In the last decade, major scientific advances in bioimaging based on the use of ultrashort (picosecond- and femtosecond-duration) optical pulses have occurred, and initial demonstrations of short-pulse diagnosis and treatment of disease have also been reported. Examples include multiphoton microscopy, optical coherence tomography imaging, and femtosecond corneal surgery. A relative weakness of optical imaging techniques is their poor depth-penetration: imaging is limited to thin (<1 mm) samples and superficial tissue. Images of structures much deeper in tissue could be obtained with wavelengths beyond 1 micron; the 1-1.3micron range appears to offer order-of-magnitude advantages. Femtosecond-pulse sources that are tunable across this wavelength range will be developed. The sources will be designed for the needs of nonlinear microscopies and optical coherence tomography. The heart of the sources will be femtosecond fiber lasers, which offer practical advantages over existing solid-state lasers including greater stability and lower cost. The developed lasers will be used in two separate collaborative studies. At Cornell University, third- harmonic generation microscopy will be applied to in vivo characterization of morphological changes in cells caused by optically-induced small-scale strokes in the rat cortex. The images will allow us to map the effects of the vascular lesion on unlabeled neural cells. At the University of California at Irvine, second-harmonic optical coherence tomography will be employed to monitor the progression of cancer in the hamster cheek pouch model. The development of new and enhanced capabilities for visualizing tissue will aid in the diagnosis and treatment of disease. In particular, third-harmonic microscopy will provide detailed morphological information about tissue that is accessible directly or by endoscopy, without exogenous labels. Second-harmonic optical coherence tomography has potential for early detection of oral cancers.
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