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研究生： 王永凱
Wang, Yung-Kai
論文名稱： 人工真皮基質之傷口癒合研究
Studies of Artificial Dermal Matrices on Wound Healing
指導教授： 黃玲惠
Huang, Lynn-L.H.
學位類別： 碩士
Master
系所名稱： 生物科學與科技學院 - 生物科技研究所
Institute of Biotechnology
論文出版年： 2002
畢業學年度： 90
語文別： 中文
論文頁數： 106
中文關鍵詞： 傷口癒合 、人工真皮
外文關鍵詞： wound healing, artificial dermis
相關次數： 點閱：83  下載：5 
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    • 本論文實驗是將透明質酸（hyaluronan）及硫酸軟骨素（chondroitin sulfate）等多醣類添加於本研究室所研發之多孔性膠原蛋白基質（porous collagen matrix）中，以觀察其對於細胞及動物實驗之影響，並與商品IntegraÒ作比較。在細胞實驗，將人類纖維母細胞（NHDF）養入含多醣類之多孔性膠原蛋白基質及IntegraÒ中，結果發現含透明質酸的多孔性膠原蛋白基質（PCM-AH）有促進人類纖維母細胞增生及促進第一型膠原蛋白的分泌，並且亦觀察到細胞a-smooth muscle actin的表現有明顯的減少。將此PCM-AH基質與IntegraÒ分別移植入天竺鼠背部全深度傷口中，發現移植PCM-AH基質的傷口外觀閉合速率較IntegraÒ快速。在手術後第六天的傷口組織，PCM-AH組的纖維母細胞數目明顯地較IntegraÒ組多。在手術後第28天的傷口組織，所植入的PCM-AH基質已完全被分解，但IntegraÒ基質仍殘存於組織中，且其周圍有較多的免疫細胞聚集。在手術後第4個月的傷口組織，發現PCM-AH組有近似於正常組織的結構，而IntegraÒ組的癒合組織之上半部真皮層結構則顯得緻密，其下半部真皮層結構則較疏鬆。以trichrome染色法及Verhoeff染色法進行癒合組織之膠原蛋白及彈性纖維染色，發現PCM-AH組之膠原蛋白纖維及彈性纖維的分布與型態，皆有類似正常組織的情形。由細胞實驗及動物實驗的結果，含透明質酸的多孔性膠原蛋白基質可作為促進傷口癒合之人工真皮，在臨床應用上可能極具潛力。

    This study investigated the effects of activated hyaluronan (AH) and chondroitin sulfate (CS) in addition to porous collagen matrix (PCM) on cell functions as well as on wound healing of guinea pigs. Integra® was studied for comparison. Our results demonstrated that PCM-AH stimulated fibroblast proliferation and secretion of type I collagen. Decreased expression of a-smooth muscle actin was observed on fibroblasts cultured in PCM-AH. In the animal experiments, full-thickness wounds with 2 cm x 3 cm each were made on the dorsal skin of guinea pigs. PCM, PCM-AH, PCM-AH in HA and Integra® were filled to wounds or left open as a control. Our results demonstrated that the closure rate of wounds filled with PCM-AH was more rapid than that with Integra®. In the 6th day post-operation, the number of fibroblasts in PCM-AH is apparently more than that in Integra®. In the 28th day post-operation, no debris of PCM-AH could be found in wounds, nor did wounds filled with Integra®, yet more leukocytes clustered around the latter. In the 4th month post-operation, the wounds filled with PCM-AH healed with the highest quality and which was similar to normal skin tissue. Staining of collagen and elastin by trichrome and Verhoeff respectively revealed the distribution and morphology of collagen fibers and elastin fibers. The PCM-AH group showed similar results to normal skin tissue. In conclusion, PCM-AH demonstrated a good potential clinically that it can promote wound healing as an artificial dermis.

    中文摘要 英文摘要 誌謝 目錄 表目錄 圖目錄 符號 第一章 緒論…………………………………………………….… 1 1.1 皮膚的構造與功能…………………………………………. 1 1.2 傷口癒合……………………………………………………. 2 1.2.1 傷口癒合的過程…………………………………………. 2 1.2.2 影響傷口癒合的因素……………………………………. 4 1.3 膠原蛋白……………………………………………………. 5 1.3.1 膠原蛋白的結構與分布…………………………………. 5 1.3.2 膠原蛋白的應用發展……………………………………. 6 1.4 皮膚替代物………………………………………….……… 7 1.4.1 理想的皮膚替代物………………………………………. 7 1.4.2 皮膚替代物的種類………………………………………. 8 1.4.3 臨床的人工皮膚…………………………………………. 9 1.5 多醣類的使用……………………………………………….. 10 1.5.1 透明質酸（hyaluronan）………………………………… 11 1.5.2 硫酸軟骨素（chondroitin sulfate）……………………… 13 1.6 研究動機……………………………………………………. 13 第二章 實驗藥品、儀器與方法…………………………………. 22 2.1. 實驗藥品…………………………………………………. 22 2.2. 實驗儀器設備…………………………………………….. 24 2.3. 實驗方法………………………………………………….. 27 2.3.1. 豬真皮層之取得………………………………………….. 27 2.3.2. 多孔性膠原蛋白基質（PCM）的製備………………… 27 2.3.3. 透明質酸的活化………………………………………….. 27 2.3.4. 含多醣類之多孔性膠原蛋白基質製備………………….. 27 2.3.5. 基質的固定、包埋與切片……………………………….. 28 2.3.6. Hematoxylin and eosin染色（H&E染色）……………..… 29 2.3.7. Alcian blue染色………………………………………….. 29 2.3.8. 掃瞄式電子顯微鏡（SEM）觀察………………………. 30 2.3.9. 多醣類的定量：glucuronic acid assay………………….. 30 2.3.10. 膠原蛋白的定量：hydroxyproline assay………………… 31 2.3.11. 人類纖維母細胞培養於多孔性膠原蛋白基質………….. 33 2.3.12. 人類纖維母細胞增生實驗……………………………….. 34 2.3.13. 觀察人類纖維母細胞分泌第一型膠原蛋白…………….. 34 2.3.14. 觀察人類纖維母細胞表現之F-actin及a-smooth muscle actin……………………………………………………….. 35 2.3.15. 多孔性膠原蛋白基質移植入天竺鼠全深度傷口之手術………………………………………………………….. 36 2.3.16. 天竺鼠傷口組織之固定，脫水，包埋，切片………….. 36 2.3.17. 天竺鼠傷口閉合之分析………………………………….. 37 2.3.18. 天竺鼠傷口內部收縮的情形…………………………….. 37 2.3.19. 天竺鼠傷口皮膚厚度的測量…………………………….. 37 2.3.20. Masson氏三色（trichrome）染色………………………. 38 2.3.21. Verhoeff氏彈性纖維染色………………………………. 39 第三章 含多醣類之多孔性膠原蛋白基質製備及對於纖維母細胞生長的影響……………………………………….…… 40 3.1 實驗目的…………………………………………………. 40 3.2 實驗材料與方法…………………………………………. 40 3.2.1 細胞實驗之多孔性膠原蛋白基質種類…………………. 40 3.2.2 多孔性膠原蛋白基質孔洞大小分析……………………. 41 3.2.3 多孔性膠原蛋白基質中膠原蛋白的含量測定…………. 41 3.2.4 含多醣類之多孔性膠原蛋白基質中多醣類含量的測定 41 3.2.5 含多醣類之多孔性膠原蛋白基質中多醣類的分布情形 42 3.2.6 含多醣類之多孔性膠原蛋白基質表面孔洞結構觀察…. 42 3.2.7 含多醣類之多孔性膠原蛋白基質內部孔洞結構觀察…. 42 3.2.8 人類纖維母細胞於多孔性膠原蛋白基質中的增生情形 42 3.2.9 人類纖維母細胞於多孔性膠原蛋白基質中表現第一型膠原蛋白的情形…………………………………………. 43 3.2.10 人類纖維母細胞於多孔性膠原蛋白基質中表現F-actin及α-smooth muscle actin的情形………………………. 43 3.3 實驗結果…………………………………………………. 43 3.3.1 多孔性膠原蛋白基質孔洞大小分析……………………. 43 3.3.2 多孔性膠原蛋白基質中膠原蛋白的含量測定………….. 44 3.3.3 含多醣類之多孔性膠原蛋白基質中多醣類含量的測定 44 3.3.4 含多醣類之多孔性膠原蛋白基質中多醣類的分布情形 45 3.3.5 含多醣類之多孔性膠原蛋白基質表面孔洞結構觀察…. 45 3.3.6 含多醣類之多孔性膠原蛋白基質內部孔洞結構觀察…. 45 3.3.7 人類纖維母細胞於多孔性膠原蛋白基質中的增生情形 46 3.3.8 人類纖維母細胞於多孔性膠原蛋白基質中表現第一型膠原蛋白的情形…………………………………………. 46 3.3.9 人類纖維母細胞於多孔性膠原蛋白基質中表現F-actin及α-smooth muscle actin的情形………………………. 47 3.4 討論………………………………………………………. 47 第四章 含多醣類之多孔性膠原蛋白基質對於天竺鼠傷口癒合的影響……………………………………………………. 70 4.1 實驗目的………………………………………………….. 70 4.2 實驗材料與方法………………………………………….. 70 4.2.1 動物實驗之傷口種類…………………………………….. 70 4.2.2 傷口的閉合情形………………………………………….. 71 4.2.3 傷口發炎情形…………………………………………….. 71 4.2.4 纖維母細胞增生情形……………………………………. 71 4.2.5 癒合組織中細胞表現F-actin及α-smooth muscle actin的情形……………………………………………………. 71 4.2.6 癒合後傷口內部的收縮情形…………………………….. 72 4.2.7 癒合後皮膚厚度的情形………………………………….. 72 4.2.8 傷口癒合後組織的型態………………………………….. 72 4.2.9 膠原蛋白纖維表現情形………………………………….. 72 4.2.10 彈性纖維表現情形……………………………………….. 73 4.3 實驗結果………………………………………………….. 73 4.3.1 傷口的閉合情形………………………………………….. 73 4.3.2 傷口發炎情形…………………………………………….. 73 4.3.3 纖維母細胞增生情形……………………………………. 74 4.3.4 癒合組織中細胞表現F-actin及α-smooth muscle actin的情形…………………………………………………….. 74 4.3.5 癒合後傷口內部的收縮情形…………………………….. 75 4.3.6 癒合後皮膚厚度的情形………………………………….. 75 4.3.7 傷口癒合後組織的型態………………………………….. 75 4.3.8 膠原蛋白纖維表現情形………………………………….. 76 4.3.9 彈性纖維表現情形……………………………………….. 76 4.4 實驗討論………………………………………………….. 77 第五章 結論………………………………………………………. 97 第六章 參考文獻…………………………………………………. 99 表目錄 表1.1 膠原蛋白種類及分佈……………………………………. 19 表1.2 膠原蛋白作為生醫材料之優缺點………………………. 20 表1.3 商品化的皮膚替代物……………………………………. 21 表4.1 手術後第6天傷口免疫細胞表現量之比較……………. 82 圖目錄 圖1.1 皮膚構造圖………………………………………………… 15 圖1.2 傷口癒合的過程…………………………………………… 16 圖1.3 第一型膠原蛋白的化學結構……………………………… 17 圖1.4 透明質酸（hyaluronan）的化學結構式…………………. 18 圖1.5 6-硫酸軟骨素（chondroitin 6-sulfate）的化學結構式….. 18 圖3.1 多孔性膠原蛋白基質（PCM）之表層（surface）、中間層（middle）及縱切面（vertical）之孔洞直徑大小範圍的分布曲線………………………………………………... 50 圖3.2 實驗基質中的膠原蛋白含量……………………………… 51 圖3.3 實驗基質中的glucuronic acid含量………………………. 52 圖3.4 實驗基質中多醣類的分布………………………………… 53 圖3.5 以實驗基質之掃描式電子顯微鏡圖觀察基質表面的孔洞結構………………………………………………………... 54 圖3.6 實驗基質內部橫切面之孔洞結構圖……………………… 55 圖3.7 實驗基質內部縱切面之孔洞結構圖……………………… 56 圖3.8 人類纖維母細胞於實驗基質中細胞增生的情形………… 57 圖3.9 人類纖維母細胞於實驗基質中培養4天的第一型膠原蛋白分泌情形……………………………………………….. 59 圖3.10 人類纖維母細胞於實驗基質中培養7天的第一型膠原蛋白分泌情形………………………………………………… 61 圖3.11 人類纖維母細胞於實驗基質中培養4天的F-actin表現情形…………………………………………………………… 63 圖3.12 人類纖維母細胞於實驗基質中培養7天的F-actin表現情形。………………………………………………………… 65 圖3.13 人類纖維母細胞於實驗基質中培養4天的α-smooth muscle actin表現情形……………………………………... 67 圖3.14 人類纖維母細胞於實驗基質中培養7天的α-smooth muscle actin表現情形……………………………………... 69 圖4.1 含多醣類的多孔性膠原蛋白基質與IntegraÒ移植入天竺鼠全深度傷口後的傷口外觀閉合結果…………….…….. 79 圖4.2 手術後第6天的傷口免疫細胞表現情形………………… 80 圖4.3 免疫細胞在基質中的形態及表現情形（day 6）……….. 81 圖4.4 手術後第6天傷口組織纖維母細胞之表現……………… 83 圖4.5 手術後第6天的纖維母細胞增生情形…………………… 84 圖4.6 手術後第6天傷口組織中細胞表現F-actin的情形…….. 85 圖4.7 手術後第28天傷口組織中細胞表現F-actin的情形…… 86 圖4.8 手術後第6天傷口組織中細胞表現α-smooth muscle actin的情形………………………………………………... 87 圖4.9 手術後第28天傷口組織中細胞表現α-smooth muscle actin的情形……………………………………………….. 88 圖4.10 手術後第28天傷口癒合組織內部寬度分析……………. 89 圖4.11 手術後第28天傷口癒合組織皮膚厚度分析……………. 90 圖4.12 手術後第28天及四個月之傷口癒合情形………………. 92 圖4.13 手術後四個月之癒合組織膠原蛋白分布………………… 94 圖4.14 手術後四個月之癒合組織彈性纖維的表現……………… 96

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