The objective of this research is to develop a new optical technique, Fourier-domain Low Coherence Interferometry (fLCI), for the purpose of probing the nuclear morphology of epithelial cells within intact tissues. Our preliminary experiments show that fLCI obtains information about sub-surface structures which scatter light as well as possessing the sensitivity to probe nuclear morphology with in vitro samples. Here we propose to further develop the fLCI technique for application to probing the nuclear morphology of epithelial cells in situ. Successful completion of the proposed research will lead to a new method for detecting the nuclear morphology changes associated with pre-cancerous tissue states. The simplicity of the fLCI setup suggests that it easily could be implemented with an optical fiber probe, suitable for application during endoscopic procedures. The fact that fLCI does not require tissue sectioning or exogenous contrast agents implies that the technique could provide a means for assessing the health of human epithelial tissues in vivo. The basis of the fLCI technique is to detect the wavelength dependence of scattered light to determine structural features while simultaneously using low-coherence interferometry to obtain depth resolution. It is this combination of light scattering and interferometry which makes fLCI well suited to the task of probing nuclear morphology within intact epithelial tissues. The ability of light scattering techniques to detect sub-wavelength structural changes enables fLCI to detect nuclear morphology variations which cannot be visualized using ordinary imaging methods. The capability for depth-resolved measurements allows for selective examination of cell nuclei features in the basal layer of the epithelium, lying approximately 100 m beneath the surface, which are most diagnostic of tissue health. The long-range goal of this research is to create an fLCI-based biomedical diagnostic device for the purpose of detecting early cancer in humans. The research plan proposed here will demonstrate the feasibility of using fLCI for this purpose by establishing that fLCI can measure nuclear morphology within intact tissue samples. In order to accomplish the stated objectives we adopt the following specific aims: (1 ) Instrument Development: We will refine our optical system to optimize the fLCI measurements for probing thick tissues. (2) Theoretical modeling: We will improve our analysis and processing of fLCI data to better the accuracy achieved in measuring light scattering structures. (3) Animal Studies: We will execute experiments with animal epithelial tissues which will demonstrate the ability of fLCI to detect nuclear morphology within intact samples and for detecting pre-cancerous changes. ? ? ?
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