或神經元之過度活化或抑制。儘管許多相關疾病已能藉由藥物控制，但藥物在治療過程中可能會對健康組織造成後遺症。目前臨床上已有許多不需使用藥物亦可局部調控神經活性的方式，但仍有缺點，例如：深層腦部電刺激屬侵入性手術並常伴隨著術後感染與誘發併發症等；穿顱電刺激與穿顱磁刺激為非侵入性治療但其空間解析度不高，可能會同時刺激到非目標區域並引起副作用，且此方法無法刺激到較深層之腦區。因此發展非侵入性、高度空間選擇性的神經調控方式，是目前臨床腦疾病治療急需解決的問題。
我們的研究團隊先期已合成出具有壓電特性之二硫化鉬奈米層片，其層狀結構僅需較小之外力即能產生壓電效應，也能增加其與細胞之反應表面積。藉由二硫化鉬奈米層片可能具有將超音波機械力轉換成電能的特性，本研究將探討以超音波照射二硫化鉬奈米層片產生之電能，改變神經細胞膜之電位差以刺激神經細胞可行性，企圖發展出一套非侵入式且具有高度空間解析度之神經調控方式。
本研究分為兩個部分：第一部分證實了2 MHz頻率之超音波可以驅使二硫化鉬奈米層片產生壓電效應，其強度與超音波聲壓為正相關。接著在細胞實驗中，利用超音波驅使二硫化鉬奈米層片產生壓電效應並觀察到細胞內Ca2+濃度的變化，我們總結出驅動二硫化鉬奈米層片產生壓電刺激細胞之聲學參數閾值之聲壓為400 kPa、週波數為10^6週期，可驅動約37.9 ± 7.4%之細胞發生細胞內Ca2+濃度變化。並利用離子通道抑制劑驗證觀察到此現象並非由超音波之機械力誘發，而是藉由二硫化鉬奈米層片之壓電效應驅使電位門控型離子通道開啟，使細胞外之Ca2+進入細胞。實驗過程中我們也確保超音波參數對細胞沒有顯著之傷害，並且避免超音波對細胞產生之熱效應。
第二部份利用穿顱注射將二硫化鉬奈米層片種植於小鼠大腦之中隔內核，並且證實加入二硫化鉬奈米層片後，相較於只有超音波刺激之組別提高約29.5 ± 12.2%之細胞比例被刺激，超音波射束以外之區域則無細胞刺激。顯示此方式可穿顱精準刺激目標腦區之神經細胞。
綜合以上資料，本研究成功利用超音波與二硫化鉬奈米層片提出一項非侵入式且高空間解析度之神經調控方式，並首次應用於動物實驗。未來工作將進一步對二硫化鉬奈米層片進行功能化與非侵入式遞送手段，使材料標靶至目標腦區或特定細胞類型，提升材料對細胞類型之選擇性。

Neuronal diseases usually caused by over excitation or inhibition of specific brain area or neurons. Most of these diseases can be controlled by drugs, however, it may affect other health tissues. To date, several clinical methods have been developed that can partially control neuronal activities without drugs, but still have some problem. Deep brain stimulation is necessary an invasive surgery, followed by attendant risks including infection and induced complications. Transcranial direct-current stimulation and transcranial magnetic stimulation are non-invasive therapies but with low spatial resolution. Therefore, developing a non-invasive and high spatial resolution method to control neuronal activities is desired.
Our team have developed a new type of piezoelectric MoS2 nanosheets based on few layers. Layered-structure may increase the reactive surface with cells and can be triggered by low mechanical stress. Taking advantage of its ability to transfer mechanical stress to electricity, we use ultrasound to trigger MoS2 nanosheets. Piezoelectricity can change the membrane potential and excite the neurons. Here we combined ultrasound with MoS2 nanosheets to develop a non-invasive and high spatial resolution way to modulate neuronal activities.
There are two parts in our research. First, we demonstrated that 2-MHz ultrasound can trigger MoS2 nanosheets generating piezoelectricity, and the dielectric strength is proportional to acoustic pressure. In cell experiments, we observed the calcium fluxes when applying ultrasound treated with MoS2 nanosheets. The ultrasound threshold to activate cells was at a pressure of 400 kPa and cycle number of 10^6, with 37.9 ± 7.4% of cells activated; moreover, we tested with appropriate blockers and demonstrated that voltage-gated ion channels on the membrane were activated and the calcium ions fluxed from the out-site of the cell, but the mechanosensitive ion channels were not involved in.
Second, we planted the MoS2 nanosheets in the septal nucleus of mice brain. Compare to ultrasound only group, applying ultrasound treated with MoS2 nanosheets activated higher proportion of cells with 29.5 ± 12.2%. In addition, applying ultrasound without MoS2 nanosheets could not activate neurons. The result showing that combining ultrasound with MoS2 nanosheets could selectively stimulate neurons in targeted brain area without affecting nearby cells.
In conclusion, we used ultrasound and MoS2 nanosheets to develop a non-invasive and high spatial resolution method to modulate neuronal activities, and first applied to in vivo experiments. Future works will focus on functionalizing the MoS2 nanosheets with cell-specific targeting ligands and development of non-invasive routes to delivery MoS2 nanosheets into brain, allowing target nanoparticles to the specific brain area or cell types.

第1章 緒論 1
1.1 神經調控（neuromodulation） 1
1.1.1 深層腦部電刺激 1
1.1.2 穿顱電刺激 3
1.1.3 穿顱磁刺激 4
1.2 超音波（ultrasound）於腦神經調控之應用 5
1.2.1 超音波 5
1.2.2 聲遺傳學（sonogenetics） 8
1.3 壓電材料（piezoelectric material） 9
1.3.1 超音波與壓電材料應用於神經調控 10
1.4 二硫化鉬（MoS_2） 12
1.4.1 二硫化鉬之生物安全性 14
1.5 研究目的與方法 15
第2章 實驗材料與方法 17
2.1 緒論 17
2.2 材料製備 17
2.2.1 壓電材料製備 17
2.2.2 可見光吸收光譜分析 18
2.2.3 粒徑與介面電位（zeta-potential）量測分析 18
2.2.4 高解像能電子顯微鏡（HRTEM）拍攝 19
2.2.5 壓電力顯微鏡（PFM）拍攝 20
2.3 活性氧物質（reactive oxygen species）量測 21
2.4 細胞實驗 23
2.4.1 人類神經母細胞瘤細胞培養與繼代 23
2.4.2 細胞存活率測試 23
2.4.3 細胞轉染 24
2.4.4壓電效應誘發細胞反應之超音波參數閾值 25
2.4.5 MoS_2 NSs濃度對細胞產生螢光變化成功比例之影響 27
2.4.6 超音波與MoS_2 NSs誘發細胞內鈣離子濃度增加之機制探討 27
2.4.7 超音波刺激細胞之升溫測試 29
2.4.8 超音波重複刺激細胞之可行性測試 30
2.4.9 細胞螢光強度結果分析 30
2.4.10 細胞經刺激後之傷害評估 31
2.5 動物實驗 31
2.5.1 穿顱注射MoS_2 NSs於小鼠大腦 31
2.5.2 超音波刺激流程 32
2.5.3 免疫染色分析 33
2.5.4 動物實驗結果統計 34
2.6 統計分析 35
第3章 結果與討論 36
3.1 材料特性分析 36
3.1.1 可見光吸收光譜量測 36
3.1.2 粒徑與介面電位量測分析 37
3.1.3 高解像能電子顯微鏡拍攝 39
3.1.4 壓電力顯微鏡拍攝 40
3.2 活性氧物質量測 42
3.2.1 2 MHz超音波參數與壓電效應之關係 42
3.3 細胞實驗 43
3.3.1 細胞毒性測試 43
3.3.2 壓電效應誘發電位門控型離子通道開啟之超音波參數最佳化 44
3.3.3 MoS_2 NSs濃度對細胞產生螢光變化成功比例之影響 52
3.3.4 超音波與MoS_2 NSs誘發細胞內鈣離子濃度增加之機制探討 54
3.3.5 超音波刺激細胞之升溫測試 57
3.3.6 超音波重複刺激細胞之可行性測試 59
3.4 動物實驗 63
3.4.1超音波結合MoS_2 NSs誘發腦神經細胞去極化 63
第4章 結論與未來工作 67
4.1 結論 67
4.2 未來應用與發展 68

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