Posted: April 25, 2007 |
New technique could be used to weigh nanoparticles |
(Nanowerk News) For the first time, MIT researchers have found a way to measure the mass of single cells with high accuracy.
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The new technique, which is based on a micromechanical detector, could allow researchers to develop inexpensive, portable diagnostic devices and might also offer a unique glimpse into how cells change as they undergo cell division.
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Unlike conventional methods, the MIT technique allows cells to remain in fluid while they are being measured, opening up a new realm of possible applications, says Scott Manalis, senior author of a paper on the work that will appear in the April 26 issue of Nature.
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Hearing mass: The illustration shows an artistic depiction of the concept that enables measuring the mass of single bacteria and single nanoparticles in fluid with very high resolution. A hollow resonator, represented by a hollow, fluid filled guitar string vibrates while small particles, represented here by a bacterium, flow through it. This is analogous to our actual measurement of particles and cells flowing free through a resonating microchannel, thereby changing the frequency (tone) of the vibration. (Image: Thomas Burg, MIT)
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In addition to weighing cells, the technology can be used to "weigh nanoparticles or sub-monolayers of biomolecules with a resolution in solution that is six orders of magnitude more sensitive than commercial mass sensor methods. One direction we're pursuing is mass-based flow cytometry, a way to weigh and count specific cells," said Manalis, an associate professor in MIT's Departments of Biological Engineering and Mechanical Engineering.
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Current mass-measurement methods achieve a resolution down to a zeptogram (10-21 grams) but only work with non-living things because the procedure must be performed inside a vacuum. So, the MIT researchers decided to turn the conventional system inside out.
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In the traditional method, the molecules to be weighed are placed on top of a tiny slab, or cantilever, made of silicon. The slab vibrates at its resonant frequency (the frequency at which the material naturally tends to vibrate) inside a vacuum. When a molecule sits on the slab, the frequency changes slightly, and the mass of the molecule can be calculated by measuring that change.
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This measurement must be performed in a vacuum to prevent air (or fluid) from interfering with the frequency of oscillation. However, cells cannot survive in a vacuum, so they must be measured in fluid, which diminishes the accuracy of the measurement.
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The researchers solved this dilemma by placing the fluid containing the sample inside the silicon slab, which still oscillates within a vacuum surrounding it. The biological sample is pumped through a microchannel that runs across the slab, without impairing its ability to vibrate.
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"The resonator is sealed in a tiny vacuum cavity inside the chip, so there is virtually no resistance to the vibration," said co-lead author Thomas Burg, a research associate in biological engineering. "This lets us measure a mass change, say 10 parts in a billion, of the already very light microcantilever."
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So far, the researchers have weighed particles with a resolution down to slightly below a femtogram (10-15 grams), but Manalis believes that with refinements, the sensitivity could potentially be lowered by several orders of magnitude within a few years. "Every step along the way will open up new possibilities," he said.
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The researchers can also measure the mass density of particles or cells "by varying the density of the surrounding solution," said Michel Godin, co-lead author and postdoctoral associate in biological engineering.
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The research team is already looking into several applications for the new technique.
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One area of great promise is creating a device that would mimic the cell-counting capabilities of flow cytometers, which are often used to monitor CD4 cell numbers in AIDS patients. By counting CD4 cells, a type of immune cell, doctors can tell how far a patient's AIDS has progressed. However, flow cytometry devices, which work by bouncing light off a flowing stream of cells, are too large and expensive to be useful in developing countries where many AIDS patients live.
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A tiny chip that could count cells using the new MIT weighing method would be a "cheap and robust" alternative to commercially available flow cytometers, which typically cost more than $20,000, Manalis said.
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"Since the device is batch-fabricated by conventional semiconductor processing techniques, it could potentially be used in a disposable format," he said.
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William Rodriguez, an AIDS researcher at Massachusetts General Hospital who is familiar with Manalis' research, said the new technology could have a tremendous impact on AIDS testing in rural areas of Africa and elsewhere.
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"Simply put, a cheap, simple CD4 counting device that can be used by a community health worker … would be a breakthrough advance in global health," according to Rodriguez.
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Manalis is also planning a collaboration with MIT associate professor of biology Angelika Amon, who is interested in studying how the mass density of a single cell changes as it goes through cell division. Using the new method, scientists can ultimately trap a single cell and observe it over a long period of time. Changes in mass could correlate to production of proteins, offering a new way to study what the cell does during division, Manalis said.
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Another application of the new technology is to measure small particles, or beads. It's important to know the size of particles used in paint, drug-delivery devices, coatings and nanocomposite materials, said Manalis, who added that the new technology could become the "gold standard" way to measure these particles one by one.
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Other authors on the Nature paper are Scott Knudsen, MIT postdoctoral associate in biological engineering; Wenjiang Shen, Greg Carlson and John S. Foster of Innovative Micro Technology in Santa Barbara, Calif.; and Ken Babcock of Innovative Micro Technology and Affinity Biosensors in Santa Barbara.
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