Using ZEMAX optical system design software, the handheld OCT sample arm was designed for clinical imaging specifically within the oral cavity. The HRF system was incorporated within the handheld OCT sample arm, providing inherently coregistered and simultaneous imaging. The HRF component of the system is designed for use with proflavine, a fluorescent dye with peak excitation and emission at 445 and 515 nm, respectively.13 Excitation wavelengths are isolated from a 455 nm LED (Thorlabs) using an excitation filter with a 45-nm bandwidth centered at 445 nm (Semrock, Rochester, New York). This light is collected using a 10-mm focal length aspheric condenser lens (L2, Thorlabs). A long-pass dichroic mirror (D2) with a 495-nm cut-on (Chroma, Bellows Falls, Vermont) reflects the excitation beam toward the sample. This beam passes through a 950-nm cut-off short-pass dichroic (D1, Semrock), where it is combined with the collimated OCT beam. This short-pass dichroic, mounted on a galvanometer, scans the reflected NIR OCT beam while transmitting the unaffected visible HRF excitation and emission light. The coregistered OCT and HRF beams then travel to the sample along a common path through a pair of 12.7-mm diameter, 30-mm focal length achromatic relay lenses (L3 and L4, Thorlabs). The final lens in the sequence is a 5-mm diameter, 10-mm focal length achromatic doublet (L5, Thorlabs). The lens sequence L3–L5 is designed to simultaneously focus the OCT beam onto the sample, while providing uniform (Köhler) illumination of the region with HRF excitation light. A glass window is fixed at the sample plane to ensure the tissue is flat and to increase imaging stability. The backscattered OCT signal and fluorescent emissions from the proflavine travel back along their original paths and are separated by the short-pass dichroic mirror (D1), which de-scans the OCT beam. Proflavine emissions are isolated from the HRF excitation light by the long-pass dichroic (D2) and a separate emission filter with an 88-nm bandwidth centered at 550 nm (Semrock). The fluorescent emission is focused onto a compact (), pixel CCD camera (Point Grey, BFLY-PGE-09S2M-CS, Richmond, British Columbia, Canada) using a 50-mm focal length achromatic doublet (L6, Thorlabs). The CCD camera’s exposure time was set to match the OCT frame rate for simultaneous image acquisition in order to minimize HRF image flicker due to the scanning OCT dichroic mirror (D1).