Manufacturing Bits: Feb. 7

Nano-hammers; cell nanoscopy; resolving protein complexes.

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The University of California at Santa Barbara claims to have developed the world’s smallest hammer.

The technology, dubbed the μHammer or microHammer, is geared for biomedical research. With funding from the National Science Foundation (NSF), the tiny hammer will allow researchers to get a cellular-level understanding when force is applied to brain cells. The project is part of the U.S.-based Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. The initiative is aimed at revolutionizing the understanding of the human brain.  

The nano-hammer, a cellular-scale machine, aims to solve a major problem. Mechanical forces are known to impact cells. But there is a lack of understanding in terms of the reactions of individual neural cells. This, in turn, could help researchers gain a better understanding of Alzheimer’s disease and other brain injuries.

The microHammer will allow researchers to get a cellular-level understanding of what happens when force is applied to neurons. (Source: UCSB)

The microHammer will allow researchers to get a cellular-level understanding of what happens when force is applied to neurons. (Source: UCSB)

Through a cell sorting technique, the μHammer is injected into a system. It flows through individual cells. Then, it subjects each of them to one of a variety of physical forces.

This in turn will elicit responses. “This project will enable precision measurements of the physical, chemical and biological changes that occur when cells are subjected to mechanical loading, ranging from small perturbations to high-force, high-speed impacts,” said Megan Valentine, an associate professor at UC Santa Barbara, on the university’s Web site. “Our technology will provide significantly higher forces and faster impact cycles than have previously been possible, and by building these tools onto microfluidic devices, we can leverage a host of other on-chip diagnostics and imaging tools, and can collect the cells after testing for longer-term studies.

“Our studies could transform our understanding of how cells process and respond to force-based signals,” she said. “These signals are essential in development and wound healing in healthy tissues, and are misregulated in diseases such as cancer.”

Cell nanoscopy
Traditional optical microscopy is used in life sciences. But the resolution is limited to half the wavelength of light or about 200nm, according to the Karlsruhe Institute of Technology (KIT).

So, the smallest cellular structures are sometimes blurred using traditional microscopy. Over the years, the industry has developed various techniques to overcome the problem, including the development of simulated emission depletion (STED) nanoscopy.

Now, KIT has refined the STED nanoscopy method. The new method, named STEDD or Stimulated Emission Double Depletion, modifies the image and suppresses the background noise. STEDD or STED2 is advantageous when analyzing three-dimensional sub-cellular structures.

A cancer cell under the microscope: The STED image (left) has a background of low resolution. In the STEDD image (right), background suppression results in much better visible structures. (Image: APH/KIT)

A cancer cell under the microscope: The STED image (left) has lower resolution. In the STEDD image (right), the resolution is better. (Image: APH/KIT)

In fluorescence microscopy, a sample is scanned with a focused light beam. This makes dye molecules emit fluorescent light, according to KIT. The light is registered pixel-by-pixel to form an image.

In STED, a beam is overlapped by another beam. The light intensity is located around this beam. It produces a fine image, but the background has a lower resolution.

KIT has extended this STED method by adding another beam. The beam follows the STED beam with a time delay. It eliminates the signal in the center, causing the background excitation to remain. “The STED method is based on recording two images,” said Gerd Ulrich Nienhaus, a professor at KIT. “Photons registered prior to and after the arrival of the STED2 beam contribute to the first and second image, respectively.”

Resolving proteins
The Institute for Research in Biomedicine (IRB Barcelona) has used various techniques to observe protein nanomachines or protein complexes in living cells at three dimensional images.

Researchers used a combination of super-resolution microscopy, cell engineering and computational modeling. This in turn allows them to observe protein complexes at 5nm resolutions. This is four times smaller than previous studies.

On the left, in vivo image of nanomachines using current microscopy; on the right, the new method allows 3D observation of nanomachines in vivo and provides 25-fold improvement in resolution (O. Gallego, IRB Barcelona)

On the left, in vivo image of nanomachines using current microscopy; on the right, the new method allows 3D observation of nanomachines in vivo and provides 25-fold improvement in resolution. (O. Gallego, IRB Barcelona)

With the technology, it will be possible to study cellular proteins for applications such as health and disease. “Being able to see protein complexes measuring 5nm is a great achievement, but there is still a long way to go to be able to observe the inside of the cell at the atomic scale that in vitro techniques would allow,” said Oriol Gallego, an IRB Barcelona researcher.

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