Cohesive CLEM, TEM, FEBSEM System for MicroED and Cryo-EM Applications (Case No. 2025-010)

Summary

UCLA researchers have developed a cohesive electron microscope system that uniquely integrates transmission electron microscopy (TEM), fluorescence microscopy, and focused ion beam scanning electron microscopy (FIB-SEM) into a single automated column. The platform supports both cryogenic and room-temperature workflows, enabling fully automated sample targeting, preparation, and imaging for advanced structural biology and materials science applications.

Background

Electron microscopy (EM) has revolutionized structural biology, but existing workflows are fragmented across separate instruments—TEM for imaging, fluorescence microscopy for localization, and FIB-SEM for milling and lamella preparation. This disjointed approach requires manual transfer between instruments, creating inefficiencies, alignment errors, and sample loss. Moreover, current cryoEM pipelines demand significant human oversight, slowing throughput and limiting reproducibility. A next-generation platform that integrates these modalities into a cohesive, automated system would address these bottlenecks and transform both research and clinical applications.

Innovation

This invention introduces a fully automated, multimodal electron microscope housed in a single column. Key features include:

• Integrated multimodality: Combines TEM, fluorescence microscopy, and FIB-SEM in one cohesive system.

• Cryo & room temperature compatibility: Allows imaging of frozen hydrated samples or room-temperature materials.

• Automated targeting and verification: The system identifies targets automatically, verifies them via fluorescence, and directs the FIB-SEM to mill and prepare lamellae or other sample regions.

• 360° sample rotation: A piezo-driven stage enables full rotational imaging, providing new opportunities for structural characterization.

• Automated MicroED data collection: The system collects microcrystal electron diffraction (MicroED) data, compiles it in a database, and provides structural information along with compositional and percentage breakdown.

• Extensible to tomography: The cohesive design can also be used for cryo-electron tomography and other cryoEM methods.

Advantages

• Consolidates three major microscopy modalities into one instrument, reducing cost, footprint, and workflow complexity.

• Fully automated pipeline minimizes human intervention, improving reproducibility and throughput.

• Automated target recognition and milling streamlines cryoEM and MicroED workflows.

• Supports both structural and compositional analysis within the same system.

• Compatible with a wide range of applications (biology, chemistry, materials science).

• Provides unique 360° rotational imaging not typically available in existing cryoEM platforms.

• Reduces sample handling and transfer, lowering risk of damage and contamination.

Potential Applications

• Structural biology: Determining atomic structures of proteins, complexes, and macromolecules with higher throughput.

• Pharmaceutical research: Accelerating drug discovery by streamlining structural analysis of drug targets and small molecules.

• Materials science: Characterizing crystalline and nanostructured materials with both structural and compositional readouts.

• CryoEM facilities and core labs: Increasing efficiency and accessibility of advanced EM techniques.

• Clinical and diagnostic applications: Future potential for rapid structural pathology or biomarker analysis.

Development to Date

• Conceptual design completed for integrating TEM, fluorescence, and FIB-SEM into a single cohesive system.

• Workflow design includes automated data collection, MicroED structural analysis, and database integration.

• Plans for prototype development with automated cryogenic/room-temperature operation and piezo-driven stage.