Major advances in cell biology and biomedical research are tightly linked to innovations in microscopy. In the modern era, many breakthroughs rely on understanding and visualizing complex molecular structures, not only in their static states but also as a function of time. The development of ultrafast electron transmission microscopy (UTEM) and variant techniques now allows scientists to record dynamic processes with spatial and temporal resolutions down to sub-angstrom and the femtosecond levels. The combination of such resolutions opens to investigation myriad fundamental, atomic-scale processes in biology and other fields. In structural biology applications, the fundamental limitation is electron beam radiation damage. There have been various strategies to keep it at a minimal level. Many of them rely on the minimization of the electron dose exposure that inevitably increase the image acquisition time required for accumulating signal to the acceptable contrast. The acquisition time in available laser-based UTEMs is governed by laser repetition rate and usually less than one MHz. At the moment, no time- resolved techniques are able to provide GHz-scale or higher sampling rates. In addition, contemporary UTEMs require substantial modification of existing TEM system with exorbitant costly femtosecond laser equipment. The necessity to both own and operate a non-standard electron microscope and an ultrafast laser system limits the technology to only a few research groups in the world. Euclid Beamlabs proposes to develop a novel retrofittable into standard TEM laser-free GHz tunable stroboscopic assembly that can enable an ordinary ??? to operate in an entirely different stroboscopic mode producing time resolved data at picosecond time intervals and GHz sampling rates, at subnano-scale spatial resolution, and to provide high-contrast imaging. Our approach replaces the expensive fs-laser system with an electromagnetic-mechanical pulser (EMMP)?a specially designed cavity commonly used in the beam physics community for particle acceleration. In the family of time-resolved electron probe methods, such laser-free GHz stroboscopic concept would fulfill a different temporal landscape that is complementary to the existing commercial solutions. The technology will preserve the default TEM thermionic/field-emission electron source providing stable highly coherent illumination with high contrast imaging for biological objects with reduced radiation damaging effects. The faster (more than 10,000 times) repetition rate will also allow unprecedented image acquisition speed that significantly increases experiment throughput. The whole user- friendly retrofittable assembly that includes EMMP, RF source, and synchronization system, will be compatible with commercial TEM platforms. It will significantly reduce the price for a UTEM system making it affordable for the larger scientific community. In Phase 1, we will design the assembly for available JEOL TEM with specific goal of maximal contrast for imaging biological, and carry out the first testing experiment as well.

Public Health Relevance

This project is designed to deliver a truly novel and advanced stroboscopic technology on a transmission electron microscope (TEM) platform that will provide ?molecular video electron microscopy? and will help to answer many new questions on dynamics and functioning biomacromolecules. In the family of time- resolved electron probe methods, such laser-free GHz stroboscopic concept will fulfill a different temporal landscape that is complementary to the existing solutions. A novel technology will be retrofittable into commercial TEMs, will cost significantly lower due to absence of expensive laser system, and will have 10,000 faster image acquisition speed.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Sammak, Paul J
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Euclid Beamlabs, LLC
United States
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