Technology Research News
When the computer chip was invented forty-four
years ago, it set the stage for computers to shrink from room-size behemoths
filled with light-bulb-size vacuum tubes to handheld devices powered by
Researchers from the California Institute of Technology are mirroring
that effort with a chip that stores tiny drops of fluid rather than magnetic
or electronic bits of information.
The researchers are aiming to replace roomfuls of chemistry equipment
with devices based on a fluidic storage chip that can store 1,000 different
substances in an area slightly larger than a postage stamp.
The technology could eventually allow experiments that involve hundreds
or thousands of liquid samples to run on desktop or even handheld devices,
potentially reducing the cost and complexity of medical testing, genetics
research and drug development, said Stephen Quake, an associate professor
of physics and applied physics at Caltech. "Small volumes mean lower cost
for expensive reagents, and mean that samples can be tested for a broader
range" of diseases, he said.
The fluidic storage chip has 1,000 chambers arranged in a 25 by 40 grid
with 3,574 microvalves. "It's small plumbing -- pipes, valves, pumps,
et cetera -- all integrated on a small rubber chip," said Quake.
Each chamber holds 250 picoliters, or about one 80th of a drop of water.
The connecting channels are 100 microns wide and nine microns high, which
is about twice as high as red blood cells are wide.
Like the bits that store 1s and 0s in computer memory, the chambers that
store fluids at the intersections of the rows and columns of the researchers'
chip can be accessed individually. The key is a pair of multiplexors that
address each chamber by row and column. Computer memory chips use similar
electronic multiplexors to access individual bits of digital information.
In the fluidic storage chip, the row multiplexor pushes fluids along one
or more rows to fill or purge the chambers in those rows, and the column
multiplexor applies pressure to close the input and output valves of the
chambers along one or more of the columns.
The fluidics multiplexors allow the researchers to control the 1,000 chambers
using only 22 connections to the chip, said Quake. "We can control exponentially
many fluid lines," as outside connections, he said. Thirty connections
could theoretically control 32,000 fluid lines and 40 connections could
theoretically control one million fluid lines. "This greatly simplifies
the input/output and connections required from the real world to the chip,"
To make the fluidic chip, the researchers etched patterns into plastic
molds using the same photolithography process used to make computer chips,
then used the molds to shape thin layers of rubber.
The top layer contains fluid channels and chambers, and the bottom layer
holds multiplexors and control lines. In between is a thin sheet of rubber.
The intersection of a fluid channel and a control line forms a valve;
hydraulic pressure in the control line deflects the thin membrane between
the top and bottom layers and pinches off the fluid channel. The multiplexors
determine where the pressure is applied in order to control the flow.
The chip is made completely of flexible silicone rubber, rather than the
hard silicon used in computer chips. Fluids enter the chip through steel
pins connected through holes punched into the rubber, which forms a tight
seal around the pins.
The researchers also made a chip-size comparator, which measures samples
against a scale or standard to determine properties like the pH concentration
of a fluid.
The researchers' comparator has an array of 256 chambers arranged in four
columns of 64, and is about twice the size of the storage chip. It contains
2,056 microvalves and performs more complicated manipulations than the
storage chip, according to Quake. Two fluids can be mixed in any number
of the chambers and the results from any chamber in each column can be
removed for further examination, he said.
The researchers took the comparator through its paces by loading individual
bacteria into some of the chambers and adding a fluid that becomes fluorescent
in the presence of a particular enzyme. This allowed the researchers to
determine which bacteria produced the enzyme.
There are limitations to the rubber chips, according to Quake. Some liquids,
like certain organic solvents, can break down the chip's rubber material,
and there is a danger of contamination from molecules diffusing through
the walls of the chambers and channels. There is also a possibility that
some molecules will stick to the walls after the chip's contents have
In addition, the chip designs are limited by the need to avoid cross-contamination
as samples are shunted about. For example, the contents of only one of
the 64 chambers in each column of the comparator can be removed without
being contaminated because any residue from the first sample would contaminate
subsequent samples passing through the channel, according to Quake.
The researchers' work is an impressive and significant advance, said Kenny
Breuer, an associate professor of engineering at Brown University. "There
have been many attempts at building such microfluidic elements, but this
is by far the most complex that I have seen, and the approach... offers
the most flexibility for building a wide variety of microfluidic systems,"
The system does have limitations, Breuer added. "There is... significant
hidden machinery that is required to operate the device -- supplies of
compressed air, banks of solenoidal valves and, most importantly, very
large volumes of fluid that need to be flushed through the system as each
cell is loaded and purged," he said. The volume of this supporting infrastructure
could limit the size and complexity of fluidic systems made with this
technology, he said.
It is also true, however, that the first electronic computer chips used
large amounts of power and were not able to do much, but "still enabled
a revolution in electronics and engineering," said Breuer. The ability
to create large-scale integrated microfluidics systems with such complexity
is very exciting, even if this particular design may eventually be supplanted
by other approaches, he said.
The researchers next plan to use the devices in biological research, said
Quake. "One area will be in environmental microbiology."
The technology could be used in practical applications in one to two years,
said Quake. There are some manufacturing issues that need to be addressed,
but "it is already working in some practical applications," he said. Quake
is a director of Fluidigm Corporation, which is commercializing the technology.
Quake's research colleagues were Todd Thorsen and Sebastian Maerkl. They
published the research in the September 26, 2002 online issue of the journal
Science. The research was funded by the Defense Advanced Research Projects
Agency (DARPA) and the Army Research Office (ARO).
Timeline: 1-2 years
TRN Categories: Microfluidics and BioMEMS; Biotechnology;
Story Type: News
Related Elements: Technical paper, "Microfluidic Large-Scale
Integration," Sciencexpress, September 26, 2002
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