Abstract. We present the first experimental result of direct delineation of the nuclei of living rat bladder epithelium with ultrahigh-resolution optical coherence tomography ͑uOCT͒. We demonstrate that the cellular details embedded in the speckle noise in a uOCT image can be uncovered by time-lapse frame averaging that takes advantage of the micromotion in living biological tissue. The uOCT measurement of the nuclear size ͑7.9± 1.4 m͒ closely matches the histological evaluation ͑7.2± 0.8 m͒. Unlike optical coherence microscopy ͑OCM͒, which requires a sophisticated high-NA microscopic objective, this approach uses a commercial-grade single achromatic lens ͑f /10 mm, NA/0.25͒ and provides a cross-sectional image over 0.6 mm of depth without focus tracking, thus holding great promise of endoscopic optical biopsy for diagnosis and grading of flat epithelial cancer such as carcinoma in situ in vivo. Noninvasive in vivo imaging identification of pathogenesis at cellular resolutions is crucial to early clinical diagnosis of cancers.1 Technological advance in confocal microscopy and endoscopy has permitted noninvasive imaging of cellular morphology in intact tissue such as skin and bladder, colon, and cervical epthelia, but imaging depth is limited to 100 to 300 m and focus-tracking is required, which is difficult in many clinical applications. Unlike confocal microscopy, the lateral and axial resolutions of optical coherence tomography ͑OCT͒ are decoupled, 2 e.g., the axial resolution is determined by the source coherence length L c =2 ln 2/ 2 / ⌬, where and ⌬ are the source central wavelength and full-width half maximum ͑FWHM͒ spectral bandwidth. Therefore, the axial sectioning resolution of OCT can be substantially improved by employing broadband sources, and subcellular imaging of low-scattering tissue such as xenopus laevis ͑mesenchymal cells͒ in vivo has been reported. 1,2 However, for mammalian epithelial cells, the smaller cell size and thus denser microorganelle content results in increased cellular scattering, leading to phase randomization, i.e., speckle noise, that may drastically degrade the image contrast and resolution for imaging subcellular details. For instance, ultrahigh-resolution OCT ͑uOCT͒ with axial resolution exceeding 0.7 m has been reported, 2 but imaging of subcellular details of the epithelium remains unsolved, preventing this promising technique from becoming an optical biopsy tool for clinical diagnosis. In this letter, we demonstrate that the subcellular details of living rat urothelium can be uncovered after proper time-lapse dynamic averaging to minimize speckle noise in uOCT imaging. Figure 1 is a schematic of the time-domain uOCT setup used in this study. A Ti:Sapphire laser ͑⌬ = 128 nm͒ was used to illuminate a wavelength-flattened broadband fiberoptic Michelson interferometer. In the sample arm, light was collimated to 4.7 mm by a fiberoptic achromatic lens, scanned laterally by a 8-mm servo mirror, and focused onto biological tissue under examination by a commercial-grade achromati...

We summarize our recent progress in the development of the optical coherence tomography (OCT) systems suitable for clinical diagnosis and the preliminary results for in vivo diagnosis of epithelial cancers (e.g., bladder cancers). The endoscopic spectral-domain OCT system allows simultaneous, real-time, cross-sectional OCT images of tissue structure and functions (i.e., local Doppler blood flow) of biological tissue for enhanced diagnosis. A new approach to use spectral demodulation of elastic scattering is discussed for potential cancer grading. The transverse and axial resolutions of the OCT scopes are 12 microm and 10 microm, respectively. Results of the preliminary clinical studies show that unlike animal carcinogenesis models, bladder cancers in humans are more complicated in terms of epithelial backscattering changes: some lesions exhibit enhanced backscattering; some show reduced scattering owing to complex surface condition changes such as asperities or invaginations induced by tumorigenesis (e.g., papillary transitional cell cancers). Nevertheless, promising results can be provided by incorporating other diagnostic parameters such as changes in local vasculature and urothelial heterogeneity.

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We present some of the recent technological advances in our MEMS-based endoscopic optical coherence tomography (OCT) system for the enhancement of image fidelity and diagnosis. The endoscopic OCT system permits simultaneous cross-sectional OCT imaging and en face white-light visual guidance as well as fluorescence imaging guidance. The transverse and axial resolutions of the OCT scope are roughly 12μm and 10μm, respectively, and the axial resolution can be enhanced to 3um if connecting it to our recent custom sub-8fs Ti:Al²O³laser. To test the endoscopic OCT system for imaging diagnosis of early epithelial cancers, rat bladder cancer models were used and the results show over 90% sensitivity and specificity. Applications in imaging of bladder functions and engineering tissue growth are demonstrated.