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研究生: 馬婉純
Wan-chun Ma
論文名稱: 超音波結合微氣泡對比劑於局部消脂及經皮穿透之應用
Ultrasound Combined with Microbubbles for the Control of Local Fat and the Application of Transdermal Permeation
指導教授: 廖愛禾
Ai-ho Liao
口試委員: 葉明功
Ming-kung Yeh
鄭耿璽
Geng-xi Zheng
高震宇
Chen-yu Kao
學位類別: 碩士
Master
系所名稱: 應用科技學院 - 醫學工程研究所
Graduate Institute of Biomedical Engineering
論文出版年: 2013
畢業學年度: 101
語文別: 中文
論文頁數: 93
中文關鍵詞: 幾丁聚醣超音波體重脂肪墊血清經皮穿透超音波微氣泡對比劑α-熊果素黑色素
外文關鍵詞: Chitosan, Ultrasound, Body weight, Fat pad, Plasma lipid level, Microbubble, Ultrasound, Transdermal delivery, α-arbutin, Melanin
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  • 第一部分 超音波結合幾丁聚醣對於老鼠內部分脂肪分解之研究
    幾丁聚醣除了被運用在減肥的輔助用途外,對於伴隨高血脂或是體重過重型的脂肪肝之改善效果也相當好,而近年來超音波運用範圍也相當廣泛,不僅可以作為觀察身體組織的病變外,對於加強脂肪消除也相當有成效,因此本研究主要是以ICR雌鼠每天餵食幾丁聚醣五週,利用幾丁聚醣對於阻斷脂肪的吸收及降低膽固醇並結合超音波所釋放的生物效應達到可部分消除脂肪、降低血脂且不傷害組織抑有保健效果。
    本研究將ICR雌鼠隨機分為(1)控制組(C)、(2)超音波組(U)、(3)甲殼素組(CI)、(4)甲殼素結合超音波組(CU)等四組進行五週的治療實驗,於治療前後利用高頻超音波影像系統量測附睪脂肪墊、腹腔脂肪之超音波影像厚度、體重紀錄及量測血脂指數作為實驗對照。實驗結果顯示治療後CU組體重下降率高達(-11.2%),U組為(-5.8%)而CIS組為(-9.3%),附睪脂肪墊部分相較於其他各組更為顯著,CU組厚度減少高達(28.2%),而於血清中三酸甘油酯及低密度膽固醇也分別降低(51.5%)及(26%),由此實驗結果可得知,可藉由飲食幾丁聚醣對於脂肪吸收的機制搭配超音波的生物效應不僅可以達到體重控制及局部脂肪消除,亦可達到降低血清等效果。

    第二部分 超音波結合微氣泡對比劑應用於經皮穿透之研究
    目前對於大部分的藥物而言,經皮穿透常受限於表皮層內的角質層所形成之屏障,導致藥物穿透不易。根據文獻得知,目前使用微氣泡之超音波對比劑主要用於注射血管中以增強影像強度、藥物釋放及基因治療;而本研究即針對微氣泡對比劑用於加強經皮穿透之效果及可行性進行驗證。
    實驗參數分為: (1)控制組(C)、(2)單純施打超音波組(U)、(3)添加微氣泡對比劑組(UB)及 (4) 添加稀釋微氣泡對比劑組(UBD)。根據實驗結果可得知,UBD組在仿體及豬皮穿透深度方面相較於控制組分別增加了47%及84%;於經皮穿透濃度分析中,UBD組穿透濃度相較控制組增加了82%;於美白效果方面進行四週動物實驗(C57BL/6J老鼠),第一週皮膚即有明顯亮度提升的效果(增加25%),於第二週持續增加(33.7%),治療於第三週後各組亮度雖上升但趨於平緩(37%),而添加稀釋型微氣泡對比劑於治療第一周時即可超越單純塗抹熊果素第四周的皮膚亮度,對於治療時間上大為縮短,而卻可達到優越的美白成效。
    由此實驗結果可以得知,結合超音波和微氣泡對比劑之治療可以加強穿透濃度及α-熊果素之藥物釋放,進而使α-熊果素在對老鼠皮膚沒有傷害的情形下更有效地到達基底層抑制黑色素生成。


    Ultrasound (US) has recently been used to reduce localized adiposity in humans. The present study evaluated the combined use of chitosan, which is used to treat hyperlipidemic diseases and fatty liver, and US to control body weight and local fat deposition in normal mice over a 5-week experimental period. Female ICR mice were randomly divided into four groups (n=5 animals per group): (1) control (C), (2) US only (U), (3) chitosan only (CIS), and (4) chitosan combined with US (CU). The following measurements were made in all of the mice before and after the 5-week treatment period: body weight, epididymal fat-pad and intra-abdominal fat thicknesses (via US imaging), and plasma concentrations of high-density lipoprotein cholesterol, triglyceride, and low-density lipoprotein cholesterol. After the 5-week treatment period, body weight was decreased significantly in the CU group (–11.2%) compared to the U (–5.8%) and CIS (–9.3%) groups (p<0.05). The reduction in epididymal fat-pad thickness in the CU group (28.2%) was significantly more marked than in the other groups (p<0.05). Furthermore, in the CU group, plasma levels of triglyceride and low-density lipoprotein cholesterol were significantly decreased, by 51.5% and 26%, respectively. This is the first demonstration of the effective control of body weight and local fat by a combination of US and a putative fat-reducing dietary supplement in mice. The described method significantly decreases local fat-pad deposition, body weight, and plasma lipid levels.

    The application of transdermal delivery to a wider range of drugs is limited due to the significant barrier to penetration across the skin which is associated with the stratum corneum layer of the epidermis. In previous study, the contrast agent of ultrasound imaging, microbubble (MB) is mainly injected to the blood pool for image enhancement, drug delivery and genetic therapy. In this study, the feasibility and effects of the MBs as the penetration enhancers for transdermal delivery were firstly demonstrated. The penetration of α-arbutin on skin was enhanced by using ultrasound energy and MBs either for in vitro or for in vivo experiments. Experiment parameters were randomly divided into four groups: (1) only penetrating α-arbutin (C); (2) ultrasound combines with penetrating α-arbutin (U) (3) ultrasound combines with MBs contrast agent and penetrating α-arbutin (UB); (4) ultrasound combines with diluted MBs (UBD). According to the results, the penetration depth of agarose phantom and mice skin of UBD group increase 47% and 84%, respectively. In skin permeation of α-arbutin, UBD group has greater arbutin concentration than control group is 82%. The whitening effect (luminosity index (L*)) of mice skin in UBD group has significantly increase 25% in one week, 33.7% in two weeks and tends towards stability in three weeks (37%) in C57BL/6J mice over a 4-week experimental period.
    Our results investigated that the treatments of ultrasound and MBs can increase skin permeability, enhance α-arbutin delivery to inhibit melanogenesis and not damage the skin in mice.

    目錄 第一部分 超音波結合幾丁聚醣對於老鼠內部分脂肪分解之研究 中文摘要 I ABSTRACT II 誌謝 V 圖目錄 VIII 表目錄 X 第一章 緒論 2 1.1肥胖簡介 2 1.2 目前局部消脂之方法 3 1.2.1 抽脂 3 1.2.1.1動力抽脂 5 1.2.1.2超音波輔助吸脂 5 1.2.1.3雷射輔助抽脂 6 1.2.1.4射頻輔助吸脂 6 1.2.2溶脂 7 1.2.2.1冷凍溶脂 7 1.2.2.2 超音波體外溶脂 8 1.3超音波基本原理 9 1.4幾丁聚醣 10 1.5高頻超音波影像系統 11 1.6 研究動機與目的 14 第二章 材料與方法 15 2.1 藥品與設備 15 2.2 小動物模型建立 15 2.3體重評估 16 2.4脂肪之高頻超音波影像 16 2.5 病理組織切片 17 2.6 布蘭德-奧特曼分析(BLAND-ALTMAN ANALYZE) 18 第三章 實驗結果與討論 19 3.1幾丁聚醣結合超音波治療期間之超音波脂肪影像 19 3.2 幾丁聚醣結合超音波治療期間之小鼠體重變化 26 3.3 血脂檢測 27 3.4小鼠脂肪及肝組織之病理切片分析 29 第四章 結論 31 第五章 參考文獻 32 圖目錄 圖1.1 美國人口於1970-2009年平均攝取熱量 2 圖1.2 (A)吸脂後的脂肪,黑色箭頭為神經纖維,(B)脂肪顯微影像 3 圖1.3四代抽脂發展史 4 圖1.4 動力抽脂供電系統及手持元件 5 圖1.5 超音波輔抽脂之(A)元件及(B)示意圖 6 圖1.6 光纖雷射用管套 6 圖1.7 雙極射頻於脂肪內示意圖 7 圖1.8 超音波溶脂示意圖 9 圖1.9 幾丁聚醣結構 10 圖1.10 腫瘤B-MODE影像 12 圖1.11 B-MODE及 M-MODE 超音波影像 12 圖1.12 COLOR DOPPLER-MODE 超音波影像 13 圖1.13 對比劑注入體內CONTRAST-MODE影像 14 圖2.1 治療流程圖 16 圖2.2 左圖所示為高頻超音波動物影像系統示意圖,右圖為超音波探頭架設後之 17 實體實驗平台 17 圖2.3布蘭德-奧特曼分析圖 18 圖3.1 附睪脂肪墊厚度治療前後之B-MODE影像 19 圖3.2各組治療前後附睪脂肪厚度之布蘭德-奧特曼分析圖,分別為C組(A、B)、U組(C、D)、CIS組(E、F)及CU(G、H) 20 圖3.3 腹腔皮下脂肪厚度治療前後之B-MODE影像 21 圖3.4各組治療前後腹腔皮下脂肪厚度之布蘭德-奧特曼分析圖,分別為C組(A、B)、U組(C、D)、CIS組(E、F)及CU(G、H) 22 圖3.5 附睪脂肪墊厚度治療前後變化 25 圖3.6 腹腔皮下脂肪厚度治療前後變化 25 圖3.7 治療五週小鼠體重變化 26 圖3.8 各組附睪脂肪墊病理切片之400倍顯微影像 29 圖3.9 各組肝組織病理切片之400倍顯微影像,箭頭表示為脂肪空泡 30 表目錄 表3.1布蘭德-奧特曼分析各組附睪脂肪墊及腹腔皮下脂肪墊厚度之平均值………...23 表3.2 小鼠治療後之血液檢測…………………………………………………………..27 目錄 第二部分 超音波結合微氣泡對比劑應用於經皮穿透之研究 中文摘要 III ABSTRACT IV 第一章 緒論 38 1.1 超音波產生之物理機制 38 1.2 超音波對比劑簡介與應用 39 1.3 皮膚構造 41 1.4 藥物經皮吸收機制 43 1.5 藥物傳輸方式 44 1.6 黑色素形成機制 46 1.7 熊果素簡介 48 1.8 實驗動機與目的 49 第二章 材料與方法 50 2.1 白蛋白微氣泡對比劑製作 50 2.2 染劑於仿體之穿透深度量測 51 2.2.1 影像處理流程 51 2.2.2 二值化設定 52 2.2.3 邊緣偵測 52 2.3 染劑穿透豬皮之冷凍切片 53 2.4 熊果素經皮穿透之HPLC定量分析 53 2.4.1逆向高效能液相層析儀 55 2.5 微氣泡對比劑結合熊果素於小鼠皮表之美 55 白試驗 55 2.5.1 Lab色度檢測 56 2.6 統計分析 56 第三章 實驗結果與討論 57 3.1 染劑於仿體之參數評估 57 3.2 染劑於仿體之穿透深度分析 58 3.3 染劑於豬皮之穿透深度分析 61 3.4 熊果素經皮穿透之濃度分析 63 3.5 小動物皮膚美白試驗之亮度分析 65 3.6 小動物皮膚組織切片黑色素之分析 68 第四章 結論 69 第五章 參考文獻 70 圖目錄 圖1.1各材質球殼以不同形式攜帶藥物之對比劑示意圖 40 圖1.2 微氣泡於超音波下產生穴蝕效應到破裂之過程 41 圖1.3 超音波施加於微氣泡對比劑時藥物傳輸之過程 42 圖1.4 皮膚結構圖 43 圖1.5 表皮層構造 44 圖1.6 經皮吸收途徑 45 圖1.7 UVA及UVB於人體皮膚的穿透深度 47 圖1.8 黑色素細胞於表皮角質層示意圖 48 圖1.9黑色素形成之途徑 49 圖1.10熊果素結構圖 49 圖2.1白蛋白微氣泡對比劑製作流程 51 圖2.2 穿透架構圖 52 圖2.3 仿體穿透圖影像處理過程 53 圖2.4 經皮穿透之架構圖,(A)DIFFUSION CELL架構圖、(B)施打超音波、(C)抽取穿透液、(D)注入RP-HPLC進行分析、(E)微氣泡對比劑於皮膚表面上產生之物理效應示意圖 55 圖2.5 色度空間圖 57 圖3.1 超音波2W及3W分別搭配不同濃度的微氣泡對比劑於仿體穿透時之顯微影像 58 圖3.2染劑穿透仿體及MATLAB影像分析圖 60 圖3.3染劑穿透仿體深度之量化圖(*為顯著差異,P<0.05) 61 圖3.4 染劑穿透豬皮之顯微影像 63 圖3.5 豬皮穿透深度之量化圖(*為有顯著差異,P<0.05) 63 圖3.6 熊果素檢量線 64 圖3.7 熊果素於小鼠皮膚之穿透濃度 65 圖3.8 四周治療後各組小鼠皮膚膚色,(A)小鼠原本膚色,(B)經過UVB照射呈現黑色素沉澱,(C) C-1組,(D) C-2組,(E) U組,(F) UB組 (G) UBD組 67 圖3.9 治療期間熊果素於小鼠皮膚亮度值(L VALUE) 68 圖3.10治療期間熊果素於小鼠皮膚亮度差異值(∆L) 68 圖3.11 各組小鼠皮表組織切片,(A) C-1組,(B) C-2組,(C) U組,(D) UB組,(E) UBD組 70 表目錄 表3.1 超音波2W及3W結合各濃度微氣泡對比劑穿透深度統計表 58 表3.2 染劑穿透深度之統計表 61

    第一部分 超音波結合幾丁聚醣對於老鼠內部分脂肪分解之研究
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    [31] 王嘉薇,「丁醯化幾丁聚醣之研究」,碩士論文,國立成功大學 台南 (2003)
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    第二部分 超音波結合微氣泡對比劑應用於經皮穿透之研究
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    [3] Victor M., Bozena B., and Michniak-Kohn., Ultrasound-based Technology for Skin Barrier Permeabilization, Handbook of Non-Invasive Drug Delivery Systems: Science and Technology, UK, pp. 119-131 (2010)
    [4] 呂禮安,「結合微氣泡灌注之聚焦式超音波照射應用於小鼠腫瘤模型腫瘤之浸潤免疫淋巴球影響及腫瘤生長抑制」,碩士論文,長庚大學,桃園 (2011)
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    [8] Lindner J. R., “Microbubbles in medical imaging: current applications and future directions,” Nature Reviews Drug Discovery, Vol. 3, No. 6, pp. 527-533 (2004)
    [9] Eleanor Stride “Physical Principles of Microbubbles for Ultrasound Imaging and Therapy,” Cerebrovasc Diseasses, Vol. 27, No. 2, pp. 1-13 (2009)
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    [17] 林銘楷,「人體皮脂對藥物角質層滲透性之研究」,碩士論文,國立成功大學,台南 (2004)
    [18] 鄭嘉雯,「含乙基維生素C微乳液之特性」,碩士論文,大同大學,台北 (2011)
    [19] Pathan I. B., Setty C. M., “Chemical Penetration Enhancers for Transdermal Drug Delivery Systems,” Tropical Journal of Pharmaceutical Research, Vol. 8, No. 2, pp. 173-179 (2009)
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    [21] Barry B.W., “Novel mechanisms and devices to enable successful transdermal drug delivery,” European Journal of Pharmaceutical Sciences. Vol. 14, No. 2, pp. 101-114 (2001)
    [22] 許濘雅,「Hydrocortisone乳軟膏之皮膚藥動學研究及外用Clobetasol乳軟膏之藥動藥效模式分析」,碩士論文,國立成功大學,台南 (2004)
    [23] Jadoul A., Bouwstra J., and Pre’at V., “Effects of iontophoresis and electroporation on the stratum corneum Review of the biophysical studies,” Advanced Drug Delivery Reviews, Vol. 35, No. 1、4, pp. 89-105 (1999)
    [24] Silva S. M., Hu L., and Sousa J. J. et al., “A combination of nonionic surfactants and iontophoresis to enhance the transdermal drug delivery of ondansetron HCl and diltiazem HCl,” European Journal of Pharmaceutics and Biopharmaceutics. Vol. 80, No. 3, pp. 663-673 (2012)
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    [26] Smith N. B., “Perspectives on transdermal ultrasound mediated,” International Journal of Nanomedicine. Vol.2, No.4, pp.585-594 (2007)
    [27] Pastila R., Effect of long-wave UV radiation on mouse melanoma: an in vitro and in vivo study, Stuk, Finland (2006)
    [28] Yoshida Y., Hachiya A., and Sriwiriyanont P. et al., “Functional analysis of keratinocytes in skin color using a human skin substitute model composed of cells derived from different skin pigmentation types,” The FASEB Journal, Vol. 21, No. 11, pp. 2829-2839 (2007)
    [29] Chan Y.Y., Kim K.H., and Cheah S.H., “Inhibitory effects of Sargassum polycystum on tyrosinase activity and melanin formation in B16F10 murine melanoma cells,” Journal of Ethnopharmacology, Vol. 137, No. 3, pp. 1183-1189 (2011)
    [30] Abdel-Malek Z., Swope V. B., and Suzuki I., “Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 5, pp. 1789-1793 (1995)
    [31] 蕭伊妙,「維他命C醣苷和熊果素對於B16色素素瘤細胞抑制色素生成之研究」,碩士論文,國立清華大學,新竹 (2007)
    [32] Lai-Cheong J. E., McGrath J. A., “Structure and function of skin, hair and nails,” Medicine, Vol. 37, No. 5, pp. 223-226 (2009)
    [33] Slominski A., Tobin D. J., and Shibahara S., “Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation,” Physiological Reviews, Vol. 84, No. 4, pp. 1155-1228 (2004)
    [34] Chan Y.Y., Kim K.H., and Cheah S.H., “Inhibitory effects of Sargassum polycystum on tyrosinase activity and melanin formation in B16F10 murine melanoma cells,” Journal of Ethnopharmacology. Vol. 137, No. 3, pp. 1183-1188 (2011)
    [35] 呂佩嘉、黃蕙君、張聰民,「生薑醇抑制黑色素生成之研究」,弘光學報,弘光科技大學,台中 (2009)
    [36] 周玉青、黃蕙君、張聰民,「莨菪素抑制酪胺酸酶功效之研究」,弘光學報,弘光科技大學,台中 (2009)
    [37] 王阿靜,「化妝品美白成分之HPLC分析方法開發」,碩士論文,朝陽科技大學,台中 (2004)
    [38] 陳世芬,「高濃度常溫安定性熊果素微脂粒脂之製備與評估」,碩士論文,樹德科技大學,高雄 (2010)
    [39] Huang H. C., Hsieh W. Y., and Niu Y. L. et al., “Inhibition of melanogenesis and antioxidant properties of Magnolia grandiflora L. flower extract,” BMC Complementary and Alternative Medicine, Vol. 12, No. 72, (2012)
    [40] Chunqiao L., Deng L., and Zhang P. et al., “Towards a cost-effective method for α-arbutin production by using immobilized hydroquinone as a glucosyl acceptor,” Process Biochemistry. (2013)
    [41] Seo D. H., Jung J. H., Ha S. J. et al., “High-yield enzymatic bioconversion of hydroquinone to α-arbutin, a powerful skin lightening agent, by amylosucrase,” Appl Microbiol Biotechnol, Vol. 94, No. 5, pp. 1189-1197 (2012)
    [42] Kazuhisa S., Takahisa N., and Koji N. et al., “Syntheses ofα-Arbutin-α-Glycosides and Their Inhibitory Effects on Human Tyrosinase,” Pharmaceutical Society of Japan, Vol. 99, No. 3, pp. 272-276 (2005)
    [43] 許羽均,「辨識肌肉纖維化之超音波影像紋理分析」,碩士論文,國立海洋大學,高雄 (2010)
    [44] 陳守信,「即時影像處理於自走車避障之設計與實現」,碩士論文,逢甲大學,台中 (2007)
    [45] Kim J., Jang J.H., and Lee J. H. et al., “Enhanced Topical Delivery of SmallHydrophilic or Lipophilic Active Agents and Epidermal Growth Factor by Fractional Radiofrequency Microporation,” Pharmaceutical Research, Vol. 29, No. 7, pp. 2017-2029 (2012)
    [46] Ishii H., Fujino K., and Todo H. et al., “Evaluation of the skin blanching of topically applied steroids using a chroma meter in animals,” Experimental Animals, Vol.61, No.2, pp.147-156 (2012)
    [47] Tsaib Y. H., Leeb K. F., and Huanga Y. B. and et al., “In vitro permeation and in vivo whitening effect of topical hesperetin microemulsion delivery system,” International Journal of Pharmaceutics, Vol. 388, No. 1, pp. 257-262 (2010)
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    [50] Park J. H., Lee J. W., and Kim Y. C. et al., “The effect of heat on skin permeability,” International Journal of Pharmaceutics, Vol. 359, No. 1-2, pp. 94-103 (2008)
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    [54] Tezel A., and Mitragotri S., “Interactions of Inertial Cavitation Bubbles with Stratum Corneum Lipid Bilayers during Low-Frequency Sonophoresis,” Biophysical Journal, Vol. 85, No. 6, pp. 3502-3512 (2003)

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