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Indirect Correlative Light and Electron Microscopy – A High Throughput Approach with Robust Quantitative Capabilities

Background: Correlative light and electron microscopy (CLEM) is emerging as a powerful tool for nanoscale structural studies in both the biological and physical sciences. However, the challenges associated with obtaining precisely registered images of nanoscale neighborhoods within a sample on multiple microscopes severely limit the adoptability and throughput of CLEM. Additionally, the low throughput and lack of robust image analysis lead to CLEM being largely used as a qualitative approach with limited ability to assess structural heterogeneity or identify subtle changes associated with early stages of disease. Thus, high-throughput CLEM approaches with robust quantitative capabilities are needed. Approach: We have developed indirect CLEM [ iCLEM ] as a low-cost, high throughput option with extensive quantitative capabilities. By taking advantage of structural fiducials / landmarks identifiable via both light and electron microscopy, iCLEM sidesteps the rate-limiting steps of conventional CLEM – preparation of samples suitable for both light and electron microscopy and precise registration of nanoscale images. Instead, iCLEM entails correlation of distributions of morphometric measurements made in relation to structural fiducials, collected from independent sets of light and electron microscopy samples. This approach readily lends itself to integration with computational modeling, providing a clearly defined pipeline to uncover structure-function relationships. Additionally, the approach is agnostic to specific imaging modalities and allows us to multiple techniques targeting different spatial scales to be seamlessly combined.