為了降低副作用或是集中藥物的功效在特定區域，藥物攜帶及傳遞系統一直是生醫領域很重要的挑戰之一。近期，除了將藥物包覆在高分子中的傳統系統外，也發展了許多可控制藥物系統，如鐵奈米粒子、氧化石墨烯奈米粒子、金奈米粒子等。在本人的研究中，初期合成了均一性相當高的五奈米鐵粒子，作為穩定藥物載體的靈魂腳色。此鐵奈米粒子擁有超順磁之性質，也就是說鐵奈米粒子本身沒有磁性，但施予外加磁場後能被吸引。還有鐵奈米粒子的藥物載體，除了有更大的藥物包覆能力外，還能提供磁性引導、熱療、藥物控制釋放、核磁共振顯影等能力。
本人博士班研究後期，將藥物載體系統應用於組織工程領域，可控制藥物載體也能在特定的時間及區域，給予刺激及作用，此研究也於今年中被《自然》之子期刊接受。研究主要以多孔性之石墨烯片狀奈米粒子作為藥物攜帶載體，此載體擁有非常大的藥物攜帶能力，在外加高頻磁場之中，能藉由磁電轉換產生電流，同時加速釋放藥物以及誘導神經細胞分。本研究還結合了光聚合型加成工藝，除了能將客製化生醫支架，以符合不同病人及各種患部的尺寸，也能妥善地將藥物載體暴露於支架的表面，增加細胞吸附且能更直接對組織及細胞進行刺激，達到了四維列印之成就。我們證實了，不論在體外實驗及體內實驗中，都有非常好的效果，封裝在支架內的藥物，也能夠成功的釋放並穿透至受損組織中，改善了動物實驗中，坐骨神經的髓鞘厚度及軸突之方向性。本研究結合了藥物控制釋放及精準醫療技術，對於神經組織在生領域提供了很大的願景。
未來研究，將著墨於解決腦創傷之臨床需求。創傷性腦損傷每年全球估計影響幾百萬人，其倖存者在身體、認知和心理社會功能方面發展有長期影響。我們將預期使用加成工藝之微針藥物系統，以解決過去腦損傷治療不足之處。微針系統內部包覆抗發炎藥物，外層以金奈米粒子修飾，在高頻磁場的感應下，可以產生微電流，刺激患處的神經再生，達到治療的效果。在腦創傷模型小鼠植入金修飾微針系統後，發現在磁電治療下的小鼠具有最好的行為表現，顯示出良好的恢復趨勢。本研究旨在開發一種新型的持續藥物釋放和磁電刺激藥物傳遞系統，希望這種方法的發展將為腦損傷區域功能的恢復提供機會，並用於其他腦和神經退行性疾病。

In order to reduce side effects and concentrate the efficacy of drugs in specific areas, drug delivery systems have been one of the most important challenges in the field of biomedical engineering. Recently, many controllable drug delivery systems have been developed, such as iron nanoparticles, graphene oxide nanoparticles, and gold nanoparticles. In my research, 5 nm with superparamagnetic properties can stabilize the polymersome-based system for large amount of pharmaceuticals encapsulation. In addition, iron oxide nanoparticles can also provide many functions such as magnetic guidance, hyperthermia, controlled drug release, nuclear magnetic resonance imaging.
Next, I promoted the controllable drug delivery system into the field of tissue engineering. This study was accepted by Nature Publishing Group at the middle of this year. In this study, mesoporous graphene oxide nanoparticles prepared by Hummer’s method as well as calcination, served as a large cargo for pharmaceuticals delivery. Besides, the nanoparticles could generate a current by magnetoelectric conversion under external high-frequency magnetic field, leading to accelerate the release of drugs and induce nerve regeneration. Incorporating with DLP-type 3D printing technologies, the scaffold can not only match to the injured parts of the patient with adjustable fabrication such as size as well as the structure of the scaffold, but also expose the nanoparticles to the surface of the stent to increase cell adhesion and the stimulation on tissues and cells directly, achieving four-dimensional printing technologies. The conduits were finally confirmed in vitro and in vivo experiments with very good results. The drug encapsulated in the conduits can be successfully released and penetrated into the damaged tissue, improving the myelin sheath of the sciatic nerve and the orientation of axons. This research combines the controlled drug release and precision medical technology to provide a great vision for the field of tissue regeneration.
In the future, I will focus on the topic of traumatic brain injury (TBI). TBI affects millions of people worldwide each year, and its survivors have long-term effects on the development of physical, cognitive, and psychosocial functions. I will use the MNs as the drug delivery system manufactured by the additive process to solve the nowadays shortcomings of the treatment of brain injury in the past. The MNs encapsulated with anti-inflammatory drugs, and gold nanoparticles were sputtered on the surface of MNs. Under the induction of a high-frequency magnetic field, it can generate micro-currents to stimulate nerve regeneration. After implanting the gold modified microneedle system in the brain trauma model mice, it was found that the mice under magnetoelectric therapy had the best behavioral performance and showed a good recovery trend. This study aims to develop a new type of sustained drug release and magnetoelectrical stimulation drug delivery system. It is hoped that the development of this method will provide an opportunity to restore the function of brain injury area and be used in other field of biomedical engineering.

Contents
摘要 1
Abstract 3
Contents 5
Chapter 1 Literature Review and Theory 7
1.1 General and controlled drug delivery system for cancer therapy 7
1.2 Principles of general 3D printing technologies 13
1.3 Advanced 3D printing technologies for biomedical applications 22
1.4 Advanced conduit for nerve regeneration 27
1.5 Microneedles for tissue engineering 35
Chapter 2 Magnetoresponsive Virus-Mimetic Nanocapsules with Dual Heat-Triggered Sequential-Infected Multiple Drug-Delivery Approach for Combinatorial Tumor Therapy 42
2.1 Abstract 42
2.2 Introduction 42
2.3 Results and discussion 46
2.4 Experimental section 71
2.5 Conclusion 77
Chapter 3 4D Printing of Stretchable Nanocookie@Conduit Hosting Biocues and Magneto-Electrical Stimulation for Neurite Sprouting 78
3.1 Abstract 78
3.2 Introduction 78
3.3 Experimental section 81
3.4 Results and Discussion 91
3.5 Conclusion 127
Chapter 4 Conducting Microneedles Capable of Wireless Charging-Mediated Precisely Actuated Neuron Regeneration in Traumatic Brain Injury 128
4.1 Abstract 128
4.2 Introduction 129
4.3 Experimental section 136
4.4 Results and Discussion 140
4.5 Conclusions 145
Chapter 5 Conclusions 146
Acknowledgement 147
Reference 148
Curriculum Vitae (CV) 170

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