Flexible dual-duration multi-wavelength fiber sources for nonlinear and multimodal imaging - The goal of this research program is to develop robust and flexible dual-duration, multi- wavelength fiber sources of light for nonlinear and multimodal imaging with orders of magnitude signal enhancement over the state of the art. Nonlinear imaging enables label-free, deep, and diffraction-limited imaging in living tissue through a variety of nonlinear interactions that are each sensitive to specific molecules, symmetries, and structures, including two-photon excitation fluorescence (2PEF), second- and third-harmonic generation (SHG and THG), and Raman- sensitive techniques such as coherent anti-Raman scattering (CARS). Moreover, combining these largely orthogonal modalities yields a rich combination of molecular, structural, and functional information which has been demonstrated for diagnosing atherosclerosis, neurological diseases, and cancer, including revealing new biomarkers and clinically relevant signatures absent even from histologically processed tissue. However, each imaging modality requires specific and incompatible pulse parameters that cannot be achieved with current ultrashort pulse technology without sacrificing orders of magnitude in imaging signal strength. This proposal will establish a new suite of technologies for ultra-short pulse generation that no longer rely on traditional mode-locked laser-based systems. Building from recent proof-of-concept demonstrations from the PIs, this research targets flexible and efficient fiber sources of inherently synchronized multi-wavelength picosecond and femtosecond pulses specific for each nonlinear imaging modality, with the ability to generate them simultaneously for multimodal imaging. The research program is based on three Aims: (1) Developing diode-laser driven fiber time-lens picosecond sources that are efficiently wavelength shifted with fiber parametric amplification for flexible, multiwavelength picosecond sources; (2) Developing Kerr resonators for femtosecond pulse generation with high efficiencies and the energy and wavelength flexibility ideal for nonlinear imaging; and (3) Establishing dual-duration multi-wavelength sources adapted for background suppressed CARS imaging and 2PEF, SHG, and THG, and demonstrating these sources for multimodal imaging with unprecedented speeds and contrast using existing multiphoton microscopes and a commercial microscope system to demonstrate the potential for widespread adaptation. Our aim is to enable a significant advance for nonlinear and multimodal imaging contrast and depth at real-time frame rates with a novel source that is low-cost and more accessible than previous technologies. Successful completion of this program will have major impact for biomedical research as well as clinical applications of ultrashort-pulse imaging.
