臺灣博碩士論文加值系統

為了使微針頭能具有輕易刺穿皮膚、不易斷裂及載藥之能力，本研究擬設計並仿造一豪豬刺之倒鉤結構之微針頭，使其可輕易刺穿皮膚組織，降低微針頭穿刺組織之阻力。故本論文設計將倒鉤結構以肋條方式結合於金字塔形狀之微針頭結構上(新型金字塔)，期望設計出較佳強度並具有仿生結構之微針頭陣列。
論文中採用ANSYS分析不同形狀微針頭(金字塔柱、新型金字塔柱)之側向撓度的臨界負載(Critical load)，微針頭最佳尺寸為參考楊益成學者採用田口分析法搭配臨界彎曲解析式所得作參考。挫曲分析結果顯示金字塔柱受力達1.18N為其臨界負載，新金字塔柱受力達1.54 N為其臨界負載，因此新金字塔錐具有較佳的抗臨界負載。
製程方面，微針材料採用羧甲基纖維素(Carboxymethyl cellulose, CMC)生物相容性材料，整合本實驗室傾斜曝光技術，製作出基座長392μm、肋條寬20μm及高35μm三角形狀、微針高650μm、針尖寬15μm的新型金字塔柱，再利用聚二甲基矽氧烷材料做精密翻模得到微針母模，最後以離心澆注得到新型微針頭結構。
實驗測試後發現，新金字塔錐雖具有較佳的抗臨界負載，但由於新字塔的肋條結構設計過小，致使針尖處較難製作成功。於翻模時，針尖處之肋條結構易附著於母模，導致脫膜時結構斷裂或針尖處結構不顯著，無法與預期設計結構或尺寸相同，因此微針頭結構尺寸需再重新設計與評估。然而，經由本研究證實所設計之製程可製做出原設計類似豪豬刺之仿生結構。
關鍵字:可溶性針頭、微針頭、傾斜曝光、仿生結構

The study is aimed to design an imitated porcupine barb structure microneedle that could easily penetrate the skin tissue, promoting the strength of the micro-needle and reducing the resistance of the micro-needle to puncture the tissue. Thus, the barb struc-ture is combined with a micro-needle structure in the shape of a pyramid (bionic pyra-mid column) by ribs. This is designed to fabrucate with a microneedle array with better mechanical strength and bionic structure.
In this study, ANSYS software was used to analyze lateral deflection critical load of the designs (pyramid column / bionic pyramid column), and the mechanical strength. The Taguchi method combined with critical buckling analysis is applied to identify the optimal size for the microneedle array in order to refer to the scholar Yang Yi Cheng's. Buckling analysis shows that the buckling load of pyramid column is 1.18 N, and the bionic pyramid column is 1.54 N. The analysis results indicate that new type pyramidal column exhibit superior cirtical load strength.
In terms of manufacturing process, an inclined exposure technique and precision micro molding method are used to fabricate the microneedle array. Carboxymethyl cel-lulose (CMC) is selected as the material of the microneedle array. The inclined exposure technique is used to produce a bionic pyramidal column-shaped (base length = 392 μm, rib width= 20μm , triangle height= 35μm , microneedle height = 650 μm, needle tip width = 15 μm). Then using polydimethylsiloxane (PDMS) material for precision micro molding is to obtain the microneedle female mold. Lastly, a bionic microneedle structure is obtained by centrifugal casting.
According the result, bionic pyramid shape needles have better design of critical loads, but the top of needles’s rib is too tiny to make the needle tip successful produc-tion. The rib structures at the tip of needles are easily sticked to the master mold when fabricating the female mold. Therefore, the size of the microneedle structure needs re-designed and modified. In this study, it is confirmed that the designed process can pro-duce a bionic structure which is similar to the porcupine barbs structure in the original design.
Keywords: Dissolving needle, Microneedle, Inclined exposure, Bionic structure

目錄
明志科技大學碩士學位論文口試委員審定書 i
摘要 iv
Abstract iii
目錄 vii
表目錄 ixi
圖目錄 xiii
第一章 緒論 1
1.1 研究背景 1
1.2 研究動機與目的 2
1.3 研究架構 2
第二章 文獻回顧 3
2.1 皮膚構造 3
2.1.1 皮膚疼痛感 4
2.1.2 皮膚刺激 5
2.1.3 皮膚感染 6
2.2 藥物傳遞主要方式 6
2.2.1 皮下注射藥物傳遞 6
2.2.2 口服藥物傳遞 7
2.2.3 經皮藥物傳遞 7
2.3 微針貼片種類 8
2.3.1 實心微針 9
2.3.2 空心微針 10
2.3.3 塗層式微針 11
2.3.4 高分子微針 12
2.3.5 可溶性微針 14
2.3.5.1 可溶性微針製作 15
2.4 微針強度 16
2.4.1 微針結構 19
2.5 倒鉤結構 20
2.5.1 豪豬刺表面結構 20
2.5.2 豪豬刺刺穿實驗 21
2.5.3 豪豬刺模擬 23
2.5.4 豪豬倒鉤結構設計分析 24
2.6 微針藥物傳輸發展 25
2.6.5 麻醉傳輸 26
2.6.6 微針陣列眼科用藥傳輸 26
2.6.7 微針陣列胰島素傳輸 28
2.7 傾斜曝光技術 29
第三章 材料特性與分析檢測方法 39
3.1 SU-8材料特性 39
3.2 感光材料特性 42
3.3 聚二甲基矽氧烷(PDMS) 43
3.4 羧甲基纖維素鈉（CMC） 44
3.5 掃描式電子顯微鏡 44
第四章 微針頭強度分析與模擬 45
4.1 微針頭有限元素分析 45
4.1.1 建立模型 45
4.1.2 擇適當元素及定義元素特性與材料性質 47
4.1.3 劃分網格 48
4.1.4 分析器 48
4.1.4.1 測試挫曲力 48
4.1.4.2 挫曲力 48
第五章 製程方法與步驟 50
5.1 Alignment Key製作 50
5.2 SU-8模具製作 51
5.3 PDMS翻模 58
第六章 實驗結果 59
6.1 ANSYS挫曲強度分析結果 59
6.1.1 第一次模擬分析結果 59
6.1.2 第二次模擬分析結果 60
6.1.3 第三次模擬挫曲分析結果 61
6.2 SU-8母模製程結果 63
6.2.1 第一組製程參數實驗結果 63
6.2.2 第二組製程參數實驗結果 64
6.2.3 第三組製程參數實驗結果 65
6.2.4 第四組製程參數實驗結果 66
6.2.5 第五組製程參數實驗結果 68
6.2.6 第六組製程參數實驗結果 70
6.2.7 SU-8針頭母模數據統整 71
6.3 PDMS母模翻製 71
6.3.1 新金字塔柱第一組翻模 71
6.3.2 新金字塔柱第二組翻模 72
6.3.3 新金字塔柱第三組翻模 73
6.3.4 新金字塔柱第四組翻模 74
6.3.5 新金字塔柱第五組翻模 75
6.3.6 新金字塔柱第六組翻模 76
6.3.7 PDMS針頭翻製數據統整 77
6.4 CMC母模翻製 77
6.4.1 新金字塔柱第一組翻模 77
6.4.2 新金字塔柱第二組翻模 78
6.4.3 新金字塔柱第三組翻模 79
6.4.4 新金字塔柱第四組翻模 80
6.4.5 CMC針頭翻模數據統整 81
第七章 結論 82
參考文獻 83
 
表目錄
表 2.4.1有限元素分析不同微針結構之挫曲力結果 19
表 2.5.1 (G)有倒鉤的刺、無倒鉤的刺、18號皮下注射針頭與北美豪豬刺在刺穿與拔除時所需的力與功 22
表 2.7.1 曝光角度與微型結構角度之比較 33
表 2.7.2 不同介質和其折射率係數 37
表 3.1.1 SU-8 光阻物理特性 40
表 3.1.2 SU-8特性與製程參數 41
表 3.2.1 正負光阻特性比較表 43
表 3.5.1 材料係數 47
表 3.5.2各形狀針頭網格劃分 48
表 6.1.1 設定參數 59
表 6.1.2 設定參數 60
表 6.1.3 設定參數 61
表 6.1.4各形狀針頭位移情況 61
表 6.1.5 各形狀針頭挫曲情況 61
表 6.1.6微針頭設計尺寸 62
表 6.2.1 SU-8與基板高度測量 67
表 6.2.2 微針頭尺寸量測 67
表 6.2.3 SU-8與基板高度測量 68
表 6.2.4微針頭尺寸量測 69
表 6.2.5微針頭尺寸量測 70
表 6.2.6 SU-8母模製程數據統整 71
表 6.2.7 PDMS針頭翻製數據統整 77
表 6.2.8 CMC針頭實驗統整 81
 
圖目錄
圖 2.1.1 皮膚構造組成[1] 4
圖 2.1.2 微針長度對於疼痛感的影響[3] 5
圖 2.1.3 微針厚度與寬度對疼痛感的影響[3] 5
圖 2.1.4 微針尖角對疼痛感的影響[3] 5
圖 2.3.1 不同種類的微針與其釋放機制[25] 9
圖 2.3.2 由矽與聚合物所製成的空心微針 11
圖 2.3.3多維度UV曝光方式 (a)正面曝光、(b)透過透明基板進行反側向的曝光、(c)傾斜正面曝光、(d)通過透明基板的傾斜反側向曝光[51] 12
圖 2.3.4 高深寬比的圓柱形結構 (a)正面曝光錐形柱結構、(b)反側向曝光 [51] 13
圖 2.3.5使用集成透鏡技術製作出的高深寬比之錐形結構(a)模擬光線透過集成透鏡的路徑、(b)結構製作結果 [51] 13
圖 2.3.6可溶性微針降解方式 15
圖 2.3.7 翻模製程流程圖 16
圖 2.4.1 微針位移和插入的力到人受試者的皮膚，插入力（圓圈）和皮膚電阻（方形）[87] 16
圖 2.4.2 微針斷裂幾何形狀分析 (A)針尖半徑 (B)壁厚 (C)壁角[87] 17
圖 2.4.3 (A)微針的插入與斷裂力之間相比 (B)微針的插入和斷裂力之間的安全係數[87] 17
圖 2.4.4 金屬空心微針與27號皮下注射針頭的SEM圖 18
圖 2.4.5 微針刺穿皮膚表面剖面圖(A)金屬中空微針(B)微針完整刺入皮膚表面之剖面圖(C)微針施壓於剛性表面後斷裂之情況(D)插入皮膚後微針斷裂於皮膚中之剖面圖 18
圖 2.4.6 微針施力與位移之關係圖，反折點代表微針斷裂。 19
圖 2.4.7 各形狀之模擬結果 20
圖 2.5.1 (A)北美豪豬刺示意圖 (B、C、E)使用FE-SEM針對針尖與尾端處進行微觀察 (D)螢光成像觀察倒鉤結構 21
圖 2.5.2 (F)分別為有倒鉤的刺、無倒鉤的刺、北美豪豬刺的刺穿力與拔除力的比較 22
圖 2.5.3 (A、B)有倒鉤刺與無倒鉤刺的刺穿皮膚剖面分析 (C、D)使用斷成掃描呈現刺穿組織時的情況 (F)刺穿深度比較 23
圖 2.5.4 (A、B)有倒鉤刺與無倒鉤刺的刺穿皮膚ANSYS模擬分析 (C)模擬結構尺寸示意圖 (D)模擬豪豬刺刺穿皮膚後拔除情況 23
圖 2.5.5 (A)豪豬刺區域分布圖 (B、C)針對不同的倒鉤結構分佈區域進行刺穿與拔除力的測試比較 (D)刺穿與拔除刺時，所需做的功 24
圖 2.6.1 實心微針刺穿屍體皮膚[90] 25
圖 2.6.2 藥物對於皮膚的滲透性[91] 25
圖 2.6.3 注射不同劑量於兔子瞳孔之縮收情況，白色方塊為上位用藥情況；淺灰色為演藥劑滴定5μg；深灰色為塗佈5.5μg於微針表面，並刺入瞳孔；黑色為滴定眼藥水500μg。 27
圖 2.6.4兔子瞳孔實際縮放情形，(A)(C)(E)皆為尚未用藥前，(B)(D)(F)為用藥後情況。 27
圖 2.6.5 刺穿大鼠皮膚中之剖面圖 28
圖 2.6.6 不同劑量之胰島素注入人體[36] 28
圖 2.7.1 傾斜曝光設備 29
圖 2.7.2 以Dark方式設計之光罩，進行二次不同方向傾斜曝光 30
圖 2.7.3 以Clear方式設計之光罩，進行二次不同方向傾斜曝光；(a)與(b)為製程示意圖、 (c)~ (e)分別為圓形、六角形以及長方形三種不同圖案之光罩對SU-8光阻進行曝光與顯影後的結果[98] 30
圖 2.7.4 傾斜曝光機台 31
圖 2.7.5 傾斜曝光機台軸向示意圖 31
圖 2.7.6 旋轉傾斜曝光的UV曝光搭配不同的光罩圖案(a)傾斜曝光使用不同尺寸與距離在同一片光罩上 (b)凹槽圖案具有不同樣的深度 (c)各式的凹槽圖案有橢圓形、三角形、方形 (d)利用PDMS翻模的結果 (e)利用clear方式與旋轉曝出的突起結構 (f)利用clear方式與旋轉曝出的突起連續陣列結構。 32
圖 2.7.7 UV光源穿透不同介質之折射情形 33
圖 2.7.8 (a)背後傾斜曝光製程流程 (b)微結構SEM圖 34
圖 2.7.9積體化光學讀取頭 (a)微光學系統示意圖 (b)封裝示意圖[101] 35
圖 2.7.10 折射情形比較 (a-d)光阻與基板間未塗佈抗反射材料 (e-h)光阻與基板間塗佈上CK-6020L消除了反射現象[101] 36
圖 2.7.11 不同曝光環境介質比較(a)曝光環境在空氣中(b)曝光環境在甘油中[101, 102] 36
圖 2.7.12 在同曝光環境與介質其結構角度差異性[101] 36
圖 2.7.13 可微調傾斜曝光角度的曝光機構[103] 37
圖 2.7.14 比較光於不同介質補償的強度 (a)空氣間隙與光強度之關係示意圖 (b)光強度於不同介質下補償空隙後的變化示意圖[104] 38
圖 2.7.15 空氣間距對於曝光結構的影響[105] 38
圖 3.1.1 SU-8 分子結構 40
圖 3.1.2 SU-8 曝光後之化學變化 40
圖 3.1.3 SU-8光阻的分子組合結構圖 41
圖 3.1.4 SU-8光阻之反應機制 42
圖 3.3.1 PDMS的分子組合結構圖 44
圖 3.5.1 ANSYS作業流程圖 45
圖 3.5.2金字塔柱結構示意圖 (a)整體微針頭尺寸 (b)俯視圖 (c)側視圖 46
圖 3.5.3新型金字塔柱結構示意圖 (a)整體微針頭尺寸 (b)俯視圖 (c)側視圖 46
圖 3.5.4 微針陣列示意圖 46
圖 3.5.5 SOLID95 47
圖 3.5.6 挫曲分析力與位移圖之關係 49
圖 3.5.1 微針頭製程流程圖 50
圖 5.1.1 Alignment key製作流程示意圖 (a)塗佈AZ5214 (b)曝光 (c)濺鍍鋁 (d)掀離AZ5214 51
圖 5.2.1 塗佈鐵氟龍之製程步驟 (a)鐵氟龍塗佈 (b)SU-8倒入 (c)軟烤 (d)貼上抗反射層膠帶 52
圖 5.2.2 SU-8 3035軟烤 53
圖 5.2.3 SU-8母模斜曝 54
圖 5.2.4 傾斜曝光製程流程圖 (a)SU-8 3035塗佈 (b)-(c)Mask A傾斜曝光 (d)-(e)Mask B傾斜曝光 (f)曝後烤 (g)顯影 55
圖 5.2.5 SU-8母模曝後烤 56
圖 5.2.6 SU-8母模顯影 57
圖 6.1.1力與位移圖 59
圖 6.1.2模擬結果圖，尚未出發挫曲 59
圖 6.1.3發散圖，無法收斂 60
圖 6.1.4力與位移關係圖 62
圖 6.2.1第一組SU-8母模結構圖，SU-8表面有氣泡坑洞 63
圖 6.2.2 SU-8明顯變形 64
圖 6.2.3第二組SU-8母模結構圖，SU-8部分沾黏於光罩上 64
圖 6.2.4紅色框的部分為SU-8傾斜曝光後鏈結的部位 65
圖 6.2.5第二組SU-8母模OM拍攝圖 65
圖 6.2.6第四組SU-8母模 66
圖 6.2.7第四組SU-8母模OM拍攝圖 67
圖 6.2.8第五組SU-8母模OM拍攝圖 69
圖 6.2.9第六組 SU-8母模OM拍攝圖 70
圖 6.2.10新金字塔柱第一組翻模SEM圖 72
圖 6.2.11新金字塔柱第二組翻模SEM圖 73
圖 6.2.12新金字塔柱第三組翻模SEM圖 74
圖 6.2.13新金字塔柱第四組翻模SEM圖 75
圖 6.2.14新金字塔柱第五組翻模SEM圖 76
圖 6.2.15新金字塔柱第六組翻模SEM圖 77

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