根據衛生署統計，台灣地區十大死亡原因，腦中風高居第二位，佔全部死亡人數的18%左右。在缺血性腦中風研究上，多以建立大白鼠腦缺血動物模式進行探討，傳統方法有結紮法和栓塞法兩種，但由於困難度高或成功率低，在技術上有其限制。為了克服傳統腦缺血動物模式之不足，本研究之目的，希望建立一個雷射誘發大白鼠頸動脈血栓的平台，透過對光敏感染料劑量與雷射功率之控制，達到血栓生成，並以影像軟體進行分析血栓栓塞後頸動脈管壁厚度，作為調整參數之條件。在動物模式建立後，將以納豆萃取物(natto extract)及阿魏酸(Ferulic acid) 投予頸動脈血栓形成之大白鼠進行治療，來探討納豆萃取物(natto extract)及阿魏酸(Ferulic acid)對本動物模式之治療成效。
本研究自行組裝出即時觀測並可分別控制雷射波長532 nm及650 nm的兩種雷射照射大白鼠顯微手術部位，可成功誘發大白鼠頸動脈內皮細胞增生之平台設備。以波長532 nm之DPSS Green Laser為誘發光源，搭配Rose bengal dye 60 mg/kg，照射600秒，四週後大白鼠頸動脈管壁明顯增生0.08 ± 0.02mm。而以波長650 nm之 Laser Diode為誘發光源，搭配Evans blue dye，嚐試多種條件組合均未引起大白鼠頸動脈內皮細胞增生。以納豆萃取物10ml/kg(natto extract)及阿魏酸80mg/kg(Ferulic acid)對大白鼠頸動脈血栓進行治療及成效評估，頸動脈切片以H&;E染色顯微鏡及螢光染色共軛焦顯微鏡觀察及影像分析，結果發現確實可以減緩頸動脈管壁的增生。本研究經由光化學反應實驗參數之修正，提出適合相近於人類慢性血栓形成病理研究之雷射誘發頸動脈血栓之平台，確實結合學術工程技術與醫學臨床應用，以促進腦中風基礎研究的發展。

According to the department of health, out of top ten leading causes of death, stroke has become the second leading cause of death, amounting to 18% of the total mortality rate in Taiwan. Traditional animal models for investigating mechanisms of ischemic stroke mostly take advantages of two different techniques: ligation- and embolism-induced ischemic stroke in rats. Although being widely used, their applications are limited due to technical challenges and low success rate. In order to avoid the technical pitfalls and limitations seen in the animal model, we developed a laser-based microplatform to induce carotid artery thrombosis in rats. Formation of thrombus can be achieved by administrating various amount of photosensizer dyes with simultaneous exposure to appropriated intensity of laser light sources. Coupling the microscopic image analysis which provides the information on vascular thickness of carotid artery, one can formulate critical parameters for desirable experimental outcomes. Once the animal model is developed, We will evaluate therapeutic effects on eliminating carotid artery thrombus induced in experimental animals by administering natto extract, an anti-thrombotic agent extracted from natto, and ferulic acid, an anticancer agent.

We developed a real-time laser-based microplatform, equipped with two different laser intensities at wavelength of 532 nm and 650 nm, to induce carotid artery thrombosis in rats. Carotid artery thrombosis was induced by a simultaneous exposure to DPSS Green Laser at 532 nm wavelength with an injection of 60 mg/kg. Rose bengal dye. A significant increase in carotid artery proliferation by 0.08 ±0.02 mm thickness was observed 4 weeks after treatment in treated animals. In contrast, rats treated with various combinations of simultaneous exposures to Laser Diode at 650 nm wavelength with injections of Evans blue dye showed no significant increase in carotid artery proliferation. Furthermore, microscopic analysis of tissue sections taken from rats developed carotid artery thrombosis induced by formal treatment, using H&E staining microscopic and immunofluorescence confocal microscopic analyses, administration of 10ml/kg natto extract and 80 mg/kg ferulic acid to treated rats significantly decreased the proliferation. By altering the various experimental parameters, our long term goal of this investigation is to develop and establish a laser-induced carotid artery thrombosis animal model that closely resembles the underline mechanism of chronic thrombosis seen in stroke patients in clinic, a classic example of bridging both academic engineering and clinical applications in stroke research.

摘要..............................................................................................................I
ABSTRACT.............................................................................................III
誌謝.............................................................................................................V
目錄..........................................................................................................VII
圖索引.........................................................................................................X
表索引....................................................................................................XIII
第一章簡介..............................................................................................1
1.1 心臟血管疾病之類....................................................................2
1.2 血栓形成........................................................................................4
1.3雷射誘導系統及其特性........................................................................6
1.3.1 雷射器件及其特性.....................................................................6
1.3.2 雷射於醫學與生物學之應用...................................................10
1.4.ROSE BENGAL(孟加拉紅)介紹............................................................11
1.4.1化學結構....................................................................................12
1.4.2 Rose bengal吸收光譜...............................................................13
1.5.EVANS BLUE 介紹.................................................................................13
1.5.1 Evans blue化學結構.................................................................14
1.5.2 Evans Blue吸收光譜.................................................................14
1.6.光化學反應..........................................................................................15
1.7.大白鼠頸動脈血栓模式之發展..........................................................18
1.8納豆的介紹..........................................................................................19
1.8.1 納豆萃取物...............................................................................19
1.8.2 納豆激酶...................................................................................20
1.9阿魏酸..................................................................................................21
1.9.1 Ferulic acid 的來源...................................................................22
1.9.2. Ferulic acid 的物理化學性質..................................................23
1.9.3. Ferulic acid 之藥理作用與活性..............................................24
1.10實驗目的............................................................................................26
第二章實驗材料與方法........................................................................27
2.1建立雷射誘發大白鼠頸動脈血栓之模式.........................................27
2.2建立雷射誘發頸動脈血栓之平台.....................................................30
2.3納豆萃取物(NATTO EXTRACT)及阿魏酸(FERULIC ACID)對大白鼠頸動脈血栓進行治療................................................................................33
2.4雷射誘發大白鼠頸動脈血栓之效果.................................................34
2.4.1 雷射誘發大白鼠頸動脈血栓模式參數之建立.......................34
2.5抗血栓藥物抑制大白鼠頸動脈血栓形成之模式.............................36
2.5.1建立雷射誘發大白鼠頸動脈血栓形成動物模式....................36
2.5.2探討納豆激酶、納豆萃取物、阿魏酸對血管增生減緩效果之影響.....................................................................................................37
2.6統計分析方法(STATISTICAL ANALYSIS)..............................................39
第三章實驗結果......................................................................................40
3.1雷射體系之建立..................................................................................40
3.2實驗參數的建立..................................................................................45
3.3雷射誘發大鼠頸動脈血栓動物實驗..................................................46
第四章討論..............................................................................................56
4.1雷射波長之選擇..................................................................................56
4.2腦中風缺血型動物模式......................................................................57
4.3雷射誘發大鼠頸動脈血栓動物實驗..................................................60
第五章結論及未來展望..........................................................................63
5.1結論......................................................................................................63
5.2未來展望..............................................................................................64
參考文獻....................................................................................................65
相關發表....................................................................................................78

圖索引
圖-1動脈粥狀硬化的發展.........................................................................5
圖-2 Rose bengal化學結構式…………………………………………...12
圖-3 Rose bengal吸收光譜.......................................................................13
圖-4 Evans blue化學結構.........................................................................14
圖-5光化學反應過程(Photochemical Reaction Processes).....................15
圖-6光敏感反應........................................................................................16
圖-7實驗性血栓形成模式........................................................................17
圖-8納豆激酶立體結構及其活性部位...................................................20
圖-9 Ferulic acid化學結構式...................................................................23
圖-10股靜脈插管......................................................................................28
圖-11股靜脈插管注射染劑......................................................................28
圖-12半導體激發式固態倍頻綠光雷射.................................................31
圖-13雷射光源誘發位置示意圖.............................................................32
圖-14雷射誘發大白鼠頸動脈血栓後投予納豆萃取物及阿魏酸.........34
圖-15不同染料劑量、雷射功率與雷射誘發照射時間實驗流程.........35
圖-16自測染劑Rose bengal 及 Evans blue吸收光譜..........................40
圖-17雷射二極體激發固態綠光雷射及雷射二極體紅光雷射實體圖.41
圖-18 (A)雷射二極體激發式固態綠光雷射波長532nm，(B) 雷射光點直徑固定至半高寬0.6mm接近大白鼠頸動脈直徑....................42
圖-19自製雷射顯微觀測系統示意圖.....................................................43
圖-20光譜儀測定綠光雷射波長532nm.................................................44
圖-21半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，不同時間點犧牲大鼠，以光學顯微鏡觀察其頸動脈血管管壁增生厚度(mm).................................................................................46
圖-22半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，，術後第28天，頸動脈冷凍切片，H&E染色觀察大鼠頸動脈管壁增生。 (A) control組，(B)納豆激酶餵食組－40mg/kg，(C)納豆萃取物餵食組－10ml/ kg...........................................……..47
圖-23半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，術後第28日，頸動脈冷凍切片，H&E染色，以光學顯微鏡觀察餵食納豆激酶組和納豆萃取物組，二者皆有減緩大鼠動脈血管管壁增生的作用...................................................................48
圖-24半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，術後第28日，頸動脈冷凍切片，以螢光染色，共軛焦顯微鏡觀察大鼠頸動脈管壁。(A) 內皮細胞，(B)平滑肌，(C)細胞核，(D)影像重疊…………………………………………………………49
圖-25半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，餵食納豆激酶 35日(術前7日及術後28日)，術後第28日，頸動脈冷凍切片，螢光染色以共軛焦顯微鏡觀察大鼠頸動脈管壁增生。(A)內皮細胞(B)平滑肌(C)細胞核(D)影像重疊.........50
圖-26半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，餵食納豆萃取物 35日(術前7日及術後28日)，術後第28日，頸動脈冷凍切片，螢光染色以共軛焦顯微鏡觀察大鼠頸動脈管壁增生(A)內皮細胞(B)平滑肌(C)細胞核(D)影像重疊.............51
圖-27半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，餵食阿魏酸(80mg/kg)35日(術前7日及術後28日)，術後第28日，頸動脈冷凍切片，螢光染色以共軛焦顯微鏡觀察大鼠頸動脈管壁增生(A)內皮細胞(B)平滑肌(C)細胞核(D)影像重疊…………………………………………………………….…51
圖-28 (A)正常大鼠頸動脈，H&E組織染色切片(B)半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，術後第28日，頸動脈冷凍切片，H&E組織染色之頸動脈管壁增生………………..……………………………………………..…53
圖-29半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，術後第28日，頸動脈冷凍切片，(A) H&E染色，一般顯微鏡觀察，(B)免疫螢光染色，共軛焦顯微鏡觀察，大鼠頸動脈管壁增生…………………………..……………………………………..54
圖-30 阿魏酸對光化學反應內皮細胞增厚的影響。半導體激發式固態倍頻綠光雷射532nm，固定功率10mW，照射大鼠頸動脈600秒，在Rose bengal 染劑劑量60 mg/kg下，術後第28日，頸動脈冷凍切片，H&E染色觀察大鼠頸動脈管壁增生。.........54
表索引
表- 1不同雷射體系與其典型參考數值....................................................9
表- 2 抗原比較表......................................................................................38
表- 3 不同參數引發大鼠頸動脈內皮細胞增生比較表.........................45
表- 4過去文獻與本研究各項參數之比較..............................................59

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