建立三維列印仿生皮膚模型用於經皮藥物測試平台

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姓名

洪綺鴻(Hong-Qi Hong) 查詢紙本館藏

畢業系所

生物醫學工程研究所

論文名稱

建立三維列印仿生皮膚模型用於經皮藥物測試平台
(To Develop a Three-dimensional Printed Biomimetic Skin Model for the Testing Platform of Transdermal Drugs)

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摘要(中)

每⼀年，動物實驗的消耗數量約為⼀億五千萬隻，在研究上的花費及動物與⼈體內
環境差異甚⾄是社會的道德標準都是⼀項需要被關注及解決的問題。近年來，由於歐盟
意識的抬頭，許多國家已經禁⽌經由動物實驗的化妝產品進⼝及設⽴相關法規，但在⽇
常使⽤的保養品或是化妝品若無經過⽪膚試驗，恐對我們⼈體造成不可預知的傷害。本
研究提出⼀個模仿⼈體⽪膚真實環境來進⾏產品的試驗，解決動物實驗相關限制的問題，
並且解決動物與⼈體環境差異問題，模仿⼈體真實⽪膚的部分利⽤來源為動物 I 型去端
肽的膠原蛋⽩⽣物墨⽔（Collgel®）作為細胞⽀架並加⼊⼈類成纖維母細胞（Fibroblast,
HDF )並使⽤⽣物型 3D 列印機進⾏列印建⽴真⽪層（Dermis）的架構，並於膠原蛋⽩⽣
物墨⽔上⽅加⼊⼈類⾓質形成細胞（Keratinocyte, HaCaT）作為表⽪層的替代，以 24 孔
盤插⼊式培養⽫（Transwell）進⾏共培養以及形成氣液介⾯，並於 28 天的培養以促使
⾓質形成細胞可以有效分化形成具疏⽔性的⾓質層以模擬真實⼈體⽪膚中的特性、⽪膚
吸收之情形，將此仿⽣⽪膚平台⽤於化妝品測試並觀察表⽪層通透與否及吸收之情形。

摘要(英)

Every year, the consumption of animal experiments is about 150 million. The cost of
research, the differences in the internal environment of animals and humans, and even the moral
standards of society are issues that need to be paid attention to and solved.In recent years, due
to the rising awareness of the European Union, many countries have banned the import of
cosmetic products that have undergone animal experiments and established relevant
regulations. However, if the skin care products or cosmetics used in daily use are not tested on
the skin, they may cause unpredictable harm to our human body.This study proposes a product
test that imitates the real environment of human skin, solves the problems related to animal
experiments, and solves the problem of differences between animals and human environments.
The part that mimics the real skin of the human body uses collagen derived from pig tendon
type I atelopeptide. Protein bio-ink (Collgel®) is used as a cell scaffold and human fibroblasts
(Fibroblast, HDF ) and printed using a bio-type 3D printer to build the structure of the dermis
(Dermis), and added on top of the collagen bio-ink Human keratinocytes (Keratinocyte,
HaCaT), as a substitute for the epidermis, were co-cultured in a 24-well insert culture dish
(Transwell) and formed an air-liquid interface, and cultured for 28 days to promote the effective
differentiation of keratinocytes to form Hydrophobic stratum corneum to simulate the
characteristics of real human skin and the situation of skin absorption. Use this bionic skin
platform for cosmetic testing and observe whether the epidermis is transparent or not and the
situation of absorption

關鍵字(中)

★ ⽪膚三維培養
★ 3R 動物替代
★ 氣液介⾯
★ ⽣物 3D 列印機

關鍵字(英)

★ 3D skin culture
★ 3R animal replacement
★ Air-liquid interface
★ 3D bio-printing

論文目次

摘要 .............................................................................................................................................i
ABSTRACT ...............................................................................................................................ii
⽬錄 ...........................................................................................................................................iii
圖⽬錄 .......................................................................................................................................ix
表⽬錄 ......................................................................................................................................xii
第⼀章研究背景暨⽂獻回顧 ........................................................................................1
1-1 ⽪膚（Skin）.............................................................................................................1
1-1-1 表⽪層...............................................................................................................2
1-1-2 真⽪層...............................................................................................................3
1-1-3 ⽪下組織...........................................................................................................4
1-2 ⼆維三維細胞培養（2D/3D cell culture）..............................................................4
1-2-1 ⼆維細胞培養...................................................................................................5
1-2-2 三維細胞培養...................................................................................................5
1-2-3 三維⽀架...........................................................................................................6
1-2-4 ⼆維三維細胞培養優缺點...............................................................................7
1-3 ⽣物墨⽔（Bioink）.................................................................................................7
1-3-1 膠原蛋⽩⽣物墨⽔...........................................................................................9
1-3-2 明膠⽣物墨⽔...................................................................................................9
1-3-3 海藻酸鹽...........................................................................................................9
1-4 3D ⽣物列印（3D Bioprinting）............................................................................10
1-4-1 噴墨式⽣物列印.............................................................................................10
1-4-2 擠壓式⽣物列印.............................................................................................11
1-4-3 雷射輔助⽣物列印........................................................................................11
1-5 細胞培養（Cell Culture） ......................................................................................13
1-5-1 ⼈類真⽪成纖維母細胞（Fibroblast, HDF） ............................................13
1-5-2 ⼈類表⽪⾓質形成細胞（Keratinocyte, HaCaT） ....................................13
1-6-1 擠壓型⽣物 3D 列印機原理..........................................................................15
1-6-2 空氣⼒泵幫浦.................................................................................................15
1-6-3 ⽣物 3D 列印機操作平台..............................................................................16
1-7 膠原蛋⽩⽣物墨⽔（Collgel®）..............................................................................16
1-7-1 膠原蛋⽩ RGD 序列.....................................................................................17
1-8 體外⽪膚模型的建⽴（Establishment of in vitro skin model）..............................18
1-8-1 插⼊式細胞培養⽫.........................................................................................18
1-9 ⼈類真⽪成纖維母細胞與⼈類表⽪⾓質形成細胞共培養系統（Co-Culture
System).............................................................................................................................19
1-10 氣液介⾯培養系統（Air-Liquid Cell Culture System, ALI）..............................19
第⼆章研究動機與實驗⽬的 ................................................................................................21
2-1 研究動機....................................................................................................................21
2-2 研究⽬的....................................................................................................................22
第三章材料與⽅法 ................................................................................................................24
3-1 膠原蛋⽩⽣物墨⽔（Collgel®）.............................................................................24
3-1-1 膠原蛋⽩⽣物墨⽔製備（Collgel® preparation） .......................................24
3-1-2 纖維母細胞之膠原蛋⽩⽣物墨⽔製備（Preparation of collagen bioink
from fibroblasts）.....................................................................................................24
3-2 氣液介⾯培養系統（Air-Liquid Cell Culture System, ALI）.................................25
3-2-1 纖維母細胞之膠原蛋⽩⽣物墨⽔與⾓質形成細胞（Collgel® of
Fibroblasts and Keratinocytes） ..............................................................................25
3-2-3 插⼊式細胞培養⽫中氣液介⾯培養（Air-liquid Interface Culture in
Inserted Cell Culture ）...........................................................................................25
3-3 膠體內細胞分析（In vivo cell analysis） ...............................................................26
3-3-細胞固定（Cell Fixation）...............................................................................26
3-3-2 膠體內纖維母細胞死活染⾊分析（Analysis of live and dead staining of
fibroblasts in collgel®） ...........................................................................................27
3-3-3 膠體內纖維母細胞與⾓質形成細胞⾻架染⾊分析（Staining Analysis of
Fibroblast and Keratinocyte Skeleton in Collgel®）................................................27
3-3-4 膠體上⽅⾓質形成細胞分化染⾊分析（Staining analysis of keratinocyte
differentiation above the Collgel®）........................................................................27
3-4 細胞培養（Cell Culture） .......................................................................................28
3-4-1 ⼈類成纖維母細胞（Fibroblast,HDF） .......................................................28
3-4-2 ⼈類⾓質形成細胞（Keratinocyte, HaCaT） ..............................................29
3-5 ⼈類⾓質形成細胞分化培養基測試（Human Keratinocyte Differentiation
Medium Test）.................................................................................................................30
3-5-1 ⼈類⾓質形成細胞培養基（Human Keratinocyte Medium）.....................30
3-5-2 ⼈類⾓質形成細胞分化培養基（Human Keratinocyte Differentiated
Medium）.................................................................................................................31
3-5-3 分化培養基與未分化培養基⽐較測試（Differentiation Medium vs.
Common Medium Comparison Test）.....................................................................32
3-6 膠原蛋⽩⽣物墨⽔結構與細胞存活率測試（Collgel® structure and cell viability
test）.................................................................................................................................33
3-6-1 膠原蛋⽩⽣物墨⽔濃度選取（Collgel® Concentration Selection）............33
3-6-2 膠原蛋⽩⽣物墨⽔細胞數量選取（Collgel® Cell Count Selection） ........33
3-6-3 不同程度滅菌之膠原蛋⽩⽣物墨⽔結構測試（Structural testing of
collgel® sterilized to different degrees）..................................................................33
3-6-4 特殊滅菌之膠原蛋⽩⽣物墨⽔之細胞存活率（Cell viability of collgel®
sterilized to different degrees） ...............................................................................34
3-7 ⾓質形成細胞分化之疏⽔性測試（Hydrophobicity test for keratinocyte
differentiation） ...............................................................................................................34
第四章結果與討論 ................................................................................................................35
4-1 膠原蛋⽩⽣物墨⽔列印（Collgel® Printing）.......................................................35
4-1-1 ⽣物 3D 列印機設定之參數與操作（Parameters and operation of
biological 3D printer settings） ...............................................................................35
4-1-2 ⽣物 3D 列印檔案之膠體設計（Colloid Design for Bio-3D Printing
Files） ......................................................................................................................35
4-1-3 ⽣物 3D 列印之 STL 檔案與 Ultimaker Cura 參數設定（STL file for
biological 3D printing and Ultimaker Cura parameter setting） .............................36
4-1-4 ⽣物 3D 列印機列印纖維母細胞之膠原蛋⽩⽣物墨⽔（Collgel® for
printing fibroblasts with 3D bio-printing）..............................................................38
4-1-5 膠原蛋⽩⽣物墨⽔ 3D 列印成果（Collgel® 3D printing results）.............38
4-1-6 膠原蛋⽩⽣物墨⽔放⼊插⼊式培養⽫中（Collgel® in Transwell）..........39
4-2 膠原蛋⽩⽣物墨⽔結構與細胞存活率測試（Collgel® structure and cell viability
test）.................................................................................................................................40
4-2-1 膠原蛋⽩⽣物墨⽔濃度選取（Collgel® Concentration Selection） ...........40
4-2-2 膠原蛋⽩⽣物墨⽔細胞數量選取（Collgel® Cell Count Selection） ........42
4-2-3 不同程度滅菌之膠原蛋⽩⽣物墨⽔結構測試（Structural testing ofcollgel® sterilized to different degrees）..................................................................43
4-2-4 特殊滅菌之膠原蛋⽩⽣物墨⽔之細胞存活率（Live and Dead of collgel®
sterilized to different degrees） ...............................................................................49
4-3 ⼈類⾓質形成細胞分化培養基測試（Human Keratinocyte Differentiation Medium
Test）................................................................................................................................50
4-3-1 ⼈類⾓質形成細胞培養基（Human Keratinocyte Medium）.....................50
4-3-2 ⼈類⾓質形成細胞分化培養基（Human Keratinocyte Differentiated
Medium）.................................................................................................................52
4-3-3 分化培養基與未分化培養基⽐較測試（Differentiation Medium vs.
Common Medium Comparison Test）.....................................................................53
4-4 ⾓質形成細胞分化之疏⽔性測試（Hydrophobicity test for keratinocyte
differentiation） ...............................................................................................................55
4-5 膠體內細胞分析（In vivo Collgel® analysis）........................................................57
4-5-1 膠體上⽅⾓質形成細胞分化染⾊分析（Staining analysis of Keratinocyte
Differentiation above the colloid）………………………………………………………….57
第五章結論 ............................................................................................................................60
第六章參考⽂獻 ....................................................................................................................61

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指導教授

陳靖昀(Ching-Yun Chen)

審核日期

2023-2-2

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