臺灣博碩士論文加值系統

　　本論文使用實驗室自行生長的摻鈦藍寶石晶體光纖之放大自發輻射(Amplified spontaneous emission; ASE)作為光源，搭配輕薄簡單的Mirau物鏡與收取二維大角度成像的CMOS相機，架設全域式光學同調斷層掃描系統，並展示量測人類活體皮膚的結果。系統於組織中的縱向解析度與橫向解析度分別為1.3 μm 與 1.25 μm。運用此系統可以在前臂、手掌、手指與手腕得到高解析度的皮膚影像，並可由影像觀察到真皮與表皮之交界、汗腺、毛孔與血管等。量測前臂端手腕、前臂、手掌與拇指腹的角質層平均厚度，按厚度排列，結果分別為4 μm、13 μm、141 μm、306 μm。除了角質層厚度，本論文也針對區域性的軸向散射強度特徵進行分析。
　　正交偏振光譜影像(Orthogonal polarization spectral imaging)有著高對比度特性，本論文使用其研究紅血球的動態變化，並與OCT三維影像進行疊合，深入探討皮膚內部動態特性。此外，紅血球在不同光源下的吸收程度不同，也會導致其與周圍組織的對比度差異。在560 nm的光源下，吸收顯著，該處較無光線返回，呈現黑色圓點；在780 nm的光源下，吸收較小，與周圍組織的散射情形沒有顯著差異，唯有血球外緣的反射光較難收取，可以觀察出血球邊緣輪廓。
　　最後，使用質點影像速度分析的技術，針對影像中的微血管與小血管進行紅血球的流速運算，並使用平均影像與追跡影像的差值之區域標準差，標定正交偏振光譜影像中的流動區域。流速計算之結果，微血管的流速大約在30 – 80 μm/s，小血管的流速則大約在70 – 100 μm/s。本論文展示之OCT結合OPSI的方法，可以得到皮膚的結構資訊與紅血球之動態變化，可能可以提供醫師一些疾病診療的參考。

　　In this thesis, Mirau-based full-field optical coherence tomography system using homemade Ti:sapphire crystal fiber amplified spontaneous emission (ASE) as light source was demonstrated. The lateral and axial resolution of the system are 1.25 μm and 1.3 μm in tissue, respectively. High-resolution in-vivo human skin images acquired from various locations such as dorsal forearm, palm, finger and wrist were demonstrated. Besides the morphology, dermal-epidermal junction, sweat gland, pore and vessel could be found out. The stratum corneum thickness was compared between above locations. It is about 300 μm, the thickest, at thumb and about 4 μm, the thinnest, at wrist. Complementary to the morphology extracted with OCT system, orthogonal polarization spectral imaging (OPSI) was used to study the dynamic properties of red blood cells (RBC). Due to the absorption difference, RBC under OPSI has different appearance. At 560 nm, higher absorption, RBC is a black dot. At 780 nm, lower absorption, the boundary of RBC can be seen, but not that obvious compare with the circumstances of 560 nm. Finally, RBC velocity calculation was demonstrated with particle image velocimetry (PIV) method using cross-correlation algorithm. Using regional standard deviation, RBC flowing region can be found out. The RBC velocity of capillary is about 30 - 80 μm/s, and that in small vessel is at the range of 70 – 100 μm/s. Skin morphology acquired from OCT system combined with dynamic properties studied by OPSI and PIV may provide assistance for skin diseases related with structural change and RBC velocity change.

口試委員會審定.....I
誌謝.....II
中文摘要.....III
ABSTRACT.....IV
目錄.....V
圖目錄.....VIII
表目錄.....XV
第一章 緒論.....1
第二章 Mirau全域式光學同調斷層掃描.....5
　2.1　光學同調斷層掃描基本原理.....5
　　2.1.1　時域式光學同調斷層掃描.....5
　　2.1.2　頻域式光學同調斷層掃描.....12
　　2.1.3　全域式時域光學同調斷層掃描.....13
　2.2　摻鈦藍寶石晶體光纖寬頻光源.....13
　　2.2.1　摻鈦藍寶石晶體光纖製備.....13
　　2.2.2　摻鈦藍寶石晶體光纖放大自發輻射.....15
　　2.2.3　摻鈦藍寶石晶體光纖光源架構.....16
　2.3　Mirau全域式OCT系統.....20
　　2.3.1　干涉儀架構.....20
　　2.3.2　Mirau組件製作方法.....25
　　2.3.3　OCT系統的橫向、縱向解析度.....27
　　2.3.4　FF-OCT系統的投影透鏡考量.....30
　2.4　提取干涉訊號包絡的方法.....34
　　2.4.1　干涉訊號包絡之意涵.....34
　　2.4.2　四點運算法.....34
　　2.4.3　計算張數及掃描速度之影響.....36
第三章　OCT系統皮膚量測結果與軸向分析.....38
　3.1　皮膚的結構.....38
　　3.1.1　表皮層.....39
　　3.1.2　表皮與真皮交界、真皮層.....41
　　3.1.3　皮下組織.....41
　　3.1.4　汗腺.....41
　3.2　前臂背側的OCT影像與分析.....42
　3.3　手腕的OCT影像與分析.....54
　3.4　手掌的OCT影像與分析.....59
　　3.4.1　大魚際正面.....59
　　3.4.2　大魚際側面.....63
　　3.4.3　小魚際.....65
　3.5　手指的OCT影像與分析.....66
　　3.5.1　拇指指腹.....66
　　3.5.2　食指指腹.....68
　　3.5.3　中指背第1、2指節交界.....69
　3.6　皮膚的特色結構.....71
　　3.6.1　毛孔附近的角質層.....71
　　3.6.2　小血管.....72
　　3.6.3　表皮內汗管.....73
第四章　紅血球與正交偏振光譜影像.....75
　4.1　紅血球與血液.....75
　　4.1.1　血液組成及功能概述.....75
　　4.1.2　紅血球.....75
　　4.1.3　白血球、血小板.....76
　4.2　紅血球之光學特性.....76
　4.3　正交偏振光譜影像(OPSI)之基本原理.....77
　4.4　Ce:YAG光源系統的OPSI影像.....80
　4.5　Ti:sapphire光源系統的前臂、手腕OPSI影像.....82
　　4.5.1　前臂部位的微血管OPSI影像.....82
　　4.5.2　手腕部位的微血管、小血管OPSI影像.....84
　4.6　OCT系統的紅血球影像.....86
　4.7　相同位置的OCT與OPSI皮膚影像疊合.....87
　　4.7.1　微血管影像疊合(前臂部位).....87
　　4.7.2　小血管影像疊合(手腕部位).....91
第五章　紅血球流速計算.....93
　5.1　質點影像速度分析.....93
　　5.1.1　系統要素與分析方法.....93
　　5.1.2　位移向量的觀察框架.....95
　　5.1.3　運算方法–質心法.....96
　　5.1.4　運算方法–移動比對法.....99
　　5.1.5　二方法之比較.....102
　5.2　演算法細部解說.....105
　　5.2.1　演算法流程圖.....105
　　5.2.2　演算法步驟.....107
　　5.2.3　演算法結果驗證-直接觀察法(Visual inspection).....115
　5.3　演算法的參數優化.....116
　　5.3.1　追跡範圍大小的選擇.....116
　　5.3.2　追跡範圍的移動向量與速度之關係.....124
　　5.3.3　畫面更新率與影像間隔對速度的影響.....127
　　5.3.4　平均區間的影響.....132
　　5.3.5　標準差的分佈與流動區域的選擇.....139
　　5.3.6　高斯濾波參數.....143
　　5.3.7　靜態背景光強度梯度的影響.....148
　　5.3.8　運算條件總結與重要參數.....149
　5.4　微血管OPSI影像流速分析.....152
　　5.4.1　手腕之流速計算結果.....152
　　5.4.2　前臂之流速計算結果.....155
　5.5　小血管OPSI影像流速分析.....157
　5.6　流速計算結果與討論.....160
　　5.4.1　流速計算方向的討論.....160
　　5.4.2　流速計算量值的討論.....162
第六章　結論與未來展望.....163
　6.1　結論.....163
　6.2　未來展望.....165
參考文獻.....166

[1] A. F. Fercher, "Ophthalmic interferometry." Proceedings of the International Conference on Optics in Life Sciences, Garmisch-Partenkirchen, Germany, 12–16 August 1990.
[2] D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, J. G. Fujimoto, “ Optical coherence tomography. ” Science 254, 1178–1181 (1991)
[3] W. Drexler, J. G. Fujimoto, “ Optical Coherence Tomography – technologies and applications.” second edition
[4] A. F. Fercher, C. K. Hitzenberger, W. Drexler, G. Kamp, H. Sattmann, “In vivo optical coherence tomography. ” Am. J. Ophthalmol. 116, 113–114 (1993)
[5] E. A. Swanson, J. A. Izatt, M. R. Hee, D. Huang, C. P. Lin, J. S. Schuman, C. A. Puliafito, J. G. Fujimoto, “In vivo retinal imaging by optical coherence tomography. ” Opt. Lett. 18, 1864–1866 (1993)
[6] M. E. Brezinski, G. J. Tearney, B. E. Bouma, J. A. Izatt, M. R. Hee, E. A. Swanson, J. F. Southern, J. G. Fujimoto, “Optical coherence tomography for optical biopsy. Properties and demonstration of vascular pathology.” Circulation 93, 1206–1213 (1996)
[7] P. Parsa, S. L. Jacques, N. S. Nishioka, “ Optical properties of rat liver between 350 and 2200 nm.” Appl. Opt. 28, 2325–2330 (1989)
[8] G. J. Tearney, S. A. Boppart, B. E. Bouma, M. E. Brezinski, N. J. Weissman, J.F. Southern, J.G. Fujimoto, “ Scanning single-mode fiber optic catheter-endoscope for optical coherence tomography. ” Opt. Lett. 21, 543–545 (1996)
[9] G. J. Tearney, M. E. Brezinski, B. E. Bouma, S. A. Boppart, C. Pitvis, J. F. Southern, J. G. Fujimoto, “In vivo endoscopic optical biopsy with optical coherence tomography. ” Science 276, 2037–2039 (1997)
[10] G. J. Tearney, M. E. Brezinski, S. A. Boppart, B. E. Bouma, N. Weissman, J. F. Southern, E. A. Swanson, J. G. Fujimoto, “Catheter-based optical imaging of a human coronary artery. ” Circulation 94, 3013 (1996)
[11] J. G. Fujimoto, S. A. Boppart, G. J. Tearney, B. E. Bouma, C. Pitris, M. E. Brezinski, “High resolution in vivo intra-arterial imaging with optical coherence omography. ” Heart 82, 128–133 (1999)
[12] M. Wojtkowski, R. Leitgeb, A. Kowalczyk, T. Bajraszewski, A. F. Fercher, “In vivo human retinal imaging by Fourier domain optical coherence tomography. ” J. Biomed. Opt. 7, 457–463 (2002)
[13] J. A. Izatt, M. D. Kulkarni, H. W. Wang, K. Kobayashi, M. V. Sivak Jr., “Optical coherence tomography and microscopy in gastrointestinal tissues. ” IEEE J. Sel. Top. Quantum Electron. 2, 1017–1028 (1996)
[14] E. Beaurepaire, A. C. Boccara, M. Lebec, L. Blanchot, and H. Saint-Jalmes, “Full-field optical coherence microscopy ” OPTICS LETTERS / Vol. 23, No. 4 / February 15, 1998
[15] A. Dubois, L. Vabre, A. C. Boccara, E. Beaurepaire, “High-resolution full-field optical coherence tomography with a Linnik microscope. ” Appl. Optics 41, 805–812 (2002)
[16] L. Vabre, A. Dubois, A. C. Boccara, “Thermal-light full-field optical coherence tomography. ” Opt. Lett. 27, 530–532 (2002)
[17] J. Welzel, E. Lankenau, R. Birngruber, R Engelhardt, “Optical coherence tomography of the human skin.” J Am Acad Dermatol 37(6):958–963, S0190-9622(97)70072-0
[18] A. Nuttel, “ Spatially confined and temporally resolved refractive index and scattering evaluation in human skin performed with optical coherence tomography ” Journal of Biomedical Optics 5(1), 83–92 (January 2000)
[19] J. Welzel, “ Optical coherence tomography in dermatology: a review. ” Skin Research and Technology 2001; 7: 1–9
[20] A. Aneesh, P. Boris, “ Multispectral in vivo three-dimensional optical coherence tomography of human skin ” Journal of Biomedical Optics 15(2), 026025 (2010)
[21] http://mathworld.wolfram.com/Wiener-KhinchinTheorem.html
[22] http://www.edmundoptics.com/resources/application-notes/optics/integration-of-Optical-systems
[23] http://www.olympus-ims.com/en/microscope/terms/field_number
[24] http://www.microscopyu.com/tutorials/java/digitalimaging/pixelcalculator
[25] R. K. Wang and V. V. Tuchin, “Advanced Biophotonics: Tissue Optical Sectioning. ” Taylor & Francis, 2013.
[26] 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.
[27] 實用皮膚醫學 國立國立臺灣大學醫學院皮膚科部 編著
[28] 最新版家庭医学大全科 高久史磨
[29] https://en.wikipedia.org/wiki/Skin
[30] 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研究所, 2015.
[31] 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.
[32] 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.
[33] http://www.blood.org.tw/Internet/main/docDetail_Content_Print.aspx?uid=6536&pid=6387&docid=23909
[34] https://en.wikipedia.org/wiki/Red_blood_cell
[35] B. Vollmar, M. D. Menger “ The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair ” Physiological Reviews Published 1 October 2009 Vol. 89 no. 4, 1269-1339
[36] J. M. Steinke et. al. “Comparison of Mie theory and the light scattering of red blood cells ” Appl. Opt. 27,4027(1988)
[37] N. Bosschaart, G. J. Edelman, M. C. G. Aalders, T. G. van Leeuwen, D. J. Faber “A literature review and novel theoretical approach on the optical properties of whole blood ” Lasers Med Sci (2014) 29:453–479
[38] T. Gambichler, V. Jaedicke, S. Terras, “Optical coherence tomography in dermatology: technical and clinical aspects. ” Arch Dermatol Res (2011) 303:457–473
[39] M. C. Pierce, J. Strasswimmer, B.H. Park, B. Cense, J. F. de Boer, “ Advances in Optical Coherence Tomography Imaging for Dermatology. ” J Invest Dermatol 123:458 –463, 2004
[40] https://en.wikipedia.org/wiki/Optical_coherence_tomography
[41] C. C. Wu, G. Zhang, T. C. Huang,K. P. Lin “Red blood cell velocity measurements of complete capillary in finger nail-fold using optical flow estimation ” Microvascular Research 78 (2009) 319–324