Non-invasive optical biopsy techniques, which interrogate tissue in situ, offer a potential method to improve the detection of dysplasia, a pre-cancerous tissue state. Specifically, monitoring of Barrett's esophagus (BE) patients for dysplasia, currently done through systematic biopsy, can be improved by increasing the proportion of at-risk tissue examined. Angle-resolved low coherence interferometry (a/LCI) is an optical spectroscopic technique which measures the depth resolved nuclear morphology of tissue, a key biomarker for identifying dysplasia. Using an animal carcinogenesis model, it was shown that a/LCI can detect dysplasia with great sensitivity and specificity. However, for the clinical application of a/LCI, numerous hurdles must be overcome.

This dissertation presents the development of three new a/LCI systems which incrementally address the three main obstacles preventing the clinical application of a/LCI. First, data acquisition time is reduced by implementing a frequency-domain detection scheme using an imaging spectrograph that collects the complete depth resolved angular scattering distribution in parallel. This advance reduces data collection time to a clinically acceptable 40 ms. Second, a fiber probe is developed to enable the endoscopic application of a/LCI. The probe incorporates a single fiber for delivering light and a coherent fiber bundle for collecting the angular distribution of scattered light. Third, a portable device is created through miniaturization of the optical design, and a flexible fiber probe is created using polarization maintaining fiber to deliver the light. These advances allow for the clinical application of the system to ex vivo human tissue samples.

The performance of each described system is evaluated through a number of validation studies, including the sizing of polystyrene microspheres, a typical model used in light scattering studies, and the measurement of in vitro cell nuclear diameters, accomplished with sub-wavelength precision and accuracy. The culmination of this work is the first human study using a/LCI in which it is demonstrated that a/LCI depth resolved nuclear morphology measurements provide an excellent means to identify dysplasia in BE patients. The described results demonstrate the great potential for the in vivo application of a/LCI as a targeting mechanism for the detection of dysplasia in Barrett's esophagus patients.