Jennifer Kehlet Barton

We have designed a multimodality system that combines optical coherence tomography (OCT) and laser-induced fluorescence (LIF) in a 2.0-mm-diameter endoscopic package. OCT provides approximately 18-microm resolution cross-sectional structural information over a 6-mm field. LIF spectra are collected sequentially at submillimeter resolution across the same field and provide histochemical information about the tissue. We present the use of a rod prism to reduce the asymmetry in the OCT beam caused by a cylindrical window. The endoscope has been applied to investigate mouse colon cancer in vivo.

A side-viewing, 2.3-mm diameter, surface magnifying chromoendoscopy-optical coherence tomography (SMC-OCT) endoscope has been designed for simultaneous, nondestructive surface fluorescence visualization and cross-sectional imaging. We apply this endoscope to in vivo examination of the mouse colon. A 30,000 element fiber bundle is combined with single mode fibers, for SMC and OCT imaging, respectively. The distal optics consist of a gradient-index lens and spacer to provide a 1× magnification at a working distance of 1.58 mm in air, necessary to image the sample through a 0.23-mm thick outer glass envelope, and an aluminized right-angle prism fixed to the distal end of the gradient-index lens assembly. The resulting 1∶1 imaging system is capable of 3.9-µm lateral and 2.3-µm axial resolution in the OCT channel, and 125-lp/mm resolution across a 0.70-mm field of view in the SMC channel. The endoscope can perform high contrast crypt visualization, molecular imaging, and cross-sectional imaging of colon microstructure.

The development of colorectal cancer in the azoxymethane-induced mouse model can be observed by using a miniaturized optical coherence tomography (OCT) imaging system. This system is uniquely capable of tracking disease development over time, allowing for the monitoring of morphological changes in the distal colon due to tumor development and the presence of lymphoid aggregates. By using genetically engineered mouse models deficient in Interleukin 6 (IL-6) and Smad family member 3 (Smad3), the role of inflammation on tumor development and the immune system can be elucidated. Smad3 knockout mice develop inflammatory response, wasting, and colitis associated cancer while deficiency of proinflammatory cytokine IL-6 confers resistance to tumorigenesis. We present pilot data showing that the Smad3 knockout group had the highest tumor burden, highest spleen weight, and lowest thymus weight. The IL-6 deficiency in Smad3 knockout mice prevented tumor development, splenomegaly, and thymic atrophy. This finding suggests that agents that inhibit IL-6 (e.g. anti-IL-6 antibody, non-steroidal anti-inflammatory drugs [NSAIDs], etc.) could be used as novel therapeutic agents to prevent disease progression and increase the efficacy of anti-cancer agents. OCT can also be useful for initiating early therapy and assessing the benefit of combination therapy targeting inflammation.

Colorectal cancer (CRC) remains the second deadliest cancer in the United States. Several screening methods exist; however, detection of small polyps remains a challenge. Optical coherence tomography (OCT) has been demonstrated to be capable of detecting lesions as small as 1 mm in the mouse colon, but detection is based on measuring a doubling of the mucosa thickness. The colon microvasculature may be an attractive biomarker of early tumor development because tumor vessels are characterized by irregular structure and dysfunction. Our goal was to develop an endoscopic method of detecting and segmenting colon vessels using Doppler OCT to enable future studies for improving early detection and development of novel chemopreventive agents.