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In contrast to a broadband Ti:sapphire laser that mode locks a continuum of emission and enables broadband biophotonic applications, supercontinuum generation moves the spectral broadening outside the laser cavity into a nonlinear medium, and may thus improve environmental stability and more readily enable clinical translation. Using a photonic crystal fiber for passive spectral broadening, this technique becomes widely accessible from a narrowband fixed-wavelength mode-locked laser. Currently, fiber supercontinuum sources have benefited single-photon biological imaging modalities, including light-sheet or confocal microscopy, diffuse optical tomography, and retinal optical coherence tomography. However, they have not fully benefited multiphoton biological imaging modalities with proven capability for high-resolution label-free molecular imaging. The reason can be attributed to the amplitude/phase noise of fiber supercontinuum, which is amplified from the intrinsic noise of the input laser and responsible for spectral decoherence. This instability deteriorates the performance of multiphoton imaging modalities more than that of single-photon imaging modalities. Building upon a framework of coherent fiber supercontinuum generation, we have avoided this instability or decoherence, and balanced the often conflicting needs to generate strong signal, prevent sample photodamage, minimize background noise, accelerate imaging speed, improve imaging depth, accommodate different modalities, and provide user-friendly operation. Our prototypical platforms have enabled fast stain-free histopathology of fresh tissue in both laboratory and intraoperative settings to discover a wide variety of imaging-based cancer biomarkers, which may reduce the cost and waiting stress associated with disease/cancer diagnosis. A clear path toward intraoperative multiphoton imaging can be envisioned to help pathologists and surgeons improve cancer surgery.
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