在這篇論文中我們使用了具有調整雙層式或傳統式量測架構配置的平台式與手持式漫反射光譜系統去量測波長500到1000奈米的漫反射光譜，並使用精確的光傳播理論模型，計算出皮膚的吸收係數與散射係數。由於人類皮膚於波長500到600奈米區段具有高吸收的光學性質，於此狀況下，傳統的光學擴散理論模型無法適用；因此，本研究使用了以蒙地卡羅演算法所訓練的高效率類神經網路作為光子傳播理論模型，以正確計算皮膚光學性質。另一方面，由蒙地卡羅法模擬與假體量測的結果顯示，調整雙層式架構與傳統式架構於量測皮膚時的偵測深度時，根據皮膚光學性質的不同最淺分別可達約0.2 mm與0.5 mm，最深約0.5mm與1mm；此現象可解釋這兩種架構於活體皮膚量測時，得到迥然不同量測結果之原因。最後，為了利於臨床量測，我們基於平台式系統的架構，發展了手持式量測系統，並詳細分析比較平台式系統及手持式系統量測固態假體以及人體皮膚之差異。根據實驗結果發現，手持式和平台式系統反算不同光學性質的固態假體之間的差異最小約10%最大約15%，由此可確認手持式系統的可行性。然而，調整雙層式架構的手持式系統光源太弱，造成總量測時間高達2分鐘。我們預期未來版本的手持式系統的體積及光源強度都將可以再進一步改善，以順利應用在皮膚臨床量測，協助醫護人員客觀量化皮膚性質。

In this thesis, we constructed the benchtop and handled diffuse reflectance spectroscopy (DRS) system configured in the modified two layer (MTL) or the conventional measurement geometries to measure the diffuse reflectance of tissues. The measured diffuse reflectance could then be fit to a certain photon transport model to derive the absorption coefficient (μ_a) and reduced scattering coefficient (μ_s') of tissues in the wavelength range from 500 to 1000 nm. Due to high light absorption of skin in the wavelength range from 500 to 600 nm, the standard diffusion model is not valid in this regime. Therefore, based on Monte Carlo method simulated databases, we established efficient artificial neural network models with accuracy comparable to the Monte Carlo method, and they were used for determining μ_a and μ_s' of turbid samples. From simulation and phantom experiment results, we found that the interrogation depth of MTL and conventional geometries are 0.5mm and 1mm separately. Our finding could lead to the explaination for the distinct in vivo skin measurement results from the two measurement geometries. Finally, to facilitate clinical measurements, we developed handheld DRS systems based on the setup of the benchtop DRS systems. We found that the difference between the benchtop and the handled system are generally within 5~10%, which suggested that the handled system was useful and could be applicable in the clinical studies. However, the measurement time of MTL handled system was about 2 minutes because of the weak light source strength. We will further reduce the size and enhance the light strength of the handheld systems so that they can be easily applied by medical personnel in the clinical skin studies for objectively quantifying skin properties.

1. M. Strojnik and G. Paez, "Spectral dependence of absorption sensitivity on concentration of oxygenated hemoglobin: pulse oximetry implications," J Biomed Opt 18, 108001 (2013).
2. H. Arimoto, M. Egawa, and Y. Yamada, "Depth profile of diffuse reflectance near-infrared spectroscopy for measurement of water content in skin," Skin research and technology : official journal of International Society for Bioengineering and the Skin 11, 27-35 (2005).
3. 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, 747-760 (2015).
4. P. G. Buettner, U. Leiter, T. K. Eigentler, and C. Garbe, "Development of prognostic factors and survival in cutaneous melanoma over 25 years: An analysis of the Central Malignant Melanoma Registry of the German Dermatological Society," Cancer 103, 616-624 (2005).
5. A. Breslow, "Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma," Annals of surgery 172, 902-908 (1970).
6. C. R. Simpson, M. Kohl, M. Essenpreis, and M. Cope, "Near-infrared optical properties of ex vivo human skin and subcutaneous tissues measured using the Monte Carlo inversion technique," Phys Med Biol 43, 2465-2478 (1998).
7. F. Bevilacqua and C. Depeursinge, "Monte Carlo study of diffuse reflectance at source-detector separations close to one transport mean free path," J Opt Soc Am A 16, 2935-2945 (1999).
8. F. Bevilacqua, D. Piguet, P. Marquet, J. D. Gross, B. J. Tromberg, and C. Depeursinge, "In vivo local determination of tissue optical properties: applications to human brain," Applied optics 38, 4939-4950 (1999).
9. K. W. Calabro and I. J. Bigio, "Influence of the phase function in generalized diffuse reflectance models: review of current formalisms and novel observations," J Biomed Opt 19, 75005 (2014).
10. A. F. Fercher, "Optical coherence tomography," J Biomed Opt 1, 157-173 (1996).
11. F. Bevilacqua, A. J. Berger, A. E. Cerussi, D. Jakubowski, and B. J. Tromberg, "Broadband absorption spectroscopy in turbid media by combined frequency-domain and steady-state methods," Applied optics 39, 6498-6507 (2000).
12. S. H. Tseng, P. Bargo, A. Durkin, and N. Kollias, "Chromophore concentrations, absorption and scattering properties of human skin in-vivo," Optics express 17, 14599-14617 (2009).
13. H. Y. Lin, N. Cheng, S. H. Tseng, and M. C. Chan, "Higher-order modulations of fs laser pulses for GHz frequency domain photon migration system," Optics express 22, 3950-3958 (2014).
14. T. H. Pham, T. Spott, L. O. Svaasand, and B. J. Tromberg, "Quantifying the properties of two-layer turbid media with frequency-domain diffuse reflectance," Applied optics 39, 4733-4745 (2000).
15. T. H. Pham, O. Coquoz, J. B. Fishkin, E. Anderson, and B. J. Tromberg, "Broad bandwidth frequency domain instrument for quantitative tissue optical spectroscopy," Review of Scientific Instruments 71, 2500-2513 (2000).
16. A. Kienle, L. Lilge, M. S. Patterson, R. Hibst, R. Steiner, and B. C. Wilson, "Spatially resolved absolute diffuse reflectance measurements for noninvasive determination of the optical scattering and absorption coefficients of biological tissue," Applied optics 35, 2304-2314 (1996).
17. M. Larsson, H. Nilsson, and T. Stromberg, "In vivo determination of local skin optical properties and photon path length by use of spatially resolved diffuse reflectance with applications in laser Doppler flowmetry," Applied optics 42, 124-134 (2003).
18. R. L. van Veen, H. J. Sterenborg, A. Pifferi, A. Torricelli, E. Chikoidze, and R. Cubeddu, "Determination of visible near-IR absorption coefficients of mammalian fat using time- and spatially resolved diffuse reflectance and transmission spectroscopy," J Biomed Opt 10, 054004 (2005).
19. R. Bays, G. Wagnieres, D. Robert, D. Braichotte, J. F. Savary, P. Monnier, and H. van den Bergh, "Clinical determination of tissue optical properties by endoscopic spatially resolved reflectometry," Applied optics 35, 1756-1766 (1996).
20. D. Yudovsky and L. Pilon, "Rapid and accurate estimation of blood saturation, melanin content, and epidermis thickness from spectral diffuse reflectance," Applied optics 49, 1707-1719 (2010).
21. D. Yudovsky and L. Pilon, "Retrieving skin properties from in vivo spectral reflectance measurements," Journal of biophotonics 4, 305-314 (2011).
22. D. J. Cappon, T. J. Farrell, Q. Fang, and J. E. Hayward, "Fiber-optic probe design and optical property recovery algorithm for optical biopsy of brain tissue," J Biomed Opt 18, 107004 (2013).
23. R. E. Thilwind, G. t Hooft, and N. E. Uzunbajakava, "Improved depth resolution in near-infrared diffuse reflectance spectroscopy using obliquely oriented fibers," J Biomed Opt 14, 024026 (2009).
24. K. B. Sung and H. H. Chen, "Enhancing the sensitivity to scattering coefficient of the epithelium in a two-layered tissue model by oblique optical fibers: Monte Carlo study," J Biomed Opt 17, 107003 (2012).
25. S. H. Tseng, A. Grant, and A. J. Durkin, "In vivo determination of skin near-infrared optical properties using diffuse optical spectroscopy," J Biomed Opt 13, 014016 (2008).
26. S. H. Tseng, C. Hayakawa, J. Spanier, and A. J. Durkin, "Investigation of a probe design for facilitating the uses of the standard photon diffusion equation at short source-detector separations: Monte Carlo simulations," J Biomed Opt 14, 054043 (2009).
27. K. M. Yoo, F. Liu, and R. R. Alfano, "When does the diffusion approximation fail to describe photon transport in random media?," Physical review letters 64, 2647-2650 (1990).
28. F. Martelli, M. Bassani, L. Alianelli, L. Zangheri, and G. Zaccanti, "Accuracy of the diffusion equation to describe photon migration through an infinite medium: numerical and experimental investigation," Phys Med Biol 45, 1359-1373 (2000).
29. R. Hennessy, W. Goth, M. Sharma, M. K. Markey, and J. W. Tunnell, "Effect of probe geometry and optical properties on the sampling depth for diffuse reflectance spectroscopy," J Biomed Opt 19, 107002 (2014).
30. S. L. Jacques, "'Melanosome absorption coefficient'," http://omlc.ogi.edu/spectra/hemoglobin/index.html. (1998).
31. S. Prahl, "'Hemoglobin absorption coefficient' " http://omlc.ogi.edu/spectra/hemoglobin/index.html. (1999).
32. M. Jager, F. Foschum, and A. Kienle, "Application of multiple artificial neural networks for the determination of the optical properties of turbid media," J Biomed Opt 18, 57005 (2013).
33. T. J. Farrell, B. C. Wilson, and M. S. Patterson, "The Use of a Neural Network to Determine Tissue Optical-Properties from Spatially Resolved Diffuse Reflectance Measurements," Phys Med Biol 37, 2281-2286 (1992).
34. E. Alerstam, T. Svensson, and S. Andersson-Engels, "Parallel computing with graphics processing units for high-speed Monte Carlo simulation of photon migration," J Biomed Opt 13, 060504 (2008).
35. W. Kessler, D. Oelkrug, and R. Kessler, "Using scattering and absorption spectra as MCR-hard model constraints for diffuse reflectance measurements of tablets," Analytica chimica acta 642, 127-134 (2009).
36. D. Khoptyar, A. A. Subash, S. Johansson, M. Saleem, A. Sparen, J. Johansson, and S. Andersson-Engels, "Broadband photon time-of-flight spectroscopy of pharmaceuticals and highly scattering plastics in the VIS and close NIR spectral ranges," Optics express 21, 20941-20953 (2013).
37. a. H. I. W. L. V. Wang, "Biomedical Optics:principles and imagine," John Wiley & Sons, Inc., New Jercy (2007).
38. R. C. Haskell, L. O. Svaasand, T. T. Tsay, T. C. Feng, M. S. McAdams, and B. J. Tromberg, "Boundary conditions for the diffusion equation in radiative transfer," Journal of the Optical Society of America. A, Optics, image science, and vision 11, 2727-2741 (1994).
39. A. Kienle, M. S. Patterson, N. Dognitz, R. Bays, G. Wagninures, and H. van den Bergh, "Noninvasive determination of the optical properties of two-layered turbid media," Applied optics 37, 779-791 (1998).
40. L. Wang, S. L. Jacques, and L. Zheng, "MCML--Monte Carlo modeling of light transport in multi-layered tissues," Computer methods and programs in biomedicine 47, 131-146 (1995).
41. E. Alerstam, W. C. Lo, T. D. Han, J. Rose, S. Andersson-Engels, and L. Lilge, "Next-generation acceleration and code optimization for light transport in turbid media using GPUs," Biomedical optics express 1, 658-675 (2010).
42. a. S.-V. R. Rojas, "Neural Networks, chapter 7," (1996).
43. J. W. Pickering, S. A. Prahl, N. van Wieringen, J. F. Beek, H. J. Sterenborg, and M. J. van Gemert, "Double-integrating-sphere system for measuring the optical properties of tissue," Applied optics 32, 399-410 (1993).
44. S. C. Gebhart, W. C. Lin, and A. Mahadevan-Jansen, "In vitro determination of normal and neoplastic human brain tissue optical properties using inverse adding-doubling," Phys Med Biol 51, 2011-2027 (2006).
45. S. T. Flock, S. L. Jacques, B. C. Wilson, W. M. Star, and M. J. van Gemert, "Optical properties of Intralipid: a phantom medium for light propagation studies," Lasers in surgery and medicine 12, 510-519 (1992).
46. S. Prahl, "Hemoglobin absorption coefficient,”" http://omlc.ogi.edu/spectra/hemoglobin/index.html. (1999).
47. L. Kou, D. Labrie, and P. Chylek, "Refractive indices of water and ice in the 0.65- to 2.5-microm spectral range," Applied optics 32, 3531-3540 (1993).