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MIT Team Develops Micromechanical Chip for Mass-Based Flow Cytometry

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Researchers at the Massachusetts Institute of Technology have developed a micromechanical system that could enable mass-based flow-cytometry — a variation on the cell-counting method that could be mass produced and therefore carry a much smaller price tag than current flow cytometers, according to its developers.
 
The approach has applications in cell-based assays, according to Scott Manalis, an associate professor in MIT’s departments of biological engineering and mechanical engineering and a co-author of a paper describing the method in this week’s Nature.
 
“We now have a way to weigh each cell, and we can also weigh nanoparticles,” said Manalis, whose team is currently working on a prototype version of the system. “Similar to the way fluorescent labels are used to make specific cells brighter for the flow cytometer, it should be possible to make specific cells heavier by using a nanoparticle in place of the fluorescent label.”
 
In addition, because the chips can be mass produced in large quantities using standard semiconductor processing methods, “we could potentially have a flow cytometer that is a lot cheaper and a lot more robust than what is currently done with optical flow cytometry,” Manalis said.
 
The MIT team is already partnering with two companies to fabricate the chips: Innovative Micro Technology, a manufacturer of microelectromechanical systems, and Affinity Biosensors, a MEMS biosensor startup that plans to eventually market the devices.
 
Researchers from both firms are co-authors on the Nature paper.
 
Affinity Biosensors CEO Ken Babcock said that the company expects to have a product on the market in around two years, noting that it is initially targeting particle-sizing applications in the chemical and industrial markets.
 
Affinity is also eying biological applications for the system, and Babcock said it could take between three and five years of additional development before this application can be marketed.
 
As for cost, Babcock said that typical batch-fabrication prices start at $50 per chip, and can be reduced substantially depending on volume. Ultimately, he said, the chips could cost as little as $5 to $10.
 
However, he noted, the real advantage of the chips in mass-based flow cytometry is that they could replace the expensive and delicate optical components of current flow cytometers “with a little tiny bit of electronics.”
 
Lowering the price of the chips “maybe isn’t the most important thing,” Babcock said. “I think from the mass cytometry standpoint, the important thing is that we get rid of all these peripheral components … so it can be much more robust.”
 
In the Lab
 
Thomas Burg, an MIT researcher and lead author on the Nature paper, told CBA News that the developers are currently working on a prototype version of the system.
 
The team does have a bit of development ahead. The authors demonstrated in the paper that they could successfully measure nanoparticles and bacterial cells with sub-femtogram resolution — a million times smaller than quartz crystal microbalance, which is commonly used for mass sensing — but the microchannels in the current system are too small to handle eukaryotic cells.
 
“Making the channels bigger for this is a fairly easy thing to do from a manufacturing standpoint,” Burg said. “It is just not something we have done yet.”
 
Manalis said that the team wants to first demonstrate that the system works on smaller cells before turning to eukaryotic cells. Nevertheless, he said that they have already developed devices that can measure the mass of red blood cells.
 
“Perhaps in a year’s time we could be in a position to measure the mass of bigger cells,” he said.
 
In addition, the researchers plan to further improve the sensitivity of the method. MIT said in a press release accompanying the paper that with a few “refinements,” the sensitivity could be lowered by several orders of magnitude “within a few years.”
 

“Imagine if you replaced the fluorescence in flow cytometry with a nanoparticle and kept the antibodies the same.” Using this approach, “instead of making certain cells brighter, we make certain cells heavier,” he said.

Other micro- and nanomechanical mass-measurement technologies have been shown to achieve zeptogram-scale resolution, but these methods can only measure inorganic particles because the procedure has to be performed in a vacuum.
 
These systems rely on a silicon resonator that sits inside a vacuum. When a molecule is placed on the resonator, the frequency of its vibration changes slightly. The mass of the molecule can be calculated by measuring that change.
 
This measurement is performed in a vacuum in order to prevent any interference with the frequency of oscillation, and has been proven to be highly sensitive. The authors note in the Nature paper that “proton-level resolution seems to be within reach” for these systems.
 
However, these systems have been out of reach for biological applications because cells can’t survive in a vacuum, and if they are embedded in a solution, the fluid would impair the system due to so-called “viscous damping” of the resonator.
 
The researchers got around this problem by placing the fluid containing the sample inside the resonator itself, which still oscillates within a vacuum. The sample is pumped through a microchannel that runs across the resonator without affecting its ability to vibrate.
  
“We assumed that the viscous loss from a thin layer of water that’s flowing through the cantilever would be much less than the loss from a cantilever that’s moving while immersed in the fluid,” Manalis said.
 
That assumption turned out to be true. The energy loss from the solution inside the cantilever “turned out to be negligible compared to the intrinsic loss of our silicon resonator,” the authors wrote.
 
The researchers are currently using the method to study how the mass density of a cell changes as it goes through cell division in collaboration with another MIT research team.
 
In the longer term, they envision a range of applications for the system, including using it as an alternative to flow cytometers to monitor CD4 cell numbers in AIDS patients. This would be particularly useful for healthcare workers in developing countries, where it is too impractical and too expensive to use flow cytometers.
 
Burg said that the approach could also be used to measure molecular interactions or to study how small molecules block the ability of other molecules to bind to a binding partner that is affixed to the resonator — an application that could be particularly interesting for drug discovery.

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