在此篇論文中我們提出了一種創新的空間解析漫反射光譜法-可調式光分佈漫反射光譜法(Light Distribution Modulated Diffuse Reflectance Spectroscopy, LDMDRS)，基於本實驗室先前提出之調整雙層式(Modified Two Layer, MTL)量測探頭架構，改以可控制散射特性的高分子散射型液晶(Polymer Dispersion Liquid Crystal, PDLC)材料做為高散射層。相對於典型漫反射光譜架構必須採用多組不同距離下成對的光源與偵測端來達到空間解析，PDLC元件能在以一組光源與偵測端下藉由操作不同的電壓改變其散射特性來達到空間解析的目的。
首先，我們先以積分球系統配合逆疊加演算法量化PDLC在不同電壓下的光學特性，接著將量化後的資訊配合蒙地卡羅演算法來作為LDMDRS系統的正向模型，並且透過類神經網路（Artificial Neural Network, ANN）連結正向模型後，配合最小平方法作為LDMDRS系統的反向模型。
我們利用上述LDMDRS模擬方式配合實際反算代測物的光學特性來驗證LDMDRS系統的準確性以及可行性。另外，我們也以蒙地卡羅模擬PDLC在不同的負載電壓下改變散射對組織中光子空間分布與偵測區域深度的變化。根據量測的結果，在500 nm~1000 nm的表現上反算代測物的光學特性LDMDRS系統有平均誤差約10%的表現。另外，從模擬空間分布與偵測深度的結果可知，LDMDRS系統在不同PDLC散射下其偵測區域深度變化大約為0.1 mm，相較於傳統多距離的光源偵測器量測方式其偵測區域深度變化大約為0.6 mm到1 mm， LDMDRS系統可確保量測區域為較為集中。最後，我們也希望將此LDMDRS元件應用於臨床上，因此也將此系統設計成自製探頭，透過3D列印將產品印出並用於人體皮膚量測。我們同樣先經由假體驗證此探頭的可行性，並對此產品進行安全性測試，以便之後用於臨床量測上。

In this thesis, we proposed the new spatial diffusion spectroscopy method- Light Distribution Modulated Diffuse Reflectance Spectroscopy(LDMDRS), this system continued the idea of Modified Two Layer system, we used the Polymer Dispersion Liquid Crystal(PDLC) to be the high scattering media in our experiment architecture. In compare with typical system, LDMDRS replaced the multiple distance with the controllable scattering property by providing different voltage to PDLC at one source-detector separation to achieve the spatial resolution. We discussed the optical property in the wavelength range from 500 nm to 1000 nm. Based on Monte Carlo simulation method, we constructed the high efficient model with training the artificial neural network to recover the optical properties accurately. We found that the recover average error in the single specific wavelength less than 10% and the total wavelength range approximately 10% by LDMDRS system
We also discussed the interrogation depth variation when modulating the PDLC scattering coefficient by controlling bias voltage, We found that the LDMDRS’s variation of interrogating depth is about 0.1mm which less than the conventional multiple distance method. Finally, we also developed the handheld LDMDRS probe by 3D-printing method, the probe presents more stability and accurately on measurement.

[1] A. Cerussi, N. Shah, D. Hsiang, A. Durkin, J. Butler, and B. J. Tromberg, "In vivo absorption, scattering, and physiologic properties of 58 malignant breast tumors determined by broadband diffuse optical spectroscopy," J Biomed Opt, vol. 11, p. 044005, Jul-Aug 2006.
[2] 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, vol. 13, p. 014016, Jan-Feb 2008.
[3] 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," Appl Opt, vol. 38, pp. 4939-50, Aug 1 1999.
[4] D. L. Glennie, J. E. Hayward, and T. J. Farrell, "Modeling changes in the hemoglobin concentration of skin with total diffuse reflectance spectroscopy," J Biomed Opt, vol. 20, p. 035002, Mar 2015.
[5] D. Yudovsky and L. Pilon, "Rapid and accurate estimation of blood saturation, melanin content, and epidermis thickness from spectral diffuse reflectance," Appl Opt, vol. 49, pp. 1707-19, Apr 01 2010.
[6] M. S. Weingarten, E. S. Papazoglou, L. Zubkov, L. Zhu, M. Neidrauer, G. Savir, et al., "Correlation of near infrared absorption and diffuse reflectance spectroscopy scattering with tissue neovascularization and collagen concentration in a diabetic rat wound healing model," Wound Repair Regen, vol. 16, pp. 234-42, Mar-Apr 2008.
[7] W. Verkruysse, R. Zhang, B. Choi, G. Lucassen, L. O. Svaasand, and J. S. Nelson, "A library based fitting method for visual reflectance spectroscopy of human skin," Phys Med Biol, vol. 50, pp. 57-70, Jan 7 2005.
[8] Y. W. Chen, C. C. Chen, P. J. Huang, and S. H. Tseng, "Artificial neural networks for retrieving absorption and reduced scattering spectra from frequency-domain diffuse reflectance spectroscopy at short source-detector separation," Biomed Opt Express, vol. 7, pp. 1496-510, Apr 01 2016.
[9] A. Kienle and M. S. Patterson, "Determination of the optical properties of semi-infinite turbid media from frequency-domain reflectance close to the source," Phys Med Biol, vol. 42, pp. 1801-19, Sep 1997.
[10] 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," Appl Opt, vol. 35, pp. 2304-14, May 1 1996.
[11] 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, vol. 10, p. 054004, Sep-Oct 2005.
[12] 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, vol. 18, p. 107004, Oct 2013.
[13] F. Bevilacqua and C. Depeursinge, "Monte Carlo study of diffuse reflectance at source-detector separations close to one transport mean free path," 1999.
[14] 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, vol. 45, pp. 1359-73, May 2000.
[15] 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, vol. 14, p. 054043, Sep-Oct 2009.
[16] Y. W. Chen, J. Y. Guo, S. Y. Tzeng, T. C. Chou, M. J. Lin, L. L. Huang, et al., "Toward reliable retrieval of functional information of papillary dermis using spatially resolved diffuse reflectance spectroscopy," Biomed Opt Express, vol. 7, pp. 542-58, Feb 1 2016.
[17] J. L. Nunu Ren, Xiaochao Qu,Jianfeng Li,Bingjia Lu, Jie Tian,, "GPU-based Monte Carlo simulation for light propagation in complex heterogeneous tissues," OPTICS EXPRESS, vol. 18, 29 March 2010.
[18] D.O.HEBB, The Organization of Behavior: A Neuropsychological Theory. Taylor&Francis e-Library: Lawrence Erlbaum Associates, Inc., 2009.
[19] 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, vol. 18, p. 57005, May 2013.
[20] Y. W. Chen and S. H. Tseng, "Efficient construction of robust artificial neural networks for accurate determination of superficial sample optical properties," Biomed Opt Express, vol. 6, pp. 747-60, Mar 1 2015.
[21] M. J. van Gemert, S. L. Jacques, H. J. Sterenborg, and W. M. Star, "Skin optics," IEEE Trans Biomed Eng, vol. 36, pp. 1146-54, Dec 1989.
[22] R. Hennessy, M. K. Markey, and J. W. Tunnell, "Impact of one-layer assumption on diffuse reflectance spectroscopy of skin," J Biomed Opt, vol. 20, p. 27001, Feb 2015.
[23] Y. Lee and K. Hwang, "Skin thickness of Korean adults," Surg Radiol Anat, vol. 24, pp. 183-9, Aug-Sep 2002.
[24] E. Pery, W. C. Blondel, C. Thomas, and F. Guillemin, "Monte Carlo modeling of multilayer phantoms with multiple fluorophores: simulation algorithm and experimental validation," J Biomed Opt, vol. 14, p. 024048, Mar-Apr 2009.
[25] N. A. Takaaki Maeda, Motoji Takahashi,Yoshihisa Aizu, "Monte Carlo simulation of spectral reflectance using a multilayered skin tissue model," Optical Review, vol. 17, pp. 223-229, May 2010 2010.
[26] D. Cupelli, F. Pasquale Nicoletta, S. Manfredi, M. Vivacqua, P. Formoso, G. De Filpo, et al., "Self-adjusting smart windows based on polymer-dispersed liquid crystals," Solar Energy Materials and Solar Cells, vol. 93, pp. 2008-2012, 2009.
[27] S. A. P. John W. Pickering, Niek van Wieringen, Johan F. Beek, Henricus J. C. M. Sterenborg, and Martin J. C. van Gemert, "Double-integrating-sphere system for measuring the optical properties of tissue," Applied Optics vol. 32, pp. 399-410, 1 February 1993.
[28] P. Y. Huang, C. Y. Chien, C. R. Sheu, Y. W. Chen, and S. H. Tseng, "Light distribution modulated diffuse reflectance spectroscopy," Biomed Opt Express, vol. 7, pp. 2118-29, Jun 1 2016.
[29] F. Rengier, A. Mehndiratta, H. von Tengg-Kobligk, C. M. Zechmann, R. Unterhinninghofen, H. U. Kauczor, et al., "3D printing based on imaging data: review of medical applications," Int J Comput Assist Radiol Surg, vol. 5, pp. 335-41, Jul 2010.
[30] S. A. Prahl, M. J. van Gemert, and A. J. Welch, "Determining the optical properties of turbid mediaby using the adding-doubling method," Appl Opt, vol. 32, pp. 559-68, Feb 1 1993.
[31] S. L. J. Lihong Wnag , Liqiong Zheng, "MCML-Monte Carlo modeliing of lght transport in multi-layered tissues," Elsevier Science Ireland Ltd, 1995.
[32] G. W. Smith, "Mixing and phase separation in liquid crystal/matrix systems: Determination of the excess specific heat of mixing," Phys Rev Lett, vol. 70, pp. 198-201, Jan 11 1993.
[33] H. Ren, Y.-H. Fan, Y.-H. Lin, and S.-T. Wu, "Tunable-focus microlens arrays using nanosized polymer-dispersed liquid crystal droplets," Optics Communications, vol. 247, pp. 101-106, 2005.
[34] v. d. Hulst, A New Look at Multiple Scattering, 1963.
[35] A. B. Davis and A. Marshak, "Photon propagation in heterogeneous optical media with spatial correlations: enhanced mean-free-paths and wider-than-exponential free-path distributions," Journal of Quantitative Spectroscopy and Radiative Transfer, vol. 84, pp. 3-34, 2004.
[36] M. J. A. J. Welch, Optical-thermal response of laser-irradiated tissue five chapter, 1995.
[37] W. J. Wiscombe, "On initialization, error and flux conservation in the doubling method," Journal of Quantitative Spectroscopy and Radiative Transfer, vol. 16, pp. 358-637, 1976.
[38] W. J. Wiscombe, "Doubling initialization revisited," Journal of Quantitative Spectroscopy and Radiative Transfer, vol. 18, pp. 245-248, 1977.
[39] N. Murata, S. Yoshizawa, and S. Amari, "Network information criterion-determining the number of hidden units for an artificial neural network model," IEEE Trans Neural Netw, vol. 5, pp. 865-72, 1994.
[40] S.-V. R. Rojas "Neural Networks," ed, 1996.
[41] A. Ashkin, J. M. Dziedzic, J. E. Bjorkholm, and S. Chu, "Observation of a single-beam gradient force optical trap for dielectric particles," Opt Lett, vol. 11, p. 288, May 1 1986.
[42] C. Y. Kuo, "Investigation of the performance of benchtop and handled diffuse reflectance system configured in the modified two layer or the conventional measurement geometries," 2016.