缺血性心臟病和中風是世界上最大的殺手，在二零一六年造成一千五百二十萬人死亡。這些疾病在過去十五年中仍然是全球主要的死亡原因。血栓不論是在動脈還是在靜脈中都可能造成嚴重損傷。當它發生在動脈時可能誘發急性腦中風或心血管疾病。靜脈血栓易發生於下肢靜脈引起致命的併發症，例如肺栓塞。先前的研究認為使用藥物式溶栓、機械式溶栓或兩者結合的治療方式，溶栓的效果可能取決於血栓的年齡和特徵不同。以前的研究也表明，微氣泡引導的溶栓是一種治療腦部血栓的方法，它是利用超音波的機械力使溶栓藥物結合微氣泡釋放來加速溶栓效果。本研究主要目的為透過核磁共振影像檢測不同血栓年齡的組織弛緩時間與訊號強度比，並且評估單純使用血栓溶素或同時結合血栓溶素和聚焦式超音波的溶栓效果。試圖發現不同血栓年齡適合的治療方法。
我們在體外實驗設計了兩種不同年齡的血栓以及九個治療組別。在體外實驗中，核磁共振影像訊號無法區分第二天和第七天的血栓，且結合聚焦式超音波和血栓溶素並未提升溶栓效果，因實驗的局限性導致結果不如預期。在體內實驗中，我們使用三氯化鐵在大鼠上誘發兩種不同的血栓年齡，並建立兩種不同的治療組別。治療組分別為單純使用血栓溶素和同時結合血栓溶素和聚焦式超音波。我們可以透過核磁共振影像建構的血栓立體模型，觀察在三個不同的溶栓時期血栓溶解的情況。透過溶栓率結果顯示，我們發現第二個小時的血栓適合單純使用血栓溶素溶栓，而第六小時的血栓透過血栓溶素結合聚焦式超音波溶栓的治療方式達到較好的溶栓率。除此之外此研究發現血栓治療前的T1以及T2弛緩時間與溶栓率有正向的趨勢。
綜合上述，我們的結果表明，在第六個小時的血栓中，血栓溶素結合聚焦式超音波治療優於單獨使用血栓溶素。在這項研究中找到不同血栓年齡適合的治療方式並且3D血栓模型可以提供即時的溶栓率。透過弛緩時間與溶栓率的結果，我們猜測T1和T2弛緩時間是預測溶栓率的重要指標。

Ischemic heart disease and stroke are the world’s biggest killers, accounting for a combined 15.2 million deaths in 2016. These diseases have remained the leading causes of death globally in the last 15 years. Whether the thrombus is formed in artery or vein, it can cause serious damage. When it occurs in artery may induced acute stroke or cardiovascular disease. Venous thrombus often induced deep vein thrombosis (DVT), which would cause fatal complications such as pulmonary embolism. Previous study considered that the effect of pharmacological thrombolysis, mechanical thrombolysis or a combination of these may depend on the anticoagulation of thrombus with variant ages and characteristics. Previous studies present that microbubble-mediated thrombolysis is a promising treatment for cerebral micro thrombi and is based on thrombolysis drug-combined MBs by ultrasound to accelerate thrombolysis. The purpose of this study were detected T1,T2 relaxation time, and signal intensity (%) in different thrombus ages and evaluated thrombolysis effect in different treatment groups, including injected Urokinase (UK) alone or combined UK and Focus ultrasound (FUS). This study will try to find suitable treatments for different thrombus ages.
We designed two different thrombus ages and nine treatment groups in in vitro. In vitro experiments, Magnetic Resonance Imaging (MRI) wouldn’t distinguish the thrombus of Day 2 and Day 7, and combined FUS and UK couldn’t improve the thrombolysis effect. There are some limitations that caused the result to be less than expected in vitro experiment. In vivo experiment, the FeCl3 was used to induce two different thrombus ages in Sprague Dawley (SD) rat and designed two different treatments groups. The treatment groups were urokinase alone and combination urokinase and focus ultrasound. We would observe the thrombolysis effect in three periods of thrombolysis by 3D model of thrombus. Based on thrombolysis (%) results, we found that thrombus age of Hour 2 was suitable for urokinase treatment group. And the thrombus of Hour 6 was suitable for combination urokinase and focus ultrasound. In addition, we find that the T1 and T2 relaxation time have positive trend with thrombolysis (%).
In conclusion, our results demonstrated the treatment group of Focus ultrasound combined with UK was better than UK alone in thrombus of Hour6. In this study find the treatment groups suitable for different thrombus ages. And the 3D thrombus model can provide thrombolysis in real-time. Based on the correlation of T1, T2 relaxation time and thrombolysis (%), we guess the T1 and T2 relaxation time are important indexes to predict thrombolysis effect.

Table ix
Figure xi
Chapter 1 Introduction 1
1.1 Thrombus 1
1.1.1 Formation of thrombus 1
1.1.2 Different thrombus ages 2
1.2 Focused Ultrasound and Microbubbles 4
1.2.1 Focused Ultrasound 4
1.2.2 Microbubbles 4
1.2.3 Mechanisms of Microbubbles Combined with Focused Ultrasound 5
1.2.4 Application of FUS and Microbubbles in thrombolysis 7
1.3 Thrombus in MRI 7
1.4 Clinical thrombolysis method 11
1.4.1 Medicine 11
1.4.2 Surgery 11
1.5 Motivation 12
1.6 Orientation of Dissertation 13
Chapter 2 Theory 15
2.1 T1 T2 mapping MRI 15
Chapter 3 Materials and Methods 18
3.1 Preparation of Microbubble and Phantom 18
3.2 In Vitro Experiment 19
3.2.1 Experimental Set-Up 19
3.2.2 Thrombus Preparation 21
3.2.3 MRI Acquisition 22
3.2.4 Ultrasound Parameter 22
3.2.5 Data Analysis Process 23
3.3 In Vivo Experiment 24
3.3.1 Experimental Set-Up 24
3.3.2 FeCl3 injury thrombosis models 25
3.3.3 Animal Preparation 28
3.3.4 Ultrasound Parameter 29
3.3.5 MRI Acquisition 29
3.3.6 Data Analysis 31
3.3.7 Tissue histology 33
3.4 Statistics analysis 34
Chapter 4 Results and Discussion: In Vitro 35
4.1 Quantification of T1 and T2 of thrombus 35
4.2 Thrombolysis effect 38
4.3 Discussion 40
4.4 Limitation 43
Chapter 5 Results and Discussion: In Vivo 44
5.1 Thrombus induced by 50% FeCl3 44
5.1.1 Pre-thrombolysis of MRI 44
5.1.2 Treatment group: UK 50K & UK 50K+FUS 49
5.1.3 3D thrombus model 60
5.1.4 Tissue histology 67
5.2 Thrombus induced by 12.5% FeCl3 69
5.2.1 Pre-thrombolysis of MRI 69
5.2.2 Control group 73
5.2.3 Treatment group: UK 3K 74
5.2.4 Treatment group: UK 6K 78
5.2.5 Tissue histology 80
5.3 Thrombus of Day 7 81
5.4 Discussion 86
5.4.1 Thrombus induced by 50% FeCl3 86
5.4.2 Thrombus induced by 12.5% FeCl3 88
5.4.3 Thrombus of Day7 90
5.5 Limitation 90
Chapter 6 Conclusions 91
6.1 Conclusions 91
6.2 Future Work 93
Chapter 7 References 94
Appendix 99
8.1 Response of Oral Defense 99
8.2 Turnitin 101

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