This Small Business Innovation Research (SBIR) Phase I project will demonstrate the scientific and technical feasibility of an optical microscope accessory for electron and ion microscopes to enable in situ brightfield and fluorescence microscopy simultaneously with electron or ion imaging/processing. This directly addresses a critical opportunity in the area of correlative light and electron microscopy (CLEM), a fundamental application applied broadly in structural biology for advancing understanding of health and disease. Light microscopy provides low magnification overviews, fluorescence imaging identifies rare cells and events (but reveals only signal location and intensity), and electron microscopy provides high resolution to study ultrastructure associated with the fluorescent signal. Correlative microscopy bridges the different length scales of these methods from micron to nanometer resolution and provides the detail missing in fluorescence images.The broader impacts of this research are widely applicable to materials, food science, and nanotechnology and include a dramatic new capability for biological investigation that contributes to advancing the pace of development in applications such as cancer treatment, drug discovery and proteomics research. It can be fanned out at low cost through a simple accessory on broadly existing SEM and FIB platforms. This promotes new research innovations. The significant accuracy and time savings with in situ CLEM can speed research, enabling faster discovery and development of biomarkers for clinical research and drug development. The FDA estimates that just a 10% improvement in the ability to predict drug failures before clinical trials could save US$100 million in development costs per drug.
