N/A A. 370 Specific Aims Recent decades have witnessed the rapid development and successful applications of light to medicine. One emerging promising biophotonic approach uses low coherence enhanced backscattering (LEBS) of light for depth selective detection of dysplastic epithelial cells in the superficial layer of tissue [57,66,88,89]. The long-term goal of the proposed research is to develop a novel diagnostic and prognostic tool for microscopic imaging of the superficial layer of tissue based on low coherence enhanced backscattering of light. The proposed technique, low coherence enhanced backscattering tomography (LEBT), can image intact biological tissues at the microscopic scale ex vivo and in vivo based on optical contrast, extending LEBS to a three dimensional (3D) tomographic imaging modality. By detecting only low-order backscattering light via spatial coherence gating, LEBT solves the low spatial resolution problem due to light diffusion and achieves excellent depth selection. At the same time, low-order scattering light is sensitive to the microarchitecture and the molecular conformation of biological tissues, relating to physiological states such as the morphological alteration due to carcinogenesis and the oxygenation of hemoglobin. moo (1) U-0 CAD -CD vii -Co The proposed low coherence enhanced backscattering tomography combines the high resolution advantage with use of low coherence light and the high sensitivity advantage of light scattering to tissue structure and composition. This hypothesis is based on the Q-4 [unreadable]0-ocm=_0 following observations. First, depth-selective detection of the superficial layer has been shown feasible with low coherence enhanced backscattering light and confirmed by our earlier investigations [57,129]. The penetration of light can be confined within the superficial layer where most cancer initiates and cancer may be detected at its earliest stage using this technique [66, 88]. Second, wavelength-dependent light scattering is highly sensitive to sub-wavelength nuclear and coo I'D) =gym .61 (D- vii= n'< cellular alterations [43,47,75]. Based on these observations, the focus of this proposal is to design and test LEBT to generate a high-resolution 3D image of the nuclear morphology and cellular structure for the superficial layer of tissue from low coherence enhanced backscattering light. A 3D morphometric and oxygenation image of 1Ozm axial resolution pro will be obtained by LEBT for the epithelium or the epithelium plus the underlying vascularized stroma, which are most diagnostic of tissue health. Two specific aims are proposed to address the goals of the proposal. 1. Development of system and method for LEBT. CD- .., (a) Design and implementation of LEBT experimental system (b) Develop the forward model for LEBT for imaging homogeneous and stratified media 0 (c) Develop inverse reconstruction algorithms for LEBT for imaging homogeneous and stratified media E 2. Computational and experimental validation of LEBT. (a) Computational validation based on electric field Monte Carlo simulations (b) Experimental validation with homogeneous and multiple layer tissue phantoms -a_ 0 (c) Perform LEBT on ex vivo normal and abnormal colon tissues and correlate the generated image with histopathology