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Physical chemistry

Emulsions : Emulation in Action

From cosmetics to pharmaceuticals, diagnosing disease or modeling biological mechanisms, researchers are exploring the myriad applications of very special fluids called colloids.

couetteAs soon as our research bears its first fruit, we move on to something else,” says Jérôme Bibette, head of the Colloids and Divided Materials Laboratory (LCMD).1 This sums up the entire philosophy of the lab, set up in 2001 at ESPCI2 in Paris, at the invitation of Pierre-Gilles de Gennes, ESPCI's director at the time. The lab now has a staff of 15 (of whom 3 are permanent), and has already chalked up over 30 publications, 7 PhD theses and no fewer than 15 patents. The lab specializes in the application of colloids and emulsions–particles and droplets approximately a micrometer in size suspended in liquids–to biophysics and biotechnologies. As Bibette explains, “as soon as an idea appears promising, we explore it using a scaled-down team. Of course it doesn't work every time, but if the results are good, we don't spend any more time on it and we prefer to hand it over.” For Bibette, “handing it over” means granting licenses to industry, or even better, creating start-up companies–two of which are already up and running, with another one in the works.

VITAMIN C IN AN EGG
Manufacturing medicines is one such bright idea that has already paid off. The lab works with the industrial pharmaceutical company Etypharm, and uses an innovative method for producing emulsions which was developed by Bibette, and patented in 1996. It is now in charge of manufacturing a drug whose phase III clinical trials are under way. “These trials will make it possible to assess the relevance of our process,” Bibette explains. “How does it work? The tablets are prepared from a dual emulsion: droplets of the active ingredient, trapped within drops of a crystallizable oil (triglyceride), which are themselves suspended in a solvent.” When the temperature is lowered, the crystallizable oil solidifies and forms a capsule of triglyceride crystals around the active ingredient, which turns out to be very easily assimilated by the body. The encapsulation of active products using emulsions thus appears to be a very promising approach. “One of our concepts is actually based on the egg,” enthuses Bibette. “Eggs are impermeable but brittle. By using dual emulsions we are able to reproduce these same characteristics.” The 'colloidal egg' could be used to encapsulate vitamin C, and thus protect it from air, which causes it to oxidize and become inactive. The microcapsules could be incorporated into creams or toothpastes, ensuring that the vitamin C is released at the right moment by the mechanical action of the user (when applying cream or brushing teeth, for example). The lab is working with Unilever in this field.
Yet emulsions and colloids have another, non-negligible advantage: they can be grafted with other molecules selected for specific functions. For instance, the researchers recently grafted onto particles just 50 nanometers in diameter, molecules that target specific cells in mice, together with a fluorescent dye to make it all detectable. They were thus able to follow the pathway of this emulsion through the body of a mouse. This work, carried out in collaboration with the French Atomic Energy Agency (CEA) in Grenoble, is paving the way for novel anticancer strategies. By grafting molecules that recognize only malignant cells, it would be possible to pinpoint tumors with great accuracy. “And eventually we could use such colloids as medicine carriers,” Bibette adds.

MAGNETIC COLLOIDS

filament

At LCMD, there are plenty of ideas bouncing off in other directions. “Five years ago, we embarked on a program on magnetic colloids,” recalls researcher Jean Baudry. “The concept was really quite simple: to make colloids containing particles of iron oxide, which could thus react to a magnetic field.” Today, these magnetic colloids have found a host of applications, both in fundamental research and industry. For instance, they make it possible to study the growth of filaments of actin, the protein of which muscle fiber is made.3 “We grafted the ends of the filaments onto the magnetic beads,” Baudry explains. “As the filaments grow, the beads move away from each other. This lets us calculate the elongation rate as well as the force applied, and therefore the mechanical force of the filament.” By using flexible magnetic microfilaments rather than beads, the LCMD researchers have also managed to create microswimmers–a sort of artificial spermatozoa–that help them study the possibilities of locomotion of microscopic systems, whether natural or not.
Another major application for magnetic colloids lies in the diagnosis of diseases. “There are currently two major methods for detecting a specific antigen:4 the enzymatic method or ELISA (Enzyme-Linked Immunosorbent Assay)5 and the agglutination by colloids or Latex Agglutination Immunoassay (LAI),” explains Baudry. “The latter method uses colloidal particles covered with antibodies which clump together in the presence of the antigen, making the reaction medium cloudy. All you have to do then is to measure the turbidity–in other words, the cloudiness–of the solution to make a diagnosis.” Each of these methods has advantages and disadvantages: The ELISA is very sensitive but complex to carry out, while the LAI is simpler but much less sensitive. Using magnetic colloids, the researchers have managed to increase the sensitivity of the LAI test to that of the ELISA test, while maintaining its simplicity of use. This is because, when placed in a magnetic field, magnetic colloidal particles line up in chains and clump together much more easily and rapidly than non-magnetic particles. This improves the LAI sensitivity by a factor of a hundred, or even a thousand. Two French industrial groups are currently developing machines which will incorporate this technology. They are aiming for a total of two million tests a year by 2010.

ONE CELL PER DROP

microfluidic

With the development of magnetic colloids hardly out of the way, Bibette and his colleagues already have their minds set on another adventure: microfluidics. “This field will soon be a major activity for our lab,” says its director. It all began back in 2003, when Harvard University researcher David Weitz invented a system for producing perfectly calibrated drops of water. Bibette suggested they use this same system to create a type of 'microfluidic electronics.' Together with two other colleagues, the two men founded the Raindance Technologies company in Connecticut. This company developed modules to produce, separate by size, store, and detect the drops in microchannels filled with oil. Specific drops can then be reassembled according to the final purpose.
Today, with the success of its so-called 'combinatory' microfluidics, Raindance Technologies has just raised $25 million. “These technologies will give rise to a new kind of science in the labs,” Bibette claims. His plan is to apply advanced statistical analysis to biology. “Take the example of the time it takes for a cell to divide. Finding out how long it takes for each of these cells to divide within a very large population is currently impossible, and capturing a rare event (like a rapidly dividing cell) is very difficult. And yet, isolating cells that reproduce quickly in difficult conditions would be a good strategy for studying adaptability and evolution.” Combinatory microfluidics will make it possible to isolate one cell per drop, let each cell divide, and then count the number of daughter cells in each drop... at a rate of ten drops per second, i.e., 600,000 in less than a day. “That's six hundred times better than current technologies for automatic counting,” Bibette points out. Future prospects are considerable, and LCMD's projects have already been incorporated into a European research network, the Human Frontier Science Program, as well as in two of the French national research agency's programs.

Fabrice Demarthon

Notes :

1. Laboratoire Colloïdes et matériaux divisés (CNRS / Université Paris-VI / ESPCI).
2. École supérieure de physique et de chimie industrielles.
3. This work is carried out in collaboration with groups led by Marie-France Carlier at Gif-sur-Yvette, and Marc Fermigier at ESPCI.
4. Molecule recognized by antibodies. Bacterial and viral surface molecules are antigens, as well as some cancer cell markers.
5. A staining technique to detect the presence of specific antibodies in a patient's blood.

Contacts :

LCMD, Paris.
> Jérôme Bibette, jerome.bibette@espci.fr
> Jean Baudry, jean.baudry@espci.fr


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