在現有的藥物遞送技術中，如何能夠穩定且精準的在複雜的人體環境下將藥物遞送至病灶區極具挑戰。研究指出縱使透過先進的標靶藥物技術進行治療，藥物的遞送效率仍難有效提升(<0.7%)，而且連帶的可能須付出更高額的醫療成本。因此，如果能夠開發出高效、簡易且非侵入式的藥物遞送技術，將能夠大幅提升藥物治療效果與病患的醫療品質。因此我們提出以龍捲風為靈感之漩渦式聲鉗技術，藉由超音波產生類似於龍捲風的效果於組織中對藥物進行非侵入式的捕捉與精確操控。在研究中結合了超音波顯影劑微氣泡作為藥物載體進行高效的藥物遞送測試，其結果顯示漩渦式聲鉗可對微氣泡產生將近 0.75 nN 的強大捕捉力並成功於流場中累積微氣泡進行藥物遞送的效果。結合功能性的超音波釋藥脈衝序列可有效提升遞送效率至少7.2倍，除此之外，在活體複雜血流環境中遞送的測試結果也證實有顯著的局部藥物濃度提升至少1.7倍並且沒有毒性反應。這些結果反應出漩渦式聲鉗有機會在未來發展為一種更安全可靠的藥物遞送技術。

Spatially concentrating and manipulating biotherapeutic agents within the circulatory system is a longstanding challenge in medical applications due to the high velocity of blood flow, which greatly limits drug leakage and retention of the drug in the targeted region. To circumvent the disadvantages of current methods for systemic drug delivery, we propose tornado-inspired acoustic vortex tweezer (AVT) that generate net forces for noninvasive intravascular trapping of lipid-shelled gaseous microbubbles (MBs). MBs are used in a diverse range of medical applications, including as ultrasound contrast agents, for permeabilizing vessels, and as drug/gene carriers. We demonstrate that AVT can produce strong trapping force of nearly 0.75 nN and can successfully accumulate MBs to increase their local concentration in both static and flow conditions at least 7.2–fold efficiency improvement. Furthermore, MBs signals within mouse capillaries could be locally improved 1.7–fold and the location of trapped MBs could still be manipulated during the initiation of AVT. The proposed AVT technique is a compact, easy-to-use, and biocompatible method that enables systemic drug administration with extremely low doses.

內容
中文摘要 i
Abstract ii
致謝 iii
List of Symbols viii
List of Figures 9
List of Tables 19
Chapter 1 20
Introduction 20
1.1 Need and Concept 20
1.2 Contactless trapping technique 21
1.3 Acoustic tweezers 25
1.4 Acoustic vortex tweezers 28
1.5 Microbubbles as drug carriers 31
Chapter 2 34
Tornado-inspired Acoustic Vortex Tweezers for Trapping and Manipulating Microbubbles 34
2.1 Introduction 34
2.2 Materials and Methods 37
2.2.1 The Acoustic Vortex Principle and Transducer Design 37
2.2.2 The Experiment Design for Implementing Drug Delivery Application 44
2.2.3 The Feasibility Assessment of In Vivo Experiments 46
2.2.4 Window Chamber Model Preparation for In Vivo Study 49
2.2.5 2D Array Transducer and Asymmetric Acoustic Vortex 51
2.2.6 Verasonics Open Source Research Ultrasound System 52
2.2.7 Microscope Photography Experimental Setup 53
Chapter 3 55
Result 55
3.1 The Acoustic Vortex Field 55
3.2 Acoustic Vortex Trapping Force on Microbubble 56
3.3 The Feasibility Study of Acoustic Vortex Trapping Microbubbles in Static Condition 57
3.3.1 The Trapping Behavior of Microbubbles in Static Condition 57
3.3.2 Effects of Trapping Efficiency on the Microbubbles 60
3.3.3 Dynamic Manipulation of Trapped Microbubbles 62
3.4 In Vitro Acoustic Vortex Enhanced Drug Delivery 63
3.4.1 The Spatial Distribution of Microbubbles in the Static Chamber 63
3.4.2 The Outcomes with Different Drug Delivery Sequence 66
3.5 Acoustic Vortex Trapping Microbubbles in the Flow Condition 68
3.5.1 The Relation Between Trapping Capability and Flow Velocity 68
3.5.2 The Stability and Manipulation of the Trapped Cluster in the Flow 71
3.6 The Risk Assessment to Performing Acoustic Vortex Trapping In Vivo 71
3.6.1 Measured Acoustic Vortex Field after Penetrating Brain Tissue 71
3.6.2 The Effect of Red Blood Cell after the Acoustic Vortex Trapping 73
3.6.3 The Size Distribution of Microbubbles after the Acoustic Vortex Trapping 76
3.7 Application of Acoustic Vortex Tweezers to the Mouse Circulation 77
3.7.1 Trapping and Manipulating Microbubbles In Vivo 77
3.7.2 The Safety of Trapping Microbubbles In Vivo 79
3.8 Simulated and Measured Asymmetric Acoustic Vortex Field 84
3.9 Microbubbles Dynamics of Asymmetric Acoustic Vortex Trapping in Flow and In Vivo 86
Chapter 4 91
Discussion 91
Chapter 5 95
Conclusion and Future Work 95
References 99
Publication List 108

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