For the first time, MIT researchers have found a
way to measure the mass of single cells with high
accuracy.
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.
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.
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.
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.
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.
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.
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.
"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."
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.
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.
The research team is already looking into several
applications for the new technique.
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.
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.
"Since the device is batch-fabricated by
conventional semiconductor processing techniques, it
could potentially be used in a disposable format," he
said.
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.
"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.
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.
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.
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.
The research was funded by the National Institutes
of Health Cell Decision Process Center, the Institute
for Collaborative Biotechnologies from the U.S. Army
Research Office, the Air Force Office of Sponsored
Research, the National Science Foundation and the
Natural Sciences and Engineering Research Council of
Canada.
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Source: |
Massachusetts Institute Of
Technology |
Published on 30 April 2007
