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Biotechnology

Cellular Biology on a Chip

Researchers at the Toulouse-based LAAS(1) have devised new types of chips enabling three-dimensional imaging of cells and experimentation at the single-cell level.

No matter how good a microscope's resolution, the two-dimensional view in its eyepiece will only reveal a small part of a cell's mysteries.
“To get 3D images,” explains Aurélien Bancaud of LAAS, “a researcher would need multiple images of the cell from multiple angles”—a process that up to now was both slow and damaging to the cells being studied.
Bancaud has devised an elegantly simple solution—a mirrored chip2—with an unlikely inspiration. “When you walk into certain hotel bathrooms, there are mirrors that you can adjust to see yourself head-on or from the sides. Basically, we adopted that technology, but adjusted the size for yeast cells,” says Bancaud.
Of course, he is simplifying matters. Bancaud, whose background is in biophysics, used the LAAS microfabrication facility to create a tiny silicon wafer, into which were grooved several trenches. When coated with a thin sheen of aluminum, the sides of these grooves formed a two-angled mirror.
Yeast cells with fluorescent-tagged proteins, when passed through the trenches of this reflective “lab on a chip,” become visible from multiple angles in a single viewing. These images can then be combined to create a three-dimensional model that gives researchers a deeper understanding of their subjects.

v-shaped

© D. Villa/LBME

A hundred V-shaped micro-mirrors (orange scheme) allow 3D imaging of biological material (here yeast nuclei, in the lower right corner) by this lab-on-a-chip device.



The device is especially useful for tracking fast biological reactions, like those involving DNA, without risking damage to the cells through the multiple light flashes required by more cumbersome 3D imaging techniques. Bancaud's particular interest is to study yeast chromosomes, and the first experiments using the chip tracked the actions of a fluorescent-tagged chromosome in yeast cells, which he was able to capture in almost real time.
Although the size and angle of the mirrors are easily adjustable, the technology is currently best suited to smaller cells like yeast; the larger the cell, the more distant its organelles from the mirror. Bancaud is collaborating with researchers in Paris to test the feasibility of using his chip to observe neurites—small projections from a neuron.
While yeast cells are easily trapped and guided by Bancaud's reflective trenches, lymphocytes are much more difficult to pin down. Lymphocytes are like cellular butterflies in the human circulatory system: they flutter about freely in the currents.
And if lymphocytes are butterflies, Liviu Nicu is an avid collector. With colleagues in Grenoble, the LAAS-based physicist has developed a method for pinning down lymphocytes to a microscopic chip.3 By doing so, scientists can now study these key elements of the body's immune system on an individual cell basis.

bio pens

© L.Nicu

Bio-pens depositing specific antibodies on a slide to trap live cells.



“The challenge is that these cells do not normally stick onto a surface, because they move about constantly through the blood vessels in our body. To study how the cell operates on a single cell level, you have to find a way to stick the cell onto a surface and study it while it is still alive on this surface,” explains Nicu.
The solution is to glue each cell into place in an orderly fashion. He thus devised a “bio-pen” —a series of micro-scaled silver silicon cantilevers. Each pen is filled with a biological solution, which is deposited by simple contact onto surfaces for different applications.
In this case, the solution was specifically formulated to hold slippery lymphocytes in place, though the system could easily be adapted for other types of cells or viruses. The end result is a chip containing orderly rows of cells. Each cell can then be exposed to stresses and chemicals, and its reactions tested and measured individually—unlike in the free-flowing chaos of a Petri dish, where tracking the reaction of a single cell is almost impossible.
“The challenge is to look at the pathologies on the single-cell level,” says Nicu. The applications for this system are many: it could be used in drug screening, for example, and the technology has already been licensed by a French private company (Microbiochip, Paris) for manufacturing protein chips on-demand.

Mark Reynolds

Notes :

1. Laboratoire d'analyse et d'architecture des systèmes (CNRS).
2. H. Hajjoul et al., “Lab-on-chip for fast 3D particle tracking in cells,” Lab on a Chip, 2009. 9: 3054-8.
3. Y. Roupioz et al., “Individual Blood-Cell Capture and 2D Capture on Microarrays,” Small, 2009. 5: 1493-7.

Contacts :

LAAS, Toulouse.
Aurélien Bancaud,
abancaud@laas.fr
Liviu Nicu,
nicu@laas.fr


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