疾病的早期檢測可以早期發現問題並及早治療，微小核糖核酸為一微小非編碼的單股RNA分子，可藉由轉譯效率達到參與調控目標基因的表現。血液中的miRNA已被證實可以當成生物標記來偵測癌症和其他疾病。然而，目前用於偵測miRNA的方法卻是亟待改進，雖然用聚合酶鏈鎖反應的方法可以準確的偵測miRNA的有無，但偵測所需的時間太長及聚合酶鏈鎖反應機器的售價太高，導致這方法必須在有規模的生物實驗室才能進行。

表面電漿共振(Surface Plasmon Resonance, SPR)感測器可量測生物分子在固體與液體或固體與氣體界面間發生交互作用時，其界面上介電常數之微小變化。本論文中提出之表面電漿共振空間影像系統可觀察反射光波相位空間變化情形，並將此系統應用於檢測微小核醣核酸分子，本系統可即時量測、靈敏度高以及不需對生物分子標記等優點。

一般表面電漿共振影像感測器的影像分析是採用位移進動方式做多步還原演算法解相，亦即擷取多張不同相位的干涉條紋影像做演算法計算。本論文提出一具新穎性之表面電漿共振空間相關影像感測系統，量測上，除了運用光頻譜分析儀做影像Fringe Visibility的優化外，也使用窗口傅立葉轉換來分析空間干涉條紋相關影像，以得知待測物之濃度變化。

於本論文中，本架構量測microRNA-21之相位靈敏度為-0.067( rad/μM )，影像靈敏度為-7.5"×" 〖"10" 〗^"-2" （μm/μM）。

Early diagnostics of the disease can discover the body malfunctions and apply the appropriate treatment in an early stage. MicroRNA (miRNA) is a small non-coding RNA which functions in post-translational regulation of gene expression. The detection of miRNA expression level could be useful for cancer diagnosis in early stage. For disease diagnosis, the serum miRNAs can serve as potential biomarkers for the detection of various cancers and other diseases. However, the time cost of PCR (Polymerase chain Reaction)-based miRNA detection method still needs improved.

The surface plasma resonance (SPR) sensor could detect the small dielectric constant variation at the interface between the solid and liquid or the solid and gas. The SPR spatial imaging system proposed in this project can observe the phase change from reflected light for miRNA-21 detection in real time and biomarkers free with high sensitivity.

The typical SPR image sensor is using the multi-step algorithm to resolve the sensitivity and resolution through interference fringe images. A novel SPR image sensing system is proposed to utilize the prism for spatial correlated image analyses. The main functions are taking the windowed Fourier transform to analyze relative images interference displacements from various analytes besides the fringe visibility optimization through optical spectrum analyzer.

In this thesis, the interference phase and image sensitivity for microRNA-21 DNA are characterized as -0.067 (rad/μM) and-7.5"×" 〖"10" 〗^"-2" （μm/μM） respectively.

[1] V. Ambros, "The functions of animal microRNAs", Nature, vol. 431, no. 7006, pp. 350-355, 2004.
[2] L. Barrett, S. Fletcher and S. Wilton, "Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements", Cellular and Molecular Life Sciences, vol. 69, no. 21, pp. 3613-3634, 2012.
[3] E. Bandres, X. Agirre, N. Ramirez, R. Zarate and J. Garcia-Foncillas, "MicroRNAs as Cancer Players: Potential Clinical and Biological Effects", DNA and Cell Biology, vol. 26, no. 5, pp. 273-282, 2007.
[4] G. Wan, Q. 'En Lim and H. Too, "High-performance quantification of mature microRNAs by real-time RT-PCR using deoxyuridine-incorporated oligonucleotides and hemi-nested primers", RNA, vol. 16, no. 7, pp. 1436-1445, 2010.
[5] S. Rabbany, W. Lane, W. Marganski, A. Kusterbeck and F. Ligler, "Trace detection of explosives using a membrane-based displacement immunoassay", Journal of Immunological Methods, vol. 246, no. 1-2, pp. 69-77, 2000.
[6] K. Komolov, I. Senin, P. Philippov and K. Koch, "Surface Plasmon Resonance Study of G Protein/Receptor Coupling in a Lipid Bilayer-Free System", Analytical Chemistry, vol. 78, no. 4, pp. 1228-1234, 2006.
[7] S. Chen, Y. Su, F. Hsiu, C. Tsou and Y. Chen, "Surface plasmon resonance phase-shift interferometry: Real-time DNA microarray hybridization analysis", Journal of Biomedical Optics, vol. 10, no. 3, pp. 034005, 2005.
[8] D. J. Barber and I. C. EFreestone, "An investigation of the origin of the colour of the Lycurgus Cup by analytical transmission electron microscopy," Archaeometry, vol. 32, pp. 33-45, 1990.
[9] R. Wood, "On a Remarkable Case of Uneven Distribution of Light in a Diffraction Grating Spectrum", Proceedings of the Physical Society of London, vol. 18, no. 1, pp. 269-275, 1902.
[10] U. Fano, "The Theory of Anomalous Diffraction Gratings and of Quasi-Stationary Waves on Metallic Surfaces （Sommerfeld’s Waves）", Journal of the Optical Society of America, vol. 31, no. 3, pp. 213, 1941.
[11] R. Ritchie, "Plasma Losses by Fast Electrons in Thin Films", Physical Review, vol. 106, no. 5, pp. 874-881, 1957.
[12] E. A. Stern and R. A. Ferrell, "Surface Plasma Oscillations of a Degenerate Electron Gas," Physical Review, vol. 120, pp. 130-136, 1960.
[13] A. Otto, "Excitation of nonradiative surface plasma waves in silver by the method of frustrated total reflection", Zeitschrift für Physik A Hadrons and nuclei, vol. 216, no. 4, pp. 398-410, 1968.
[14] E. Kretschmann, "Decay of non radiative surface plasmons into light on rough silver films. Comparison of experimental and theoretical results", Optics Communications, vol. 6, no. 2, pp. 185-187, 1972.
[15] C. Nylander, B. Liedberg and T. Lind, "Gas detection by means of surface plasmon resonance", Sensors and Actuators, vol. 3, pp. 79-88, 1982.
[16] B. Liedberg, C. Nylander and I. Lunström, "Surface plasmon resonance for gas detection and biosensing", Sensors and Actuators, vol. 4, pp. 299-304, 1983.
[17] K. Giebel et al., "Imaging of Cell/Substrate Contacts of Living Cells with Surface Plasmon Resonance Microscopy", Biophysical Journal, vol. 76, no. 1, pp. 509-516, 1999.
[18] W. Barnes, A. Dereux and T. Ebbesen, "Surface plasmon subwavelength optics", Nature, vol. 424, no. 6950, pp. 824-830, 2003.
[19] A. Parks and S. Spence, "Weak value amplification of an off-resonance Goos–Hänchen shift in a Kretschmann–Raether surface plasmon resonance device", Applied Optics, vol. 54, no. 18, pp. 5872, 2015.
[20] J. Sambles, G. Bradbery and F. Yang, "Optical excitation of surface plasmons: An introduction", Contemporary Physics, vol. 32, no. 3, pp. 173-183, 1991.
[21] B. Prabowo, A. Purwidyantri and K. Liu, "Surface Plasmon Resonance Optical Sensor: A Review on Light Source Technology", Biosensors, vol. 8, no. 3, pp. 80, 2018.
[22] B. Gupta, A. Shrivastav and S. Usha, "Surface Plasmon Resonance-Based Fiber Optic Sensors Utilizing Molecular Imprinting", Sensors, vol. 16, no. 9, pp. 1381, 2016.
[23] J. Homola, Surface plasmon resonance based sensors, Berlin: CH 1-3, Springer, 2006.
[24] A. Chaubey and B. Malhotra, "Mediated biosensors", Biosensors and Bioelectronics, vol. 17, no. 6-7, pp. 441-456, 2002.
[25] X. Sun, S. Shiokawa and Y. Matsui, "Interactions of surface plasmons with surface acoustic waves and the study of the properties of Ag films", Journal of Applied Physics, vol. 69, no. 1, pp. 362-366, 1991.
[26] P. Gershon and S. Khilko, "Stable chelating linkage for reversible immobilization of oligohistidine tagged proteins in the BIAcore surface plasmon resonance detector", Journal of Immunological Methods, vol. 183, no. 1, pp. 65-76, 1995.
[27] R. Leach, Optical Measurement of Surface Topography. Berlin: Springer, 2014.
[28] J.Brockman, B.Nelson, and R.Corn,"surface plasmon resonance imaging measurements of ultrathin organic films", Annual Review of Physical Chemistry, vol. 51, no. 1, pp. 41-63, 2000.
[29] P. A. Flournoy, R. W. McClure, and G. Wyntjes, "White-Light Interferometric Thickness Gauge," Applied Optics, vol. 11, pp. 1907-1915, 1972.
[30] B. E. Bouma, G. J. Tearney, I. P. Bilinsky, B. Golubovic, and J. G. Fujimoto, "Self-phase-modulated Kerr-lens mode-locked Cr:forsterite laser source for optical coherence tomography," Optics Letters, vol. 21, pp. 1839-1841, 1996.
[31] U. Morgner, W. Drexler, F. X. Kärtner, X. D. Li, C. Pitris, E. P. Ippen, et al., "Spectroscopic optical coherence tomography," Optics Letters, vol. 25, pp. 111-113, 2000.
[32] R. C. Youngquist, S. Carr, and D. E. N. Davies, "Optical coherence-domain reflectometry: a new optical evaluation technique," Optics Letters, vol. 12, pp. 158-160, 1987.
[33] J. Goodman, Statistical optics. New York, N.Y.: Wiley, 1985.
[34] R. Leach, Optical Measurement of Surface Topography. Berlin: Springer Berlin, 2014.
[35] J. C. Wyant and K. Creath, "Recent Advances in Interferometric Optical Testing, " Laser Focus, pp. 118–132, 1982.
[36] P. Hariharan, B. F. Oreb, and T. Eiju, "Digital phase-shifting interferometry: a simple error-compensating phase calculation algorithm," Applied Optics, vol. 26, pp. 2504-2506, 1987.
[37] M. Takeda, H. Ina and S. Kobayashi, “Fourier-transform method of fringe-pattern analysis for computer-based topography and interferometry,” Journal of the Optical Society of America 72, pp. 56-160, 1982.
[38] B. Kimbrough, J. Millerd, J. Wyant, and J. Hayes, "Low-coherence vibration insensitive Fizeau interferometer," SPIE Optics + Photonics, vol. 6292, pp. 12, 2006.
[39] S. Fang, H. J. Lee, A. W. Wark, and R. M. Corn, "Attomole Microarray Detection of microRNAs by Nanoparticle-Amplified SPR Imaging Measurements of Surface Polyadenylation Reactions," Journal of the American Chemical Society, vol. 128, pp. 14044-14046, 2006.
[40] Z. S. Sípová H, Dudley AM, Galas D, Wang K, Homola J., "Surface Plasmon Resonance Biosensor for Rapid Label-Free Detection of Microribonucleic Acid at Subfemtomole Level," Analytical Chemistry, vol. 82, pp. 10110-10115, 2010.
[41] S. Chen, Y. Su, F. Hsiu, C. Tsou and Y. Chen, "Surface plasmon resonance phase-shift interferometry: Real-time DNA microarray hybridization analysis", Journal of Biomedical Optics, vol. 10, no. 3, pp. 034005, 2005.
[42] C. Wong et al., "Two-dimensional biosensor arrays based on surface plasmon resonance phase imaging", Applied Optics, vol. 46, no. 12, pp. 2325, 2007.
[43] Y. Su, S. Chen and T. Yeh, "Common-path phase-shift interferometry surface plasmon resonance imaging system", Optics Letters, vol. 30, no. 12, pp. 1488, 2005.
[44] X. Chen and Q. Lv, "Phase-shift interferometry combined with surface plasmon resonance effect for two-dimensional bio-surface analysis", Optik, vol. 121, no. 9, pp. 818-820, 2010.
[45] J. Lee, T. Chou and H. Shih, "Polarization-interferometric surface-plasmon-resonance imaging system", Optics Letters, vol. 33, no. 5, pp. 434, 2008.
[46] J. E. Millerd and N. J. Brock , "Method and apparatus for splitting, imaging, and measuring wavefornts in interferometry" , US patent , US7170611B2 , 2001.
[47] A. D. Rakić, A. B. Djurišić, J. M. Elazar, and M. L. Majewski, "Optical properties of metallic films for vertical-cavity optoelectronic devices," Applied Optics, vol. 37, pp. 5271-5283, 1998.
[48] P. B. Johnson and R. W. Christy, "Optical Constants of the Noble Metals," Physical Review B, vol. 6, pp. 4370-4379, 1972.
[49] S. T. Ltd, "optical glass data sheets," 2015.
[50] T. Dahmen, H. Kohr, N. de Jonge and P. Slusallek, "Reconstruction Strategies for Combined Tilt- and Focal Series Scanning Transmission Electron Microscopy", Microscopy and Microanalysis, vol. 21, no. 3, pp. 2337-2338, 2015.
[51] D. Beebe, G. Mensing and G. Walker, "Physics and Applications of Microfluidics in Biology", Annual Review of Biomedical Engineering, vol. 4, no. 1, pp. 261-286, 2002.
[52] V. Chokkalingam, B. Weidenhof, M. Krämer, W. Maier, S. Herminghaus and R. Seemann, "Optimized droplet-based microfluidics scheme for sol–gel reactions", Lab on a Chip, vol. 10, no. 13, pp. 1700, 2010.
[53] T. Dahmen, H. Kohr, N. de Jonge and P. Slusallek, "Reconstruction Strategies for Combined Tilt- and Focal Series Scanning Transmission Electron Microscopy", Microscopy and Microanalysis, vol. 21, no. 3, pp. 2337-2338, 2015.