漫反射光譜學（DRS）是一項可以非侵入式量化活體生物組織之光學性質的技術，再搭配調整雙層式演算法或CUDA-MC人工類神經演算法，DRS系統便可以縮短光源與偵測器距離，進而量化皮膚內的色團濃度以評估皮膚的膚質狀態。
本論文在一開始先簡短的介紹皮膚結構和兩種目前尚未有根治方法的皮膚疾病，蟹足腫以及乾癬，並帶出研究的動機，利用DRS的特性優勢於臨床評估皮膚與病灶的狀態，期望能進一步提供皮膚科醫師更多的資訊來評估病情，而膠原蛋白濃度的量化，更是目前臨床上尚未出現相似功能的機台。接著將本研究所使用的兩種演算法之背景理論詳加說明，解釋如何可快速運算準確獲得皮膚的光學參數，並進一步用色團擬合來獲取皮膚內主要色團之濃度。硬體方面，也提出了基本DRS系統的架構以及所需要的設備，並且對於實際DRS運用上作基本的描述，並且說明如何運用假體校正以減少系統響應，進一步秀出此校正手法不僅操作方便，確實在半年內的持續使用下，系統還是能保有相當高的穩定性。接著提到我們運用DRS系統和成大醫院皮膚科合作所作的臨床研究。在蟹足腫的研究中我們運用平台式DRS系統收集了71位患者共計228筆蟹足腫疤痕的光譜資訊，並做了色團濃度分析，發現到DRS技術不僅能夠區別蟹足腫的嚴重程度，更可以用來評估治療效果的好壞；而在乾癬的研究中，我們微縮了DRS系統成手持式裝置，不僅大幅度的減少系統體積與設備建置的花費，也能提供臨床醫師不同於肉眼檢視的資訊。另外也運用假體實驗與動物實驗，來檢驗我們的膠原蛋白量化技術是否具有專一性以及準確性，結果發現膠原蛋白的量化並不會被咖啡濃度(類似黑色素吸收光譜)有顯著的影響；而動物實驗也運用切片的方式，與另一項光學技術二倍頻顯微鏡來做比對，結果也顯示出兩者的量化結果有很高的相關。
故本研究希望能提供一些客觀且嚴謹的研究手法，證明DRS系統在皮膚科學上的潛力，進一步推廣DRS系統能運用於各種皮膚病學的研究上。

Diffuse reflectance spectroscopy (DRS) technology is a noninvasive optical technique capable of determining the optical properties of biomedical tissues in vivo, furthermore, combining modified two-layered (MTL) algorithm or CUDA-MC artificial neural network (ANN) algorithm, the DRS system can be able to determine the major chromophore concentrations of skin tissue with short source-detector separation (SDS) probe to evaluate skin condition.
In the beginning, skin and two relative diseases, keloid and psoriasis, in briefly, and the advantages of DRS technique in dermatology research are introduced. Next, the theoretical background of MTL diffusion model, CUDA-MC ANN diffusion model, and the chromophore fitting algorithm have been described. Chapter 3 describes the fundamental DRS system setup and the protocol of measurement in practice, but also shows the results of stability of our benchtop system to demonstrate the calibration method is work. The phantom study shows the coffee chromophore (similar to melanin) has no direct influence on collagen concentration recovery. Moreover, the animal study shows high positive correlations between the DRS system and collagen evaluation of biopsy section with second harmonic generation (SHG) microscopy evaluation (Chapter 4).Further, the keloid and psoriasis studies are presented in Chapter 5 and 6, these results indicated our DRS system can help dermatologists to have different insights for these skin diseases.
This thesis describes two kinds of DRS system, a benchtop system and a portable handheld system, which we have developed for two skin diseases studies and one animal skin study to demonstrate the potential of DRS technique in dermatology research.

1. T. J. Farrell, M. S. Patterson, and B. Wilson, "A Diffusion-Theory Model of Spatially Resolved, Steady-State Diffuse Reflectance for the Noninvasive Determination of Tissue Optical-Properties Invivo," Medical Physics 19(4), 879-888 (1992).
2. R. M. Doornbos et al., "The determination of in vivo human tissue optical properties and absolute chromophore concentrations using spatially resolved steady-state diffuse reflectance spectroscopy," Physics in medicine and biology 44(4), 967-981 (1999).
3. S. F. Malin et al., "Noninvasive Prediction of Glucose by Near-Infrared Diffuse Reflectance Spectroscopy," Clinical Chemistry 45(9), 1651-1658 (1999).
4. G. Zonios et al., "Diffuse reflectance spectroscopy of human adenomatous colon polyps in vivo," Applied Optics 38(31), 6628-6637 (1999).
5. G. Zonios, J. Bykowski, and N. Kollias, "Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy," J Invest Dermatol 117(6), 1452-1457 (2001).
6. A. Cerussi et al., "In vivo absorption, scattering, and physiologic properties of 58 malignant breast tumors determined by broadband diffuse optical spectroscopy," Journal of biomedical optics 11(4), 044005 (2006).
7. A. Cerussi et al., "Predicting response to breast cancer neoadjuvant chemotherapy using diffuse optical spectroscopy," Proceedings of the National Academy of Sciences 104(10), 4014-4019 (2007).
8. A. Kienle, and T. Glanzmann, "In vivo determination of the optical properties of muscle with time-resolved reflectance using a layered model," Physics in medicine and biology 44(11), 2689-2702 (1999).
9. G. Yu et al., "Time-dependent blood flow and oxygenation in human skeletal muscles measured with noninvasive near-infrared diffuse optical spectroscopies," Journal of biomedical optics 10(2), 024027-02402712 (2005).
10. S.-H. Tseng et al., "Chromophore concentrations, absorption andscattering properties of human skin in-vivo," Optics Express 17(17), 14599-14617 (2009).
11. P. D. Kaplan et al., "Geometric constraints for the design of diffusing-wave spectroscopy experiments," Applied Optics 32(21), 3828-3836 (1993).
12. K. M. Yoo, F. Liu, and R. R. Alfano, "When does the diffusion approximation fail to describe photon transport in random media?," Phys Rev Lett 64(22), 2647-2650 (1990).
13. A. H. Hielscher, R. E. Alcouffe, and R. L. Barbour, "Comparison of finite-difference transport and diffusion calculations for photon migration in homogeneous and heterogeneous tissues," Physics in medicine and biology 43(5), 1285 (1998).
14. V. V. Tuchin, and V. Tuchin, Tissue optics: light scattering methods and instruments for medical diagnosis, SPIE press Bellingham (2007).
15. R. Zhang et al., "Determination of human skin optical properties from spectrophotometric measurements based on optimization by genetic algorithms," Journal of biomedical optics 10(2), 024030 (2005).
16. T. Gambichler et al., "A comparative pilot study on ultraviolet-induced skin changes assessed by noninvasive imaging techniques in vivo," Photochemistry and photobiology 82(4), 1103-1107 (2006).
17. J. Sandby-Moller, T. Poulsen, and H. C. Wulf, "Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits," Acta dermato-venereologica 83(6), 410-413 (2003).
18. A. R. Young, "Chromophores in human skin," Physics in medicine and biology 42(5), 789-802 (1997).
19. K. A. Saha, Clinical Methods & Interpretation in Medicine, illustrated ed., Jaypee Brothers,Medical Publishers Pvt. Limited (2015).
20. T. Lister, P. A. Wright, and P. H. Chappell, "Optical properties of human skin," Journal of biomedical optics 17(9), 0909011-09090115 (2012).
21. J. A. McGrath, and J. Uitto, "Anatomy and Organization of Human Skin," in Rook's Textbook of Dermatology, pp. 1-53, Wiley-Blackwell (2010).
22. C.-K. Hsu et al., "Non-invasive evaluation of therapeutic response in keloid scar using diffuse reflectance spectroscopy," Biomedical optics express 6(2), 390-404 (2015).
23. S.-H. Tseng et al., "Noninvasive evaluation of collagen and hemoglobin contents and scattering property of in vivo keloid scars and normal skin using diffuse reflectance spectroscopy: pilot study," Journal of biomedical optics 17(7), 077005 (2012).
24. V. Tuchin, and S. o. P.-o. I. Engineers, Tissue Optics: Light Scattering Methods and Instruments for Medical Diagnosis, SPIE (2015).
25. G. M. Bran et al., "Keloids: current concepts of pathogenesis (review)," Int J Mol Med 24(3), 283-293 (2009).
26. J.-Y. Lee et al., "Histopathological differential diagnosis of keloid and hypertrophic scar," Am J Dermatopathol 26(5), 379-384 (2004).
27. G. P. Sidgwick, and A. Bayat, "Extracellular matrix molecules implicated in hypertrophic and keloid scarring," J Eur Acad Dermatol Venereol 26(2), 141-152 (2012).
28. J. Peltonen et al., "Activation of collagen gene expression in keloids: co-localization of type I and VI collagen and transforming growth factor-beta 1 mRNA," J Invest Dermatol 97(2), 240-248 (1991).
29. P. D. Butler, M. T. Longaker, and G. P. Yang, "Current progress in keloid research and treatment," J Am Coll Surg 206(4), 731-741 (2008).
30. M. Jalali, and A. Bayat, "Current use of steroids in management of abnormal raised skin scars," The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland 5(3), 175-180 (2007).
31. B. Ardehali et al., "Objective assessment of keloid scars with three-dimensional imaging: quantifying response to intralesional steroid therapy," Plast Reconstr Surg 119(2), 556-561 (2007).
32. R. Ogawa, "The most current algorithms for the treatment and prevention of hypertrophic scars and keloids," Plast Reconstr Surg 125(2), 557-568 (2010).
33. S. Ud-Din et al., "Identification of steroid sensitive responders versus non-responders in the treatment of keloid disease," Archives of dermatological research 305(5), 423-432 (2013).
34. C. Profyris, C. Tziotzios, and I. Do Vale, "Cutaneous scarring: Pathophysiology, molecular mechanisms, and scar reduction therapeutics Part I. The molecular basis of scar formation," J Am Acad Dermatol 66(1), 1-10; (2012).
35. N. Brusselaers et al., "Burn scar assessment: a systematic review of different scar scales," J Surg Res 164(1), e115-123 (2010).
36. R. Fearmonti et al., "A review of scar scales and scar measuring devices," Eplasty 10(e43 (2010).
37. M. van der Wal et al., "Objective color measurements: clinimetric performance of three devices on normal skin and scar tissue," J Burn Care Res 34(3), e187-194 (2013).
38. S. J. Lin et al., "Evaluating cutaneous photoaging by use of multiphoton fluorescence and second-harmonic generation microscopy," Opt. Lett. 30(17), 2275-2277 (2005).
39. B. A. Torkian et al., "Modeling aberrant wound healing using tissue-engineered skin constructs and multiphoton microscopy," Arch. Facial Plast. Surg. 6(3), 180-187 (2004).
40. A. T. Yeh et al., "Imaging wound healing using optical coherence tomography and multiphoton microscopy in an in vitro skin-equivalent tissue model," J. Biomed. Opt. 9(2), 248-253 (2004).
41. J. Chen et al., "Multiphoton microscopy study of the morphological and quantity changes of collagen and elastic fiber components in keloid disease," Journal of biomedical optics 16(5), 051305 (2011).
42. V. Da Costa et al., "Nondestructive imaging of live human keloid and facial tissue using multiphoton microscopy," Arch Facial Plast Surg 10(1), 38-43 (2008).
43. P. J. Su et al., "Discrimination of collagen in normal and pathological skin dermis through second-order susceptibility microscopy," Opt Express 17(13), 11161-11171 (2009).
44. T. H. Tsai et al., "Visualizing radiofrequency-skin interaction using multiphoton microscopy in vivo," J. Dermatol. Sci. 65(2), 95-101 (2012).
45. B. Werner et al., "Comparative study of histopathological and immunohistochemical findings in skin biopsies from patients with psoriasis before and after treatment with acitretin," Journal of cutaneous pathology 35(3), 302-310 (2008).
46. H. Kittler et al., "Diagnostic accuracy of dermoscopy," The Lancet Oncology 3(3), 159-165 (2002).
47. M. Binder et al., "Epiluminescence microscopy of small pigmented skin lesions: Short-term formal training improves the diagnostic performance of dermatologists," J Am Acad Dermatol 36(2), 197-202 (1997).
48. P. Clarys et al., "Skin color measurements: comparison between three instruments: the Chromameter(R), the DermaSpectrometer(R) and the Mexameter(R)," Skin research and technology : official journal of International Society for Bioengineering and the Skin 6(4), 230-238 (2000).
49. M. D. Shriver, and E. J. Parra, "Comparison of narrow-band reflectance spectroscopy and tristimulus colorimetry for measurements of skin and hair color in persons of different biological ancestry," Am J Phys Anthropol 112(1), 17-27 (2000).
50. H. Takiwaki, L. Overgaard, and J. Serup, "Comparison of Narrow-Band Reflectance Spectrophotometric and Tristimulus Colorimetric Measurements of Skin Color," Skin Pharmacology and Physiology 7(4), 217-225 (1994).
51. M. Baquié, and B. Kasraee, "Discrimination between cutaneous pigmentation and erythema: Comparison of the skin colorimeters Dermacatch and Mexameter," Skin Research and Technology 20(2), 218-227 (2014).
52. M. Mogensen et al., "OCT imaging of skin cancer and other dermatological diseases," Journal of biophotonics 2(6-7), 442-451 (2009).
53. Y. Sun et al., "Investigating mechanisms of collagen thermal denaturation by high resolution second-harmonic generation imaging," Biophys J 91(7), 2620-2625 (2006).
54. B. G. Wang, K. Konig, and K. J. Halbhuber, "Two-photon microscopy of deep intravital tissues and its merits in clinical research," J Microsc 238(1), 1-20 (2010).
55. B. R. Masters, P. T. So, and E. Gratton, "Multiphoton excitation microscopy of in vivo human skin. Functional and morphological optical biopsy based on three-dimensional imaging, lifetime measurements and fluorescence spectroscopy," Ann N Y Acad Sci 838(58-67 (1998).
56. S.-H. Tseng et al., "Quantitative spectroscopy of superficial turbid media," Opt Lett 30(23), 3165-3167 (2005).
57. S.-H. Tseng et al., "Determination of optical properties of superficial volumes of layered tissue phantoms," IEEE transactions on bio-medical engineering 55(1), 335-339 (2008).
58. Y.-W. Chen, and S.-H. Tseng, "Efficient construction of robust artificial neural networks for accurate determination of superficial sample optical properties," Biomedical optics express 6(3), 747-760 (2015).
59. H. Ding et al., "Refractive indices of human skin tissues at eight wavelengths and estimated dispersion relations between 300 and 1600 nm," Physics in medicine and biology 51(6), 1479-1489 (2006).
60. M. H. Niemz, Laser-tissue interactions: fundamentals and applications, Springer Science & Business Media (2013).
61. D. R. Busch, "Computer-aided, multi-modal, and compression diffuse optical studies of breast tissue," in Physics and Astronomy, University of Pennsylvania, Publicly Accessible Penn Dissertations (2011).
62. A. Ishimaru, Wave propagation and scattering in random media, Academic press New York (1978).
63. D. P. Kroese et al., "Why the Monte Carlo method is so important today," Wiley Interdisciplinary Reviews: Computational Statistics 6(6), 386-392 (2014).
64. L. V. Wang, and H.-i. Wu, Biomedical optics: principles and imaging, John Wiley & Sons (2012).
65. R. C. Haskell et al., "Boundary conditions for the diffusion equation in radiative transfer," J Opt Soc Am A 11(10), 2727-2741 (1994).
66. A. Kienle et al., "Noninvasive determination of the optical properties of two-layered turbid media," Applied Optics 37(4), 779-791 (1998).
67. S.-H. Tseng, A. Grant, and A. J. Durkin, "In vivo determination of skin near-infrared optical properties using diffuse optical spectroscopy," Journal of biomedical optics 13(1), 014016 (2008).
68. S.-H. Tseng et al., "Investigation of a probe design for facilitating the uses of the standard photon diffusion equation at short source-detector separations: Monte Carlo simulations," Journal of biomedical optics 14(5), 054043 (2009).
69. L. H. Wang, S. L. Jacques, and L. Q. Zheng, "Mcml - Monte-Carlo Modeling of Light Transport in Multilayered Tissues," Computer Methods and Programs in Biomedicine 47(2), 131-146 (1995).
70. I. Lux, Monte Carlo particle transport methods: neutron and photon calculations, Citeseer (1991).
71. N. Metropolis, and S. Ulam, "The Monte Carlo Method," Journal of the American Statistical Association 44(247), 335-341 (1949).
72. B. C. Wilson, and G. Adam, "A Monte Carlo model for the absorption and flux distributions of light in tissue," Med Phys 10(6), 824-830 (1983).
73. S. T. Flock et al., "Monte Carlo modeling of light propagation in highly scattering tissues. I. Model predictions and comparison with diffusion theory," IEEE Transactions on Biomedical Engineering 36(12), 1162-1168 (1989).
74. Q. Liu, and N. Ramanujam, "Scaling method for fast Monte Carlo simulation of diffuse reflectance spectra from multilayered turbid media," J. Opt. Soc. Am. A 24(4), 1011-1025 (2007).
75. C. K. Hayakawa et al., "Perturbation Monte Carlo methods to solve inverse photon migration problems in heterogeneous tissues," Opt Lett 26(17), 1335-1337 (2001).
76. T. Hayashi, Y. Kashio, and E. Okada, "Hybrid Monte Carlo-diffusion method for light propagation in tissue with a low-scattering region," Applied Optics 42(16), 2888-2896 (2003).
77. M. N. S. Yusoff, and M. S. Jaafar, "Performance of CUDA GPU in Monte Carlo simulation of light-skin diffuse reflectance spectra," 2012 IEEE-EMBS Conference on Biomedical Engineering and Sciences 264-269 (2012).
78. O. Yang, and B. Choi, "Accelerated rescaling of single Monte Carlo simulation runs with the Graphics Processing Unit (GPU)," Biomedical optics express 4(11), 2667-2672 (2013).
79. N. Ren et al., "GPU-based Monte Carlo simulation for light propagation in complex heterogeneous tissues," Optics express 18(7), 6811-6823 (2010).
80. Q. Fang, and D. A. Boas, "Monte Carlo simulation of photon migration in 3D turbid media accelerated by graphics processing units," Optics express 17(22), 20178-20190 (2009).
81. C. Zhu, and Q. Liu, "Review of Monte Carlo modeling of light transport in tissues," Journal of biomedical optics 18(5), 50902 (2013).
82. E. Alerstam, T. Svensson, and S. Andersson-Engels, "Parallel computing with graphics processing units for high-speed Monte Carlo simulation of photon migration," Journal of biomedical optics 13(6), 060504-060504-060503 (2008).
83. Y.-W. Chen, "Development of an artificial neural network for recovering the optical properties of superficial volume of biological tissues in the non-diffusion regime," in Department of Photonics, National Cheng Kung University (2014).
84. T.-C. Chou, "Quantification of chromophore concentrations and thickness of human skin using a two-layer diffuse reflectance model," in Department of Photonics, National Cheng Kung University (2017).
85. Z.-X. Sie, "Scattering modulated diffuse reflectance spectroscopy for determining optical properties of turbid media," in Department of Photonics, National Cheng Kung University (2014).
86. N. Murata, S. Yoshizawa, and S. Amari, "Network information criterion-determining the number of hidden units for an artificial neural network model," IEEE transactions on neural networks 5(6), 865-872 (1994).
87. R. Rojas, Neural Networks - A Systematic Introduction, Springer-Verlag Berlin Heidelberg (1996).
88. T. M. Bydlon et al., "Chromophore based analyses of steady-state diffuse reflectance spectroscopy: current status and perspectives for clinical adoption," Journal of biophotonics 8(1-2), 9-24 (2015).
89. L. Kocsis, P. Herman, and A. Eke, "The modified Beer–Lambert law revisited," Physics in Medicine & Biology 51(5), N91 (2006).
90. S. L. Jacques, "Optical properties of biological tissues: a review," Physics in medicine and biology 58(11), R37-61 (2013).
91. D. Yudovsky, and L. Pilon, "Rapid and accurate estimation of blood saturation, melanin content, and epidermis thickness from spectral diffuse reflectance," Appl Opt 49(10), 1707-1719 (2010).
92. P. Taroni et al., "Absorption of collagen: effects on the estimate of breast composition and related diagnostic implications," Journal of biomedical optics 12(1), 014021 (2007).
93. P. Taroni et al., "Diffuse optical spectroscopy of breast tissue extended to 1100 nm," Journal of biomedical optics 14(5), 054030 (2009).
94. R. Nachabe et al., "Diagnosis of breast cancer using diffuse optical spectroscopy from 500 to 1600 nm: comparison of classification methods," Journal of biomedical optics 16(8), 087010 (2011).
95. D. J. Cappon et al., "Fiber-optic probe design and optical property recovery algorithm for optical biopsy of brain tissue," Journal of biomedical optics 18(10), 107004 (2013).
96. R. Nachabe et al., "Effect of bile absorption coefficients on the estimation of liver tissue optical properties and related implications in discriminating healthy and tumorous samples," Biomedical optics express 2(3), 600-614 (2011).
97. A. Kim et al., "A fiberoptic reflectance probe with multiple source-collector separations to increase the dynamic range of derived tissue optical absorption and scattering coefficients," Opt Express 18(6), 5580-5594 (2010).
98. Q. Liu, and N. Ramanujam, "Sequential estimation of optical properties of a two-layered epithelial tissue model from depth-resolved ultraviolet-visible diffuse reflectance spectra," Applied Optics 45(19), 4776-4790 (2006).
99. R. Bays et al., "Clinical determination of tissue optical properties by endoscopic spatially resolved reflectometry," Applied Optics 35(10), 1756-1766 (1996).
100. M. Pilz, S. Honold, and A. Kienle, "Determination of the optical properties of turbid media by measurements of the spatially resolved reflectance considering the point-spread function of the camera system," Journal of biomedical optics 13(5), 054047 (2008).
101. T. Coleman, and Y. Li, "On the convergence of interior-reflective Newton methods for nonlinear minimization subject to bounds," Mathematical Programming 67(1-3), 189-224 (1994).
102. S.-Y. Tzeng et al., "Portable handheld diffuse reflectance spectroscopy system for clinical evaluation of skin: a pilot study in psoriasis patients," Biomedical optics express 7(2), 616-628 (2016).
103. J. Y. Lee et al., "Histopathological differential diagnosis of keloid and hypertrophic scar," American Journal of Dermatopathology 26(5), 379-384 (2004).
104. T. A. Mustoe et al., "International clinical recommendations on scar management," Plast Reconstr Surg 110(2), 560-571 (2002).
105. P. D. Verhaegen et al., "Differences in collagen architecture between keloid, hypertrophic scar, normotrophic scar, and normal skin: An objective histopathological analysis," Wound Repair Regen 17(5), 649-656 (2009).
106. M. J. Baryza, and G. A. Baryza, "The Vancouver Scar Scale: an administration tool and its interrater reliability," J Burn Care Rehabil 16(5), 535-538 (1995).
107. R. Ogawa et al., "Postoperative radiation protocol for keloids and hypertrophic scars: statistical analysis of 370 sites followed for over 18 months," Annals of plastic surgery 59(6), 688-691 (2007).
108. H. P. Ehrlich et al., "Morphological and immunochemical differences between keloid and hypertrophic scar," Am J Pathol 145(1), 105-113 (1994).
109. A. Al-Attar et al., "Keloid pathogenesis and treatment," Plast Reconstr Surg 117(1), 286-300 (2006).
110. A. N. Bashkatov et al., "Optical properties of human skin, subcutaneous and mucous tissues in the wavelength range from 400 to 2000 nm," J Phys D Appl Phys 38(15), 2543-2555 (2005).
111. V. Venugopalan, J. S. You, and B. J. Tromberg, "Radiative transport in the diffusion approximation: An extension for highly absorbing media and small source-detector separations," Phys Rev E 58(2), 2395-2407 (1998).
112. C. W. Kischer, and G. S. Brody, "Structure of the collagen nodule from hypertrophic scars and keloids," Scanning Electron Microscopy Pt 3), 371-376 (1981).
113. R. Ogawa et al., "The relationship between skin stretching/contraction and pathologic scarring: the important role of mechanical forces in keloid generation," Wound Repair Regen 20(2), 149-157 (2012).
114. A. Kienle et al., "Determination of the optical properties of anisotropic biological media using an isotropic diffusion model," Journal of biomedical optics 12(1), 014026 (2007).
115. B. J. Wilhelmi, S. J. Blackwell, and L. G. Phillips, "Langer's Lines: To Use or Not to Use," Plast Reconstr Surg 104(1), 208-214 (1999).
116. S.-H. Tseng et al., "Noninvasive evaluation of collagen and hemoglobin contents and scattering property of in vivo keloid scars and normal skin using diffuse reflectance spectroscopy: pilot study," Journal of Biomedical Optics 17(7), 077005 (2012).
117. T. Ishiko et al., "Chondroitinase injection improves keloid pathology by reorganizing the extracellular matrix with regenerated elastic fibers," The Journal of dermatology 40(5), 380-383 (2013).
118. M. R. Shetlar et al., "Involution of keloid implants in athymic mice treated with pirfenidone or with triamcinolone," J Lab Clin Med 132(6), 491-496 (1998).
119. X. Wei et al., "A phosphoinositide 3-kinase-gamma inhibitor, AS605240 prevents bleomycin-induced pulmonary fibrosis in rats," Biochem Biophys Res Commun 397(2), 311-317 (2010).
120. Q. Zhang et al., "Mechanisms of hypoxic regulation of plasminogen activator inhibitor-1 gene expression in keloid fibroblasts," J Invest Dermatol 121(5), 1005-1012 (2003).
121. Y.-R. Kuo et al., "Suppressed TGF-beta1 expression is correlated with up-regulation of matrix metalloproteinase-13 in keloid regression after flashlamp pulsed-dye laser treatment," Lasers in surgery and medicine 36(1), 38-42 (2005).
122. S. Chadwick, R. Heath, and M. Shah, "Abnormal pigmentation within cutaneous scars: A complication of wound healing," Indian journal of plastic surgery : official publication of the Association of Plastic Surgeons of India 45(2), 403-411 (2012).
123. T. S. Alster, and E. L. Tanzi, "Hypertrophic scars and keloids: etiology and management," American journal of clinical dermatology 4(4), 235-243 (2003).
124. S. Coimbra et al., Psoriasis: Epidemiology, Clinical and Histological Features, Triggering Factors, Assessment of Severity and Psychosocial Aspects, INTECH Open Access Publisher (2012).
125. S. R. Feldman, and G. G. Krueger, "Psoriasis assessment tools in clinical trials," Annals of the Rheumatic Diseases 64(suppl 2), ii65-ii68 (2005).
126. S. A. Prahl, M. J. van Gemert, and A. J. Welch, "Determining the optical properties of turbid media by using the adding–doubling method," Applied optics 32(4), 559-568 (1993).
127. S. H. Tseng et al., "Chromophore concentrations, absorption and scattering properties of human skin in-vivo," Opt Express 17(17), 14599-14617 (2009).
128. M. A. Lowes, A. M. Bowcock, and J. G. Krueger, "Pathogenesis and therapy of psoriasis," Nature 445(7130), 866-873 (2007).
129. V. Koivukangas et al., "Increased collagen synthesis in psoriasis in vivo," Archives of dermatological research 287(2), 171-175 (1995).
130. L. Panzella et al., "Increased cysteinyldopa plasma levels hint to melanocyte as stress sensor in psoriasis," Exp Dermatol 20(3), 288-290 (2011).
131. M. Leroy et al., "Using infrared and Raman microspectroscopies to compare ex vivo involved psoriatic skin with normal human skin," Journal of biomedical optics 20(6), (2015).
132. C. Q. F. Wang et al., "IL-17 and TNF Synergistically Modulate Cytokine Expression while Suppressing Melanogenesis: Potential Relevance to Psoriasis," J Invest Dermatol 133(12), 2741-2752 (2013).
133. I. Flisiak, P. Porebski, and B. Chodynicka, "Effect of psoriasis activity on metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in plasma and lesional scales," Acta dermato-venereologica 86(1), 17-21 (2006).
134. L. Z. Carrenho et al., "Investigation of anti-inflammatory and anti-proliferative activities promoted by photoactivated cationic porphyrin," Photodiagnosis and photodynamic therapy 12(3), 444-458 (2015).
135. S.-H. Tseng et al., "Noninvasive evaluation of collagen and hemoglobin contents and scattering property of in vivo keloid scars and normal skin using diffuse reflectance spectroscopy: pilot study," Journal of biomedical optics 17(7), 077005 (2012).
136. E. C. Naylor, R. E. Watson, and M. J. Sherratt, "Molecular aspects of skin ageing," Maturitas 69(3), 249-256 (2011).
137. S. J. Moloney et al., "The hairless mouse model of photoaging: evaluation of the relationship between dermal elastin, collagen, skin thickness and wrinkles," Photochemistry and photobiology 56(4), 505-511 (1992).
138. S. E. Fligiel et al., "Collagen degradation in aged/photodamaged skin in vivo and after exposure to matrix metalloproteinase-1 in vitro," J Invest Dermatol 120(5), 842-848 (2003).
139. J. Varani et al., "Inhibition of type I procollagen synthesis by damaged collagen in photoaged skin and by collagenase-degraded collagen in vitro," Am J Pathol 158(3), 931-942 (2001).
140. P. Martin, "Wound Healing--Aiming for Perfect Skin Regeneration," Science 276(5309), 75-81 (1997).
141. A. T. Yeh et al., "Imaging wound healing using optical coherence tomography and multiphoton microscopy in an in vitro skin-equivalent tissue model," Journal of biomedical optics 9(2), 248-253 (2004).
142. J. R. De Vito et al., "Role of Borrelia burgdorferi in the pathogenesis of morphea/scleroderma and lichen sclerosus et atrophicus: a PCR study of thirty-five cases," Journal of cutaneous pathology 23(4), 350-358 (1996).
143. K. Kikuchi et al., "A new quantitative evaluation method for age-related changes of individual pigmented spots in facial skin," Skin research and technology : official journal of International Society for Bioengineering and the Skin 22(3), 318-324 (2016).
144. M. J. Koehler et al., "In vivo assessment of human skin aging by multiphoton laser scanning tomography," Opt Lett 31(19), 2879-2881 (2006).
145. Y.-H. Liao et al., "Quantitative analysis of intrinsic skin aging in dermal papillae by in vivo harmonic generation microscopy," Biomedical optics express 5(9), 3266-3279 (2014).
146. S. Y. Chen et al., "In Vivo Virtual Biopsy of Human Skin by Using Noninvasive Higher Harmonic Generation Microscopy," Ieee Journal of Selected Topics in Quantum Electronics 16(3), 478-492 (2010).
147. R. Y. Ha et al., "Analysis of facial skin thickness: defining the relative thickness index," Plast Reconstr Surg 115(6), 1769-1773 (2005).
148. A. M. De Grand et al., "Tissue-like phantoms for near-infrared fluorescence imaging system assessment and the training of surgeons," Journal of biomedical optics 11(1), 014007 (2006).
149. J. R. Cook, R. R. Bouchard, and S. Y. Emelianov, "Tissue-mimicking phantoms for photoacoustic and ultrasonic imaging," Biomedical optics express 2(11), 3193-3206 (2011).
150. F. W. Esmonde-White et al., "Biomedical tissue phantoms with controlled geometric and optical properties for Raman spectroscopy and tomography," Analyst 136(21), 4437-4446 (2011).
151. E. A. Bauer, and J. Uitto, "COLLAGEN IN CUTANEOUS DISEASES," International Journal of Dermatology 18(4), 251-270 (1979).
152. I. Nishidate, Y. Aizu, and H. Mishina, "Estimation of melanin and hemoglobin in skin tissue using multiple regression analysis aided by Monte Carlo simulation," Journal of biomedical optics 9(4), 700-710 (2004).
153. F. Vasefi et al., "Quantifying the optical properties and chromophore concentrations of turbid media using polarization sensitive hyperspectral imaging: optical phantom studies," Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XI 85870Z-85870Z-85879 (2013).
154. M. Seaton, A. Hocking, and N. S. Gibran, "Porcine models of cutaneous wound healing," ILAR J 56(1), 127-138 (2015).
155. T. P. Sullivan et al., "The pig as a model for human wound healing," Wound Repair Regen 9(2), 66-76 (2001).
156. J. F. Wang et al., "Molecular and cell biology of skin wound healing in a pig model," Connect Tissue Res 41(3), 195-211 (2000).
157. T.-Y. Kuo et al., "Lanyu Minipig is a Better Model System for Studying Wound Healing," J Biomater Tiss Eng 5(11), 886-894 (2015).
158. C.-Y. Lin et al., "Investigation of two-photon excited fluorescence increment via crosslinked bovine serum albumin," Opt Express 20(13), 13669-13676 (2012).
159. T. H. Tsai et al., "Visualizing radiofrequency-skin interaction using multiphoton microscopy in vivo," J Dermatol Sci 65(2), 95-101 (2012).
160. Y.-W. Chen et al., "Toward reliable retrieval of functional information of papillary dermis using spatially resolved diffuse reflectance spectroscopy," Biomedical optics express 7(2), 542-558 (2016).