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Wide-field fluorescent imaging for fluorescence molecular guidance has become a promising technique for use in imaging guided surgical navigation, but quick and intuitive microscopic inspection of fluorescent hot spots is still needed to confirm local disease states of tissues. To address this unmet need, we have developed a clinically translatable dual-modality handheld surgical microscope that incorporates both, wide-field (mesoscopic) fluorescence imaging and high-resolution (microscopic) horizontal optical-sectioning. This is accomplished by integrating a commercially available wide-field fiberscope, modified for two-color (660nm and 785nm) fluorescent detection, into a compact package (5.5 mm dia.) which also contains a dual-axis confocal (DAC) microscope. DAC microscopy is a high-sensitivity, high-resolution fluorescent imaging technology that benefits from the specificity of molecular probes, and enables interrogation of deeper regions of tissue by performing optical-sectioning of tissue. The DAC microscope has been designed with custom catadioptric micro-lenses to provide broadband multispectral capability for fluorescence imaging of multiple fluorophores over a broad spectral range (VIS to NIR), and also uses a novel MEMS-based scanning system for horizontal sectioning, and thus enables access to deeper regions of tissue at resolutions comparable to histological analysis. Large field-of-view (mm scale) is further provided by image mosaicing. The instrument thus provides simultaneous mesoscopic and microscopic fluorescence imaging over a broad spectral range for intuitively performing fast in-vivo search and microscopic confirmation of optical molecular markers in tissue, which is a capability that will become increasingly important for precise tumor resection in oncology as more optical molecular markers become approved for human use.

MEMS based microendoscopes have become important imaging tools for early cancer diagnosis and precise tumor resection. Due to various technical challenges, few microendoscopes have been translated to clinics or applied to human patients. Through synergistic collaborations, we have developed novel MEMS scanner enabled microendoscopic multispectral (640nm to 780nm) three- dimensional dual-axis confocal fluorescent imaging system for translational applications, including early cancer detection and staging on colorectal cancer, molecular imaging guided surgical navigation on head and neck cancer. Based on dual-axis confocal microscopic architecture, we have miniaturized the imaging system with compact form-factor by integrating micro-optics and a patterned gold coated MEMS scanners, which have been custom-made and mass-produced in the nanofabrication foundry. The metal coating of the scanning mirror provide over 80% high reflectivity over near infra-red range. Both axes of the MEMS scanner could perform large tilting angle (> 6 degree mechanical scan angle) at DC and resonant mode. By advanced computational imaging approach, we have achieved real-time cross-sectional imaging in either raster or lissajous pattern scanning with fast frame rate (> 10 Hz) with large field-of-view (> 600 microns). Advanced real-time mosaicing algorithm has been developed to achieve broader view in millimeter scale. By utilizing molecular contrast probes conjugated with fluorescence dye, we have successfully demonstrated multi-spectral ex-vivo and in-vivo imaging on small animal tumor models and human tissue specimens, aimed for both early cancer detection and molecular imaging guided surgical navigation.