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Yale U.: Nano-diagnostics becoming a reality at Yale
(U-Wire Via Acquire Media NewsEdge)
By Divya Subrahmanyam, Yale Daily News (Yale U.)
NEW HAVEN, Conn. --
A team of Yale engineers has collaborated to create a new generation of
nanowire sensors that can accurately and specifically diagnose diseases
at the site of patient care within minutes.
This technology offers many advantages over current systems and methods
not only because of its sensitivity but because it is on a platform
that is easily customizable, said Erin Steenblock ENG 11, a biomedical
engineering graduate student who worked on the study.
The sensors, which are used in the devices in conjunction with simple
microprocessor electronics, detect the activation of immune cells in
response to certain antigens, which can range from bacteria to viruses
to cancer cells.
Senior author of the paper Tarek Fahmy, professor of biomedical
engineering, said the sensors act as miniature pH meters, measuring the
acid that T-cells -- a type of white blood cells -- produce when faced
with an antigen. Though each sensor wire can only detect a particular
antigen, Eric Stern, a postdoctoral associate in biomedical engineering
and lead author, said that a single one-square-centimeter sized chip
can hold as many as half a million nanowires.
The devices are sensitive enough to detect as few as 200 activated
cells, researchers say.
[It s as if the device] can go inside a crowded room and point out the
people who are poets, or the people who are scientists, Fahmy said
about the sensors sensitivity.
This work builds upon previous research by the same team, which looked
the reactions of all cells to a nonspecific stimulus. The older
technology the lab created could only report if the cells were
reacting, not if they were reacting to a specific pathogenic stimulus,
Fahmy said, whereas the new sensors are more specific.
What sets this technology apart from older diagnostic methods is its
ability to read the immune system s reaction itself, instead of the
symptoms or bodily reactions caused by the disease, which are often
nonspecific and can occur as a result of a variety of diseases. The
most sensitive detector on the planet is built in us, he said. It s
called the immune system. It has honed itself for years and is chiseled
to the point of ultrasensitivity.
From the Battlefield Into the Lab
The nanowires are tiny about the size of an iPod, Fahmy said. Their
size, coupled with low fabrication costs, make them relatively cheap
and easily distributable to markets that need them most.
Fahmy said that poorer countries, for example, suffer not so much from
issues of unavailable therapies, but from incorrect diagnoses and
misunderstanding of disease. Often, he said, people in such regions are
unable to determine how serious a medical problem is but the new system
can.
Human immune cells are micron-sized, about 1/100th the width of a human
hair. But their landscapes are as complex as the Manhattan skyline,
with numerous structures and molecules jutting out from the surface.
In order to be able to sense the output of these structures, the
scientists knew that they had to use a device that was significantly
smaller.
The obvious option was nanotechnology.
In 2003, at a time when the United States had just invaded Iraq and
concern about stockpiled biological and chemical weapons was high,
Stern was working on a semiconductor project in Reed s lab. It was
funded by the Defense Advanced Research Project Association, which
funds academic research that could potentially contribute to national
defense.
The goal of the project at the time was to create tiny sensor chips
that soldiers could wear on their uniforms to detect biological and
chemical weapons, Stern said.
But he realized the sensors could also have biomedical applications,
especially in the field of disease diagnosis, and so he turned to Fahmy.
But the sensors are unique not only from a medical standpoint; they are
also techonologically unique.
Reed said that, starting in 2001, scientists became interested in
making nanowire sensors and have published various types of research on
models with very high sensitivity. The problem, he said, was that they
were expensive and difficult to fabricate, as they did not rely on the
power of integrated circuits, which are used in typical microprocessor
chips. The technology he and Stern have worked on does.
Additionally, Fahmy said that older forms of nanotechnology are
constructed from scratch, while Stern and Reed take a less expensive,
top-down approach starting with a piece of silicon and paring it down
to the nano-scale.
A New Generation of Diagnostic Tools
Older technologies, which use larger equipment, are less effective,
Fahmy said. Such techniques use methods of visual and electronic
diagnosis, such as various types of body scanning. But the older
generation of sensors, like glucose sensors used for diabetic patients,
have a fairly low level of sensitivity, said Mark Reed, a professor of
engineering and applied science who headed the lab in which Stern
worked.
Still, Stern said, even current medical technology cannot sense the
large molecules that serve as disease markers, such as the complex
proteins on the surface of cancer cells. Past forms of chemical testing
include what is called upstream processing. In order to identify a
molecule that may signal the presence of a diseased cell, scientists
generally react it with another material that elicits a chemical signal
that can be measured, Stern said.
But nanosensors sidestep this entirely by enabling scientists to
directly sense the molecule.
The sensors are made of silicon semiconductors, which allow a certain
amount of current to flow through, Stern said. This level of current
changes according to the amount of charge around the device so when the
sensor is exposed to the tissue, its current is a measure of the amount
of protein around it.
Rather than needing some sort of indirect pathway to get a signal, for
the first time you re measuring the amount of protein that s bound onto
the surface of the cell, Stern said. It allows us to sense things
without labeling, or modifying the molecule to be able to see it.
To use the device, Fahmy said, a diagnostician must take a sample of
blood or tissue from the patient and incubate it in the device. The
antigen of the suspected disease is then added to the sample.
If the tissue is healthy and has never encountered the antigen before,
the immune cells will not react immediately. But if the tissue is
diseased and therefore recognizes the antigen, the T-cells will begin
secreting acid, which the device will detect and report, Fahmy said.
But what about cells with immunity? When the human body fights and
eliminates a disease, the immune cells retain a memory blueprint of the
antibodies they produced in response to the pathogen, so that they can
mount the same fight the next time around. So it may seem that cells
with immunity would react to the antigen just like diseased cells.
Not so, Fahmy said. Cells with immunity will react somewhat to the
antigen, but with far less intensity.
Because the nanowires are so sensitive, the device can be used to
detect disease quickly and early, directly at the abnormal region. It
allows physicians to diagnose early, propose treatment and frequently
evaluate how well a therapy is working.
For example, Fahmy said, with the tool, surgeons can use the nanowires
to pinpoint the exact areas of a cancer, remove it, and then
double-check that none is left behind , instead of relying on the
traditional approach of aggressively removing all tissue surrounding a
cancer to ensure its complete elimination.
What s next?
Because of stringent U.S. Army standards, Stern said the military chips
may not come into use for another eight to 10 years.
But Fahmy said they hope to get the devices on the medical market
within five to 10 years, though Stern said they could become widely
used in diagnostics within three to five. The research team is
currently working with the Yale Office of Cooperative Research to
create a company that would market the technology. The office is
currently seeking a source of capital to fund the venture, as well as a
chief executive, to whom the researchers would serve as consultants.
Since the sensors themselves are produced in the same way as a computer
chip, chips with multiple sensors can be cheaply mass-produced, Stern
said. The issue, then, is not fabrication, but getting the technology
on the market.
Because the devices are handheld and not used inside the body, the team
will face fewer regulatory hurdles than scientists other medical
technologies, Fahmy said, though they must deal with a few.
The most important next step, Fahmy said, will be to extensively test
the device to determine accuracy statistics. Currently, he said, they
have found the accuracy to be around 90 percent. Failure is easily
detectable and tends to occur when the device simply does not deliver a
reading. Fahmy said there is a slight possibility of false negatives
and false positives in the readout, depending on the antigen, but they
do not yet know if there are specific antigens that are more likely to
produce a false reading.
Reed said the scientists are already looking into further applications
of this technology, including diagnosing cancer in its early stages and
detecting its triggers.
We re really hopeful that this is going to have a lot of applications
to a lot of systems to prevent disease, Reed said.
This research was funded by the Department of Defense, the National
Institutes of Health, the Department of Homeland Security and the
National Science Foundation.
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Copyright ? 2008 U-Wire
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