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系統識別號 U0026-3105201911471700
論文名稱(中文) 經皮藥物傳遞結合電穿孔技術運用之微針陣列設計與模擬
論文名稱(英文) Design and Simulation of Microneedle Arrays for Transdermal Drug Delivery by Electroporation
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 107
學期 2
出版年 108
研究生(中文) 賴鏡峰
研究生(英文) Ching-Feng Lai
學號 P86041079
學位類別 碩士
語文別 英文
論文頁數 63頁
口試委員 指導教授-莊漢聲
口試委員-魏憲鴻
口試委員-葉明龍
口試委員-蔡政穆
中文關鍵字 電穿孔  微針  藥物傳遞  經皮輸送  多重物理模擬分析 
英文關鍵字 Electroporation  Microneedle  Drug Delivery  Transdermal  Finite Element Simulation 
學科別分類
中文摘要 經皮藥物運輸在新型藥物輸送的方法裡具有相當高的效率,相比於傳統的口服或者塗抹方式,經皮藥物運輸此種方法有快速、低副作用並且可以達到精確的藥量控制而避免浪費。此外,現代社會的醫療不僅僅只要求療效,也強調從患者的角度出發,相比傳統利用針頭的皮下注射,微針可以大幅降低患者接受注射所引起的疼痛感及恐懼。
經皮藥物輸送最普遍且有效率的方法就是結合微針,皮膚是人體最大的組織,而微針技術在過去數年來已經取得相當的成果,舉凡疫苗接種,基因療法,甚至可以傳遞治療皮膚癌的藥物,都可以藉由此方法來達到治療的效果。依照微針輸送藥物的方式可以分成空心微針、塗抹穿刺、溶解型微針等方式。空心微針相較於後面兩種,屬於較早開發之方式,此原理是利用微針中間為鏤空之空間結合流體幫浦以及基底模組將藥物輸送至皮膚組織內。雖然空心微針具有相當不錯的效率,但是微針裝置需要搭配幫浦且操作較繁複,因此塗抹穿刺以及溶解型微針是目前主流研究領域。
在本篇論文中,將以”塗抹穿刺”型態之微針為主要目標,提供設計的概念,以當產品模型之依據並且結合電場施加電壓,使用電穿孔的模式來達到細胞通透性增加以提升藥物輸送之效益。此外,微針是由金屬或者其他具有高強度機械性質之材料構成,所以也有一定的強度能夠刺穿人體皮膚且不會引起結構性的破壞。為了微針的模擬以達提供設計的概念,本論文中使用COMSOL 多重物理模擬分析軟體來進行,主要可以分成:力學分析、電場分析以及物質運輸分析。在模擬模型中,生物體內的係數也將會列入考量,舉凡皮膚的基本性質等等。模擬的微針模型將會以微針刺穿皮膚後,放置在皮膚內的方式呈現,對於微針的設計,材料的選擇能否提供足夠的機械強度去承受皮膚所給的抵抗力,以及不同的排列方式會不會影響藥物在皮膚內擴散的分布,這些都是設計微針模型的一大重點,如何在不同的材料選擇,微針陣列排列中,找出適合結合經皮運輸的模型。模擬結果之部分,將以電場和物質運輸為主要考量來提供微針設計的概念,希望在未來可以運用到產品開發的領域。
英文摘要 Transdermal drug delivery is one of the most efficiency way in transporting drug into human body. Compared to traditional method, transdermal drug delivery features in fast, less side effect, specific drug control. In modern medicine, the main idea not only focus on the efficiency of treatment but also puts emphasize at patient’s feeling. Microneedle can reduce painful feeling apparently compares to traditional subcutaneous injection due to its small diameter.
Furthermore, microneedle is an effective tool which has been under developed in past decades. Besides drug delivery, microneedle can applied to gene therapy, target treatment against cancer especially for carcinoma and for vaccine. Microneedle can be divided into several types due to its pathway such as hollow, coat and poke, dissolving. Hollow microneedle combines with microfluidic and microneedle patch form a whole device. Although hollow microneedle reveals good efficiency in drug delivery, there are still some disadvantages. In this article, the aim is addressing design concept of “coat and poke” microneedle which combines with electric field. “Coat and poke” microneedle type is with protein-based drug coated or DNA-based vaccine at the surface of microneedle.
As microneedle is made of metal material which is electrically conductive, it can exert electric field in human skin conducts electroporation to enhance efficiency of drug delivery. Furthermore, microneedle is in micro diameter (100~500μm) while it provides sufficient mechanical strength to penetrate skin without mechanical fracture and prevent patient feeling painful. In this study, microneedle with shorter length(<200 μm) and larger wall angle(>8°) show the greater ability to resist mechanical failure. Besides diameter, material selection is also a critical factor of design. Three types of material are chosen which are, Titanium Beta-21S, Stainless Steel 316L, Ni-Co-Cr-Mo alloy. Among these materials, Titanium Beta-21S shows the widest range of application so this material is recommended to microneedle application.
To evaluate efficiency of drug delivery, diluted species and electric field distribution are important things for indicating which kinds of microneedle is better. Three kinds of design are applied, rectangular array, hexagon array with 4 potentials and hexagon array with 6 potentials. From the simulation result, hexagon array with 4 potentials can provide the largest effective volume formed by concentration and electric field at time=9s so that it reveals the appropriate moment to conduct electric field to reach greater efficiency.
Combined with different physics, this study addresses design concept of microneedle array and hope that it can be applied in future.

論文目次 CONTENTS
誌謝-----------------------------------------------------------------------------------------------I
摘要----------------------------------------------------------------------------------------------II
ABSTRACT-----------------------------------------------------------------------------------IV
CONTENTS-----------------------------------------------------------------------------------VI
LIST OF FIGURES-----------------------------------------------------------------------VIII
LIST OF TABLES--------------------------------------------------------------------------XII
CHAPTER 1 INTRODUCTION-----------------------------------------------------------1
1.1 Overview and Motivation-----------------------------------------------------------1
1.2 Transdermal drug delivery-----------------------------------------------------------3
1.3 Microneedle applications------------------------------------------------------------5
1.4 Microneedle simulation aspect----------------------------------------------------10
1.5 Aims and Contributions------------------------------------------------------------10
CHAPTER 2 MATERIALS AND METHODS-----------------------------------------12
2.1 Design of Microneedle array-------------------------------------------------------12
2.1.1 Rectangular Array--------------------------------------------------------------13
2.1.2 Hexagon Array-----------------------------------------------------------------14
2.2 Skin Model----------------------------------------------------------------------------15
2.3 Simulation Model---------------------------------------------------------------------17
2.4 Force Model---------------------------------------------------------------------------20
2.4.1 Insertion Force------------------------------------------------------------------20
2.4.2 Fracture Force------------------------------------------------------------------21
2.4.3 Buckling Force-----------------------------------------------------------------22
2.4.4 Bending Force------------------------------------------------------------------23
2.5 Drug Diffusion-----------------------------------------------------------------------25
2.6 Force Model--------------------------------------------------------------------------26
CHAPTER 3 RESULTS AND DISCUSSION-------------------------------------------27
3.1 Force Simulation Model of Microneedle-------------------------------------------27
3.1.1 Design of Microneedle---------------------------------------------------------27
3.1.2 Buckling Bending and Fracture Force of Microneedle--------------------27
3.2 Buckling Load and Fracture Force--------------------------------------------------31
3.3 Bending Force--------------------------------------------------------------------------40
3.4 Margin of Safety-----------------------------------------------------------------------42
3.4.1 Margin of Safety in Buckling and Fracture----------------------------------43
3.4.2 Margin of Safety in Bending---------------------------------------------------46
3.5 Drug Release and Electric Field-----------------------------------------------------48
CHAPTER 4 CONCLUSION---------------------------------------------------------------58
CHAPTER 5 FUTURE WORK------------------------------------------------------------60
LIST OF REFERENCES--------------------------------------------------------------------61
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