臺灣博碩士論文加值系統

皮膚切片是醫師常用於判斷皮膚疾病的方法，一般分為鑽取活組織(Punch biopsy)、刮削活組織(Shave biopsy)、切口活組織檢查(Incisional biopsy)，而這些皮膚切片的檢查是屬於侵入式(Invasive)的檢測方式，使得病患在檢測的過程中流血甚至留下疤痕，光學同調斷層掃描術於1991年發明至今，已在生物醫學影像上佔有一席地位，其在量測的過程中不需要特殊記號，並且能夠以非侵入式的方式得到3D立體結構生物醫療影像。
本文中使用實驗室生長的摻鉻鎂橄欖石晶體光纖以520nm綠光雷射泵浦產生放大自發輻射(Amplified spontaneous emission; ASE)作為Mirau-based全域式光學同調斷層掃瞄系統所使用的光源，共使用兩顆1-W 520nm之雷射二極體泵浦摻鉻鎂橄欖石晶體光纖，對於沿C軸方向生長的摻鉻鎂橄欖石晶體光纖可以產生1.4 mW ASE，中心波長900 nm、頻寬250 nm，可以使OCT系統上在活體組織中有1.18 μm的縱向解析度能力；沿B軸方向生長的摻鉻鎂橄欖石晶體光纖可以產生3.3 mW ASE，中心波長900 nm、頻寬200 nm，並搭配新設計架構可使OCT系統在活體組織中有1.26 μm的縱向解析度能力；再搭配40X物鏡下得到0.65μm的橫向解析度能力，而搭配20X物鏡下可得到1.31 μm的橫向解析度能力，進行活體皮膚之量測，使用20X下得到247 μm的縱向穿透能力，可以量測到角質層、表皮層與真皮層之交界等三維結構資訊。
改良目前系統設計使得有效進入待測物的光功率上升，使干涉效率由6.52%上升至25.1%，可有效抑制雜訊。 

skin biopsy is the gold standard for doctor to diagnosis skin cancers. There are several ways to do the skin biopsy such as punch biopsy, shave biopsy, incisional biopsy, incisional biopsy. These methods are all invasive that make the patient bleed and leave scar. Optical coherence tomography is one of the techniques in the biomedical imaging system. It is a noninvasive, label-free and 3D imaging method.

In this thesis, Cr:forsterite crystal fiber amplified spontaneous emission(ASE) light source was used to build a Miura-based full-field Optical coherence tomography system. using two 520-nm laser diode to pumped the different axis Cr:forsterite crystal fiber, the C-axis fiber ASE centered 900 nm with a bandwidth of 250 nm was generated. The mirau-based full-field OCT has an axial resolution of 1.18 μm in tissue
. The B-axis fiber ASE centered 900 nm with a bandwidth of 200 nm was generated. The mirau-based full-field OCT has an axial resolution of 1.26 μm in tissue. two kinds of water immersion objective lens were employed, when employed 40x mirau objective was achieved a lateral resolution of 0.65 um and 20x mirau objective was achieved a lateral resolution of 1.31 μm

Using this system, we can measure in-vivo skin and get the high-resolution 3D volume structure. Utilizing the low absorption light source, the penetration depth of in-vivo skin measurement is about 247 μm. we can us this high-resolution OCT image to quantize the thickness of stratum corneum and can distinguish the dermo-epidermal junction.
Improved of optical power of incident sample light source made the interference efficiency growth from 6.52% to 25.1% and effectively noise suppression.

摘要 I
ABSTRACT II
致謝 III
目錄 I
圖目錄 V
表目錄 XIII
第一章 導論 1
1.1 緒論 1
1.2 研究動機 3
1.3 文獻回顧 4
第二章 光學同調斷層掃描術的基本原理 7
2.1 低同調干涉術 7
2.1.1 縱向解析度 13
2.1.2 橫向解析度 15
2.2 全域式光學同調斷層掃描術 17
2.3 摻鉻鎂橄欖石晶體光纖寬頻光源 19
2.3.1 Cr:forsterite 晶體材料特性 19
2.3.2 Cr:forsterite 晶體光學特性 25
2.3.3 Cr:forsterite 晶體光纖傳輸模態原理 29
2.3.4 Cr:forsterite 雙纖衣晶體光纖之製備 32
2.4 活體皮膚介紹 37
2.4.1 活體皮膚組織 38
2.4.2 皮膚光學特性 41
第三章 全域式光學同調斷層掃描設計 44
3.1 摻鉻鎂橄欖石晶體光纖光源模組 44
3.2 MIRAU干涉儀設計 49
3.2.1 Mirau 物鏡 50
3.2.2 干涉儀組件設計[85] 52
3.2.3 Mirau物鏡元件 54
3.2.4 膜層設計[86] 57
3.3 MIRAU干涉儀掃描距離 63
3.4 MIRAU物鏡製作 65
3.5 MIRAU全域式光學斷層掃描系統二次改良 67
3.5.1 Mirau 干涉儀架構設計改良 68
3.5.2 系統鍍膜設計與製作 69
3.5.3 參考鏡設計與製作 71
第四章 全域式光學同調斷層掃描結果與討論 73
4.1 使用摻鉻鎂橄欖石晶體光纖光源的MIRAU-BASED 全域式同調干涉系統 73
4.2 干涉系統特性分析 79
4.2.1 縱向解析度 79
4.2.2 橫向解析度 82
4.2.3 干涉訊號處理 86
4.3 穿透深度測量 89
4.4 改良干涉儀系統特性分析 93
4.4.1 ASE頻譜與鍍膜頻譜的討論與分析 95
4.4.2 20X 縱向解析度 98
4.4.3 20X 橫向解析度 103
4.4.4 改良前後比較 106
4.5 20X MIRAU干涉系統 108
4.6 結論 112
第五章 MIRAU全域式同調斷層掃描樣品結果 113
5.1 大腸癌切片量測 113
5.2 人體手臂之前臂量測 115
5.3 圖形化藍寶石基板量測 122
5.4 實驗室自製光柵結構 127
5.5 豬里肌肉影像量測 130
5.6 掃描樣品結果結論 134
6 第六章 結論與未來展望 135
REFERENCE 137

[1] P.A. Flournoy, R. W. McClure, and G. Wyntjes, “White-Light Interferometeric Thickness Gauge,” Appl. Opt., vol. 11, no.9,p. 1907,Sep. 1972.
[2] D.Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, and C. A. Puliafito, “Optical coherence tomography,” Science, vol. 254, no. 5035,pp. 1178-1181, Nov. 1991.
[3] E. A. Swanson, J. A. Izatt, M. R. Hee, D. Huang, C. P. Lin, J. S. Schuman, C. A. Puliafito, and J.G. Fujimoto, “In vivo retinal imaging by optical coherence tomography,” Opt. Lett., vol. 18, no. 21,p. 1864, Nov. 1993.
[4] J. Welzel, “Optical coherence tomography in dermatology: a review,” Skin Res. Technol. Off. J. Int. Soc. Bioeng. Skin ISBS Int. Soc. Digit. Imaging Skin ISDIS Int. Soc. Skin Imaging ISSI, vol. 7 , no. 1, pp. 1-9, Feb. 2001.
[5] 鄭乃嘉, “結合光學同調斷層掃描與共焦螢光顯微鏡術之研究.” 國立台灣大學 光電工程研究所, 2010.
[6] M. V. Klein and T. E. Furtak, Optics: Wiley New York, 1990.
[7] Fujimoto and Drexler, “Introduction to Optical Coherence Tomography,” in Optical Coherence Tomography, Drexler and Fujimoto, Eds. Springer Berlin Heidelberg, 2008, pp. 1–45.
[8] Rayleigh criterion. Available: http://hyperphysics.phy-astr.gsu.edu/hbase/phyopt/raylei.html.
[9] A. Yariv and P. Yeh, Photonics: Optical Electronics in Modern Communications, 6 edition. New York: Oxford University Press, 2006.
[10] K. Grieve, G. Moneron, R. Lecaque, L. Vabre, and C. Boccara with A. Dubois, 97 “Ultrahigh-resolution full-field optical coherence tomography,” Appl. Opt., vol. 43, no. 14, pp. 2874–2883, May 2004.
[11] 林耀聖, “全域式光學同調斷層掃描技術之研究.” 國立台灣大學光電工程研究所, 2013.
[12] R. R. Anderson and J. A. Parrish, “The optics of human skin,” J. Invest. Dermatol., vol. 77, no. 1, pp. 13–19, Jul. 1981.
[13] C. A. Burrus and J. Stone, “Single−crystal fiber optical devices: A Nd:YAG fiber laser,” Appl. Phys. Lett., vol. 26, no. 6, pp. 318–320, Mar. 1975.
[14] W. Drexler, Y. Chen, A. Aguirre, B. Považay, A. Unterhuber, and J. G. Fujimoto, “Ultrahigh Resolution Optical Coherence Tomography,” in Optical Coherence Tomography, W. Drexler and J. G. Fujimoto, Eds. Springer Berlin Heidelberg, 2008, pp. 239–279.
[15] K.-Y. Hsu, D.-Y. Jheng, Y.-H. Liao, T.-S. Ho, C.-C. Lai, and S.-L. Huang, “Diode-laser-pumped glass-clad Ti:sapphire crystal-fiber-based broadband light source,” IEEE Photonics Technol. Lett., vol. 24, no. 10, pp. 854–856, May 2012.
[16] Zeiss Objective EC Plan-Neofluar 40x/0.75 transmittance. Available:https://www.micro-shop.zeiss.com/?s=191483241fb3b94&l=en&p=us&f=o&a=v&m=s&id=440350-9903-000&o=.
[17] 王政凱, “摻鈦藍寶石寬頻晶體光纖光源之製備與檢測.” 國立台灣大學光電工程研究所, 2011.
[18] Human skin anatomy. Available:http://www.healthhype.com/human-skin-anatomy-structure-of-epidermis-and-dermis-layers.html.
[19] T. T. Sun and H. Green, “Immunofluorescent staining of keratin fibers in cultured cells,” Cell, vol. 14, no. 3, pp. 469–476, Jul. 1978. 98
[20] H. Shimizu, Shimizu’s textbook of dermatology, 1st edition. Japan: Hokkaido University Press/Nakayama Shoten, 2007.
[21] N. Otberg, H. Richter, H. Schaefer, U. Blume-Peytavi, W. Sterry, and J. Lademann, “Variations of Hair Follicle Size and Distribution in Different Body Sites,” J. Invest. Dermatol., vol. 122, no. 1, pp. 14–19, Jan. 2004.
[22] P. Beard, “Biomedical photoacoustic imaging,” Interface Focus, vol. 1, no. 4, pp. 602–631, Aug. 2011.
[23] R. K. Wang and V. V. Tuchin, Advanced Biophotonics: Tissue Optical Sectioning. Taylor & Francis, 2013.
[24] H. Ding, J. Q. Lu, W. A. Wooden, P. J. Kragel, and X. H. Hu, “Refractive indices of human skin tissues at eight wavelengths and estimated dispersion relations between 300 and 1600 nm,” Phys. Med. Biol., vol. 51, no. 6, p. 1479, Mar. 2006.
[25] S. H. Lu, C. J. Chang, and C. F. Kao, “Full-field optical coherence tomography using immersion Mirau interference microscope,” Appl. Opt., vol. 52, no. 18, pp. 4400–4403, Jun. 2013.
[26] D. H. Sliney and J. Mellerio, Safety with Lasers and Other Optical Sources: A Comprehensive Handbook. Springer Science & Business Media, 2013.
[27] H. Salem and S. A. Katz, Alternative Toxicological Methods. CRC Press, 2003.
[28] K. P. Wilhelm, P. Elsner, E. Berardesca, and H. I. Maibach, Bioengineering of the Skin: Skin Imaging & Analysis. CRC Press, 2006.
[29] L. F. Hoyt, “New Table of the Refractive Index of Pure Glycerol at 20°C,” Ind. Eng. Chem., vol. 26, no. 3, pp. 329–332, Mar. 1934.
[30] J. M. Schmitt, A. Knuttel, M. Yadlowsky, and M. A. Eckhaus,“Optical-coherence tomography of a dense tissue: statistics of attenuation and backscattering,” Phys. Med. Biol., vol. 39, no. 10, p. 1705, Oct. 1994.
[31] C. C. Tsai, C. K. Chang, K. Y. Hsu, T. S. Ho, M. Y. Lin, J. W. Tjiu, and S. L.Huang, “Full-depth epidermis tomography using a Mirau-based full-field optical coherence tomography,” Biomed. Opt. Express, vol. 5, no. 9, p. 3001, Sep. 2014.
[32] R. Joshi, “Clues to histopathological diagnosis of treated leprosy,” Indian J.Dermatol., vol. 56, no. 5, p. 505, 2011.
[33] Stratum corneum structure. Available:http://www.reamin.co.uk/view-of-the-epidermis-and-the-uppermost-layer-of-the-skin-the-brick-and-mortar-structured-stratum-corneum/.
[34] J. Serup, G. B. E. Jemec, and G. L. Grove, Handbook of Non-Invasive Methods and the Skin, Second Edition. CRC Press, 2006.
[35] Blood vessels. Available: http://www.derm101.com/inflammatory/embryologic-histologic-and-anatomic-aspects/blood-vessels/.
[36] Sweat gland. Available: http://kids.britannica.com/comptons/art-120217/ Two-of-the-exocrine-glands-with in-human-skin-are-sweat?
[34] M. V. Klein and T. E. Furtak, Optics: Wiley New York, 1990.
[35] Fujimoto and Drexler, “Introduction to Optical Coherence Tomography,” in Optical Coherence Tomography, Drexler and Fujimoto, Eds. Springer Berlin Heidelberg, 2008, pp. 1–45.
[36] Rayleigh criterion. Available: http://hyperphysics.phy-astr.gsu.edu/hbase/phyopt/raylei.html.
[37] A. Yariv and P. Yeh, Photonics: Optical Electronics in Modern Communications, 6 edition. New York: Oxford University Press, 2006.
[38] K. Grieve, G. Moneron, R. Lecaque, L. Vabre, and C. Boccara with A. Dubois,97“Ultrahigh-resolution full-field optical coherence tomography,” Appl. Opt., vol.43, no. 14, pp. 2874–2883, May 2004.
[39] 林耀聖, “全域式光學同調斷層掃描技術之研究.” 國立台灣大學光電工程研究所, 2013.
[40] R. R. Anderson and J. A. Parrish, “The optics of human skin,” J. Invest. Dermatol., vol. 77, no. 1, pp. 13–19, Jul. 1981.
[41] Cz. Koepke, K. Wisniewski, and M. Grinberg, "Excited statespectr-oscopy of chromium ions in various valence states inglass," J. of Alloys and Compounds, 341, 19 ( 2002).
[42]U. Hommerich, X. Wu, and V. R. Davis, " Demonstration ofroom-temperature laser action at 2.5 μm fromCr2+:Cd0.85Mn0.15Te, " Opt. Lett., 22, 1180 (1997).
[43] S. B. Mirov, V. V. Fedorov, K. Graham, and I. S. Moskalev "CW and pulsed Cr2+:ZnS and ZnSe microchip lasers, "Technical Digest, Conference on Lasers and Electro-Optics,120 (2002).
[44] J. McKay, K. L. Schepler and G. C. Catella, "Efficientgrating-tuned mid-infrared Cr2+:CdSe laser," Optics Letters,24, 1575 (1999).
[45] S. Kuck, K. Petermann, and G. Huber, "Spectroscopicinvestigation of the Cr4+-center in YAG, " OSA Proceedings onAdvanced Solid-State Lasers, 10, 92 (1991).
[46] Al. A. Kaminskii, " Laser crystal,"1st ed, Springer-Verlag BerlinHeidelberg New York, pp. 241, 381, 382 (1981).
[47] S. Aoshima, H. Itoh, K. Kuroyanagi, Y. Takiguchi, Y.Ohbayashi, I. Hirano, and Y. Tsuchiya, " Tunable picosecondall solid-state Cr:LiSAF laser, " IEEE, IMTC’94, 937 (1994).
[48] Yen-Kuang Kuo, Man-Fang Huang, and Milton Bimbaum, "Tunable Cr4+:YSO Q-switched Cr:LiCAF laser," J. of QuantumElectron., 31, 657 (1995).
[49] T. Fujii, M. Nagano, and K. Nemoto, "Spectroscope and laseroscillation characteristics of high Cr4+-doped forsterite, " J. of Quantum Electron., 32, 1497 (1996).
[50] S. Kuck, J. Koetke, K. Petermann, U. Pohlmann, and G.Huber, "Spectroscopic and laser studies of Cr4+:YAG andCr4+:Y2SiO5, " OSA Proceedings on Advanced Solid-StateLasers, 15, 334 (1993).
[51]Weiyi Jia,Huimin Liu,S.Jaffe,and W.M.Yen, "Spectroscope of Cr3+ and Cr4+ ions in forsterite, " Physical Review B volume 43, Number 7 (1991)
[52]N.V. Kulesho , V.G. Shcherbitsky”, V.P. Mikhailov”, S. Hartungb, T. Dangerb, S. Kiickb,K. Petermannb, G. Huberb,” Excited-state absorption and stimulated emission measurements in Cr4 + : forsterite,” Journal of Luminescence 75(1997).
[53] A. Sennaroglu, C. Pollock, and H. Nathel, " Generation of Tunable Femtosecond Pulses in the 1.21-1.27 pm and 605-635 nm wavelength region by using a regeneratively initiated Self-Mode-Locked Cr4+:Forsterite Laser, " IEEE J. Quantum Electron., Vol. 30, No.8, August (1994).
[54]N. V. Kuleshov, A. V. Podlipensky, V. G. Shcherbitsky, A. A. Lagatsky, and V. P. Mikhailov,’’ Excited-state absorption in the range of pumping and laser efficiency of Cr4+:forsterite,’’ OPTICS LETTERS / Vol. 23, No. 13 / July 1(1998).
[55]BahaaE. A. Saleh,Malvin Carl Teich,” Fundamentals of Photonics,”ch3(1991)
[56]G. Keiser, "Optical Fiber communications, 3rd ed, " McGraw-Hill, Ch. 2, Ch. 3 (2000).
[57]Zhang Shoudu, Wang Siting, Shen Xingda, Wang Haobing, Zhong Heyu, Zhang Shunxing, and Xu Jun, "Czochralski growth of rare-earth orthosilicates-Y2SiO5 single crystals," Journal of Crystal Growth, 197, 901 (1999).
[58]C. A. Burrus and J. Stone, " Single-crystal fiber optical devices: A Nd:YAG fiber laser, " Appl. Phys. Lett., 26, 318 (1975).
[59] G. A. Magel, M. M. Fejer, and R. L. Byer, " Quasi-phase-matched second harmonic generation of blue light in periodically poled LiNbO3, " Appl. Phys. Lett., 56, 108 (1990).
[60] R. S. Feigelson, D. Gazit, and D. K. Fork, " Superconducting Bi-Ca-Sr-Cu-O fibers grown by the laser-heated pedestal growth method, " Science, 240, 1642 (1988).
[61] 張金倉, 霍玉晶, 何豫生, "激光加熱浮區生長強織構高溫超導晶纖的研究" 中國激光, 第20 卷, 第8期(1993).
[62] L. Hesseling, and S. Redfield, "Photorefractive holographic recording in strontium barium niobate fiber, " Opt. Lett., Vol. 13, pp. 877-879,1988.
[63] Human skin anatomy. Available:http://www.healthhype.com/human-skin-anatomy-structure-of-epidermis-and-dermis-layers.html.
[64] T. T. Sun and H. Green, “Immunofluorescent staining of keratin fibers in cultured cells,” Cell, vol. 14, no. 3, pp. 469–476, Jul. 1978.
[65] H. Shimizu, Shimizu’s textbook of dermatology, 1st edition. Japan: Hokkaido University Press/Nakayama Shoten, 2007.
[69] W. Drexler, Y. Chen, A. Aguirre, B. Považay, A. Unterhuber, and J. G. Fujimoto,“Ultrahigh Resolution Optical Coherence Tomography,” in Optical Coherence Tomography, W. Drexler and J. G. Fujimoto, Eds. Springer Berlin Heidelberg, 2008, pp. 239–279.
[70] S. H. Lu, C. J. Chang, and C. F. Kao, “Full-field optical coherence tomography using immersion Mirau interference microscope,” Appl. Opt., vol. 52, no. 18, pp. 4400–4403, Jun. 2013.
[71] D. H. Sliney and J. Mellerio, Safety with Lasers and Other Optical Sources: A Comprehensive Handbook. Springer Science & Business Media, 2013.
[72] H. Salem and S. A. Katz, Alternative Toxicological Methods. CRC Press, 2003.
[73] H. Ding, J. Q. Lu, W. A. Wooden, P. J. Kragel, and X. H. Hu, “Refractive indices of human skin tissues at eight wavelengths and estimated dispersion relations between 300 and 1600 nm,” Phys. Med. Biol., vol. 51, no. 6, p. 1479, Mar. 2006.
[74] S. Kuck, J. Koetke, K. Petermann, U. Pohlmann, and G.Huber, "Spectroscopic and laser studies of Cr4+:YAG andCr4+:Y2SiO5, " OSA Proceedings on Advanced Solid-StateLasers, 15, 334 (1993).
[75] refractive index Avaliable: http://refractiveindex.info/
[76] General Information About Colon Cancer. ,National Cancer Institute, May. 2014.
[77] R. Joshi, “Clues to histopathological diagnosis of treated leprosy,” Indian J.Dermatol., vol. 56, no. 5, p. 505, 2011.
[78] Stratum corneum structure. Available: http://www.reamin.co.uk/view-of-the-epidermis-and-the-uppermost-layer-of-the-skin-the-brick-and-mortar-structured-stratum-corneum/.
[79] R. K. Wang and V. V. Tuchin, Advanced Biophotonics: Tissue Optical Sectioning. Taylor & Francis, 2013.
[80]張嘉原,洪紹剛, “圖形化藍寶石基板缺陷檢測之研究”, 國立交通大學精密與自動化工程學程 2012
[81] C.L. Tsai, J.C. Chen, .W.J. Wang, “Near-infrared Absorption Property of Biological Soft Tissue Constituents”, Journal of Medical and Biological Engineering , 21(1): 7-14 2001.
[82] H.J. Swatland, “Refractometry of pork muscle and beef connective and adipose tissue”, Meat Science 62,p225-228 (2002).
[83] Japanese Pork Color Score, Food education station Available: https://www.nicolosifoods.com/food-education-station/

[84] J.Mat.Chem-2-SI - Scientific Figure on Research Gate. Available from: https://www.researchgate.net/236994636_fig5_Figure-S14-Absorption-spectrum-of-pork-muscle-tissue-and-the-calculated-penetration,accessed 3 Jul, 2016
[87] Cell Size and Scale Available , University of Utah Health Science Genetic science learning center Available: http://learn.genetics.utah.edu/content/cells/scale/
[85] 吳東憶, “高解析且高深度 Mirau 全域式同調斷層掃描之活體皮膚量測” 國立台灣大學光電工程所2015
[86] 何端書, “基於寬頻晶體光纖元件之功能性學同調斷層掃描術研究” 國立台灣大學光電工程所2015
[88] J. G. Fujimoto ,Self-phase-modulated Kerr-lens mode-locked Cr:forsterite laser source for optical coherence tomography Optics Letters Vol. 21, Issue 22, pp. 1839-1841 (1996)
[89] Wolfgang Drexler ,James G. Fujimoto,”Optical Coherence Tomography Technology and Applications Second Edition”2015
[90] A.Sennaroglu, “Analysis and optimization of lifetime thermal loading in continuous-wave Cr4+-doped solid state laser”J.Opt.Soc. Am. B, Vol. 18,No.11 , Nov 2001.