經皮吸收(Transdermal delivery)已成為一種嶄新的藥物傳遞方式，其應用於疫苗接種、醫學美容等諸多領域。不同於傳統口服或皮下注射，此方法可以避免口服藥物因肝臟首渡效應造成的藥效流失，降低藥物劑量的使用，並且也減少皮下注射而造成感染的風險。微針(Microneedle)作為一種新型的經皮無痛給藥方式，其優點為方便使用、生產且相對便宜。藉由把藥物裝載在微針內，並透過微針本身的穿刺能力可有效突破角質層之障礙，在患部給藥時，也可以更有效控制藥量。本研究結合3D PRINTING 這種已經被純熟使用的製造技術用於在微針翻模的製程，製造出可用於雄性禿治療的微針貼片。
雄性禿這種遺傳性疾病好發生在30-60歲的男性。在該研究中，使用高生物相容的聚乙烯醇做為可溶解的微針貼片。更重要的是，微針內含有Minoxdil這種含有治療效果的藥物和超順磁性氧化鐵（SPIONs）。藉由 HFMF的高頻磁場刺激可以局部地增加微針區域的溫度，以實現毛囊的擴張並加速毛囊的增殖速度
本研究首先利用DLP(Digital light processing)- 3D列印技術，可製造出不同大小、粗細、形狀的微針模具，其中針尖的部分可精細至25μm。再藉由PDMS的翻模方式製造微針，且為了達到更好的藥物遞送效果，在針尖內加入多功能性的奈米氧化鐵(SPIONs)，利用其多孔洞的特性吸附藥物，達到緩釋藥物的效果。並用高生物相容性、高溶解性的聚乙烯醇(PVA)針體，配合FDA認可的生髮藥物Minoxidi，經由機械強度測試及體外實驗證實該微針兼具可溶解性(體外一分鐘可溶解)和穿刺能力(大於文獻紀載0.17 N/needle)。再經由細胞毒性實驗驗證藥物安全性和動物實驗得知經由HFMF高周波磁場刺激可局部提高微針作用區域內溫度，使其達到毛囊內微血管的擴張，加速毛囊的增生速率達到實際生髮療效。綜合以上結論，本研究的微針貼片是個具有應用潛力的給藥模式。

Transdermal delivery has become a new way of drug delivery, which is used in many fields such as vaccination and medical beauty. Unlike traditional oral or subcutaneous injections, this method can avoid the loss of efficacy of oral drugs due to the liver's first-pass effect, the use of drug doses reduction, and the risk of infection by subcutaneous injection. As a new type of transdermal and painless administration, microneedle has the advantages of being convenient use, producing and relatively inexpensive. By loading the drug in the microneedle and through the puncture ability of the microneedle itself, the barrier of the stratum corneum can be effectively broken, and the dose can be more effectively controlled when the affected part is administered. This research combined with 3D PRINTING, a manufacturing technology that has been used skillfully, is used in the microneedle overmolding process to print a wide range of microneedle models that meet the needs.
For male baldness, this genetic disease occurs at age 30-60. In this study, a highly biocompatible polyvinyl alcohol was used to make a dissolvable microneedle patch, which was coated inside the microneedle. What’s more, the microneedle is coated with Minoxdil, which is a therapeutic effect drug and superparamaganetic Iron oxide (SPIONs). The high frequency magnetic field stimulation of HFMF can locally increase the temperature in the microneedle area to achieve the expansion in the hair follicle and accelerate the hair follicle’s rate of proliferation.
DLP (Digital light processing) - 3D printing technology is used in this study to produce micro-needle molds of different sizes, thicknesses and shapes, in which the tip portion can be fined to 25 μm. The microneedle is fabricated by the flipping method of PDMS, and in order to achieve better drug delivery effect, multifunctional nanometer iron oxide (SPIONs) is added into the needle tip, and the characteristics of the porous hole are utilized to adsorb the drug to achieve sustained release. The effect of the drug,us a highly biocompatibleand highly soluble polyvinyl alcohol (PVA) needle, is combined with the FDA-approved hair growth drug Minoxidil It was confirmed by mechanical strength test and in vitro experiments that the microneedle has solubility (in vitro one minute soluble) and puncture ability (greater than the literature record 0.17 N/needle). The cytotoxicity test and drug experiments confirmed that the high frequency magnetic field stimulation through HFMF can locally increase the temperature in the microneedle action area, so as to reach the expansion of the microvessels in the hair follicle, and accelerate the proliferation rate of the hair follicle to achieve the actual hair growth effect. Based on the above conclusions, the microneedle patch of this study is a drug delivery mode with potential application.

Table of contents
誌謝…………………………………………………………………………………………. IV
中文摘要 I
Abstract II
Table of contents I
List of schemes VIII
List of tables IX
List of figure VI
Chapter 1 Introduction 1
Chapter 2 Literature review and theory 3
2.1 Microneeldes 3
2.1.1 Transdermal Drug Delivery System 3
2.1.2 Origins and types of microneedle 5
2.1.3 Polymeric microneedles 12
2.2 3D PRINTING 13
2.2.1 Nowadays development and origin of 3D printing 13
2.2.2 DLP (Digital Light Processing) 19
2.3 Andorgenetic alepocia 21
2.3.1 Nowadays treatment on alepocia 21
2.3.2 Iron and regrowth hair 23
Chapter 3 Experimental section 25
3.1 Materials 25
3.2 Apparatus 27
3.3 Method 28
3.3.1 Formula of Microneedle 28
3.3.2 Two-Step Fabrication Process of Microneedles 28
3.4 Synthesis of mesoporous superparamagnetic iron oxide nanoparticles (SPIONs). 30
3.5 Characterizations 31
3.6 In vitro experiment 31
3.6.1 Cell culture 31
3.6.2 Cell viability aeeay 32
3.7 In vivo experments 32
Chapter 4 Results and Discussions 35
4.1 synthesis and characterization of superparamaganetic iron oxide (SPIONs) 35
4.2 Fabrication and Characterization of Microneedles 37
4.2.1 Characterization of Microneedles 38
4.3 Microneedle Mechanical Strength Test 40
4.4 Microneedle In vitro puncture test 41
4.5 Cell cytotoxicity 44
4.5.1 Mx release from IO 44
4.6 In vivo animal hair growth experiment 45

Chapter 5 Conclusions 48
Reference 49

Reference

1. Dhurat, R.; Mathapati, S., Response to Microneedling Treatment in Men with Androgenetic Alopecia Who Failed to Respond to Conventional Therapy. Indian Journal of Dermatology 2015, 60 (3), 260-263.
2. Anselmo, A. C.; Mitragotri, S., An overview of clinical and commercial impact of drug delivery systems. J Control Release 2014, 190, 15-28.
3. Brambilla, D.; Luciani, P.; Leroux, J. C., Breakthrough discoveries in drug delivery technologies: the next 30 years. J Control Release 2014, 190, 9-14.
4. Prausnitz, M. R.; Langer, R., Transdermal drug delivery. Nature Biotechnology 2008, 26 (11), 1261-1268.
5. Alkilani, A. Z.; McCrudden, M. T.; Donnelly, R. F., Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum. Pharmaceutics 2015, 7 (4), 438-70.
6. Shahzad, Y.; Louw, R.; Gerber, M.; du Plessis, J., Breaching the skin barrier through temperature modulations. Journal of Controlled Release 2015, 202, 1-13.
7. Tuan-Mahmood, T. M.; McCrudden, M. T.; Torrisi, B. M.; McAlister, E.; Garland, M. J.; Singh, T. R.; Donnelly, R. F., Microneedles for intradermal and transdermal drug delivery. Eur J Pharm Sci 2013, 50 (5), 623-37.
8. Nguyen, J.; Ita, K. B.; Morra, M. J.; Popova, I. E., The Influence of Solid Microneedles on the Transdermal Delivery of Selected Antiepileptic Drugs. Pharmaceutics 2016, 8 (4).
9. Kim, Y. C.; Park, J. H.; Prausnitz, M. R., Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev 2012, 64 (14), 1547-68.
10. Haj-Ahmad, R.; Khan, H.; Arshad, M. S.; Rasekh, M.; Hussain, A.; Walsh, S.; Li, X.; Chang, M. W.; Ahmad, Z., Microneedle Coating Techniques for Transdermal Drug Delivery. Pharmaceutics 2015, 7 (4), 486-502.
11. Chen, Y.; Chen, B. Z.; Wang, Q. L.; Jin, X.; Guo, X. D., Fabrication of coated polymer microneedles for transdermal drug delivery. J Control Release 2017, 265, 14-21.
12. Zhang, Y.; Liu, Q.; Yu, J.; Yu, S.; Wang, J.; Qiang, L.; Gu, Z., Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment. ACS Nano 2017, 11 (9), 9223-9230.
13. Fertig, R. M.; Gamret, A. C.; Cervantes, J.; Tosti, A., Microneedling for the treatment of hair loss? J Eur Acad Dermatol Venereol 2018, 32 (4), 564-569.
14. Lee, K.; Jung, H., Drawing lithography for microneedles: a review of fundamentals and biomedical applications. Biomaterials 2012, 33 (30), 7309-26.
15. Kim, J. D.; Kim, M.; Yang, H.; Lee, K.; Jung, H., Droplet-born air blowing: novel dissolving microneedle fabrication. J Control Release 2013, 170 (3), 430-6.
16. Yang, H.; Kim, S.; Huh, I.; Kim, S.; Lahiji, S. F.; Kim, M.; Jung, H., Rapid implantation of dissolving microneedles on an electrospun pillar array. Biomaterials 2015, 64, 70-7.
17. Leone, M.; Monkare, J.; Bouwstra, J. A.; Kersten, G., Dissolving Microneedle Patches for Dermal Vaccination. Pharm Res 2017, 34 (11), 2223-2240.
18. Wang, P. M.; Cornwell, M.; Hill, J.; Prausnitz, M. R., Precise microinjection into skin using hollow microneedles. J Invest Dermatol 2006, 126 (5), 1080-1087.
19. Bal, S. M.; Caussin, J.; Pavel, S.; Bouwstra, J. A., In vivo assessment of safety of microneedle arrays in human skin. European Journal of Pharmaceutical Sciences 2008, 35 (3), 193-202.
20. Bhatnagar, S.; Dave, K.; Venuganti, V. V. K., Microneedles in the clinic. Journal of Controlled Release 2017, 260, 164-182.
21. Yang, S. X.; Feng, Y.; Zhang, L. J.; Chen, N. X.; Yuan, W. E.; Jin, T., A scalable fabrication process of polymer microneedles. Int J Nanomed 2012, 7, 1415-1422.
22. Hardy, J. G.; Larraneta, E.; Donnelly, R. F.; McGoldrick, N.; Migalska, K.; McCrudden, M. T.; Irwin, N. J.; Donnelly, L.; McCoy, C. P., Hydrogel-Forming Microneedle Arrays Made from Light-Responsive Materials for On-Demand Transdermal Drug Delivery. Mol Pharm 2016, 13 (3), 907-14.
23. Park, J. H.; Allen, M. G.; Prausnitz, M. R., Polymer microneedles for controlled-release drug delivery. Pharmaceutical Research 2006, 23 (5), 1008-1019.
24. Prasad, L. K.; Smyth, H., 3D Printing technologies for drug delivery: a review. Drug Development and Industrial Pharmacy 2016, 42 (7), 1019-1031.
25. Vano-Galvan, S.; Camacho, F., New Treatments for Hair Loss. Actas Dermosifiliogr 2017, 108 (3), 221-228.
26. Rushton, D. H., Nutritional factors and hair loss. Clinical and Experimental Dermatology 2002, 27 (5), 400-408.
27. Rushton, D. H.; Ramsay, I. D.; James, K. C.; Norris, M. J.; Gilkes, J. J. H., Biochemical and Trichological Characterization of Diffuse Alopecia in Women. Brit J Dermatol 1990, 123 (2), 187-197.
28. Liu, S.; Xing, R.; Lu, F.; Rana, R.; Zhu, J.-J., One-pot template-free fabrication of hollow magnetite nanospheres and their application as potential drug carriers. The Journal of Physical Chemistry C 2009, 113 (50), 21042-21047.
29. Muller-Rover, S.; Handjiski, B.; van der Veen, C.; Eichmuller, S.; Foitzik, K.; McKay, I. A.; Stenn, K. S.; Paus, R., A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol 2001, 117 (1), 3-15.
30. Laurent, S.; Forge, D.; Port, M.; Roch, A.; Robic, C.; Elst, L.; Muller, R. N., Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chemical reviews 2008, 108 (6), 2064-2110.
31. Wahajuddin; Arora, S., Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers. Int J Nanomedicine 2012, 7, 3445-71.
32. Hu, P.; Yu, L.; Zuo, A.; Guo, C.; Yuan, F., Fabrication of monodisperse magnetite hollow spheres. The Journal of Physical Chemistry C 2008, 113 (3), 900-906.
33. Sun, Y.-k.; Ma, M.; Zhang, Y.; Gu, N., Synthesis of nanometer-size maghemite particles from magnetite. Colloids and Surfaces A: Physicochemical and Engineering Aspects 2004, 245 (1–3), 15-19.
34. Cushing, B. L.; Kolesnichenko, V. L.; O'Connor, C. J., Recent Advances in the Liquid-Phase Syntheses of Inorganic Nanoparticles. Chemical Reviews 2004, 104 (9), 3893-3946.
35. Lee, J. W.; Park, J. H.; Prausnitz, M. R., Dissolving microneedles for transdermal drug delivery. Biomaterials 2008, 29 (13), 2113-24.