NMR Technology Comes to the Lab
on a Chip
Remote Detection Makes NMR Compatible with Microfluidics
Hilty is a member of the Alexander Pines research
group and principal author of a paper in which
it was demonstrated that Nuclear Magnetic Resonance
or NMR spectroscopy can be used with microfluidic “lab-on-a-chip” devices.
CA -- A breakthrough in the technology of nuclear
magnetic resonance (NMR), one of the most powerful
analytic tools known to science, is opening the door
to new applications in microfluidic chips, devices
for studying super-tiny amounts of fluids. A team
of scientists with Lawrence Berkeley National Laboratory
(Berkeley Lab) and the University of California,
Berkeley, has demonstrated a means by which NMR can
be made compatible with microfluidic “lab-on-a-chip” devices.
This demonstration holds great promise for biomedical
research, the detection of biohazards and toxic chemicals,
and other endeavors in which the chemical composition
of a fluid must be determined.
“Our novel methodology bypasses the long-standing
problem of optimizing the two basic steps of NMR,
signal encoding and detection, by physically separating
them, and, at the same time, adds an important dimension
to the study of fluid flow dynamics with the possibility
of time-of-flight measurements,” said Alexander
Pines, one of the world’s leading authorities
on NMR technology. Pines holds a joint appointment
as a chemist with Berkeley Lab’s Materials
Sciences Division and with UC Berkeley, where he
is the Glenn T. Seaborg Professor of Chemistry.
The technique in which NMR signal encoding and detection
are carried out independently (in a conventional
NMR setup, the two actions take place within a single
device) is called remote NMR detection. In a paper
published in the online edition of the Proceedings
of the National Academy of Sciences (PNAS), for the
week of October 3, Pines and his collaborators describe
the use of remote NMR to study the flow of gases
through microfluidic devices.
“Remote detection of the NMR signal overcomes
the sensitivity limitation of NMR and enables spatially
resolved imaging in addition to time-of-flight measurements,” said
chemist Christian Hilty, a member of Pines’ research
group and the principal author of the PNAS paper. “Our
approach also offers the unique advantage of being
non-invasive. We can use it to measure microfluidic
flow without the introduction of foreign tracer particles.
This is important for the design and the operation
of microfluidic devices.”
Co-authoring the PNAS paper with Hilty and Pines
were Erin McDonnell, Josef Granwehr, Kimberly Pierce
and Song-I Han, all of whom at the time of the study
held joint appointments with Berkeley Lab and UC
The work is supported by the U.S. Department of Energy’s
Basic Energy Sciences program in the Office of Science.
is a phenomenon involving a property found in the
atomic nuclei of almost all molecules called “spin,” which
gives rise to a magnetic moment, meaning the nuclei
act as if they were bar magnets with a north and
south pole. When a sample is exposed to a strong
external magnetic field, these "bar magnets" attempt
to align their axes along the lines of magnetic force.
The alignment is not exact, resulting in a wobbly
rotation about the magnetic field lines that is unique
for each type of nuclei.
while exposed to the magnetic field, the nuclei
in a sample are also subjected to a sequence of
radiofrequency (rf) pulses, they will absorb and
re-emit energy at characteristic frequencies. This
is called the signal “encoding” phase of NMR. In the
detection phase, the frequencies of these encoded
signals are measured to obtain an NMR spectrum. This
spectrum will feature distinct peaks of varying height
that, like a set of fingerprints, can be used to
identify the sample’s chemical structure.
In a demonstration of remote NMR detection, the
letters CAL, carved through the end of a plastic
tube placed in an NMR encoding coil, were reconstructed
from 10 batches of spin-polarized xenon carried to
a detection coil at a separate location. Although
the batches arrived at different times, the spatial
arrangement of the letters was accurately reproduced.
NMR has long been a powerful tool for studying the
chemical composition of macroscopic samples, its application
to microfluidic chip devices has been hampered by low
sensitivity. When atomic nuclei align their axes along
the lines of a magnetic field, the nuclear spin of
some will point “up” while that of others
will point “down.” Obtaining an NMR signal
depends upon an excess of nuclei in a sample with spins
pointing in one direction or the other, but the natural
population difference in a typical fluid sample, even
under a powerful magnetic field, is usually no more
than one in 100,000 at room temperature.
To overcome this low spin polarization so they can
measure gas flow, Pines and his research group have
been injecting their samples with xenon whose atomic
nuclei have been hyperpolarized by laser light.
Hyperpolarized xenon boosts the NMR sensitivity of
a sample by at least four orders of magnitude, and,
xenon being inert, does not interfere with the other
sample constituents as it is carried along in the
When working with microfludic samples of gas, Pines
and his collaborators apply their NMR encoding technique
to the hyperpolarized xenon. With its long spin-relaxation
time (several minutes), hyperpolarized xenon is well-suited
for transporting the encoded NMR information to a
separate site for detection. By staging the encoding
and detection phases at separate sites, each site
can be customized to obtain optimal results.
“Xenon’s long spin-relaxation time (several
minutes), make it an ideal carrier of an NMR signal
for remote measurements of gas flow,” said
Microfluidic devices are essentially miniaturized
chemistry laboratories, featuring a series of micrometer-sized
channels etched into a chip in which nanoliter-sized
samples of fluids can be analyzed.
Such analyses can provide a wealth of information
for biomedical and analytical chemistry studies.
Because of their incredibly small sample sizes
-- thousands of times smaller in volume than a
typical droplet – microfluidic “labs on a chip” are
highly prized for providing rapid analysis at relatively
Currently, the most common way to analyze gas flow
in a microfluidic device is to inject it with marker
particles that will fluoresce under optical illumination,
or that are of sufficient size to be viewed under
a microscope. Using remote NMR instead offers several
“With remote detection of NMR, we don’t
need the addition of markers that perturb the flow
because we can use the spins of the hyperpolarized
xenon nuclei,” said Hilty. “Also, when
we apply the hyperpolarized xenon for the encoding
step of remote detection, we can individually tag
a fluid sample in any and all points within the device,
whereas we can inject a fluorescent marker only at
a device’s inlet.”
According to Hilty and Pines, their NMR remote detection
technology is ready to be applied to any existing
microfluidic device, so long as the fluid is transported
to the detection site within the spin relaxation
time of encoded NMR information.
“In our PNAS paper, we describe an application
in which we measure gas flow in microfluidic devices
by remote detection of NMR,” said Hilty.
“However, the same principles are applicable
without hyperpolarization to the less challenging
case of liquids, which have a much higher spin-density.”
Another limiting factor for the widespread use of
NMR with microfluidic devices is the relatively high
cost of an NMR spectrometer. Pines and his research
group are working on the development of alternative,
less expensive means of detecting encoded NMR signals
-- for example, a magnetometer. According to Hilty,
preliminary results on this line of research have
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laboratory located in Berkeley, California. It conducts
unclassified scientific research and is managed by
the University of California. Visit our Website at
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