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New Biosensing Technology Coud Facilitate Personalized Medicine

Atlanta, GA

The multi-welled microplate, long a standard tool in biomedical research
and diagnostic laboratories, could become a thing of the past thanks to
new electronic biosensing technology developed by a team of
microelectronics engineers and biomedical scientists at the Georgia
Institute of Technology.

Essentially arrays of tiny test tubes, microplates have been used for
decades to simultaneously test multiple samples for their responses to
chemicals, living organisms or antibodies. Fluorescence or color
changes in labels associated with compounds on the plates can signal the
presence of particular proteins or gene sequences.

The researchers hope to replace these microplates with modern
microelectronics technology, including disposable arrays containing
thousands of electronic sensors connected to powerful signal processing
circuitry. If they're successful, this new electronic biosensing
platform could help realize the dream of personalized medicine by making
possible real-time disease diagnosis -- potentially in a physician's
office -- and by helping select individualized therapeutic approaches.

"This technology could help facilitate a new era of personalized
medicine," said John McDonald, chief research scientist at the Ovarian
Cancer Institute in Atlanta and a professor in the Georgia Tech School
of Biology. "A device like this could quickly detect in individuals the
gene mutations that are indicative of cancer and then determine what
would be the optimal treatment. There are a lot of potential
applications for this that cannot be done with current analytical and
diagnostic technology."

Fundamental to the new biosensing system is the ability to
electronically detect markers that differentiate between healthy and
diseased cells. These markers could be differences in proteins,
mutations in DNA or even specific levels of ions that exist at different
amounts in cancer cells. Researchers are finding more and more
differences like these that could be exploited to create fast and
inexpensive electronic detection techniques that don't rely on
conventional labels.

"We have put together several novel pieces of nanoelectronics technology
to create a method for doing things in a very different way than what
we have been doing," said Muhannad Bakir, an associate professor in
Georgia Tech's School of Electrical and Computer Engineering. "What we
are creating is a new general-purpose sensing platform that takes
advantage of the best of nanoelectronics and three-dimensional
electronic system integration to modernize and add new applications to
the old microplate application. This is a marriage of electronics and
molecular biology."

The three-dimensional sensor arrays are fabricated using conventional
low-cost, top-down microelectronics technology. Though existing sample
preparation and loading systems may have to be modified, the new
biosensor arrays should be compatible with existing work flows in
research and diagnostic labs.

"We want to make these devices simple to manufacture by taking
advantage of all the advances made in microelectronics, while at the
same time not significantly changing usability for the clinician or
researcher," said Ramasamy Ravindran, a graduate research assistant in
Georgia Tech's Nanotechnology Research Center and the School of
Electrical and Computer Engineering.

A key advantage of the platform is that sensing will be done using
low-cost, disposable components, while information processing will be
done by reusable conventional integrated circuits connected temporarily
to the array. Ultra-high density spring-like mechanically compliant
connectors and advanced "through-silicon vias" will make the electrical
connections while allowing technicians to replace the biosensor arrays
without damaging the underlying circuitry.

Separating the sensing and processing portions allows fabrication to be
optimized for each type of device, notes Hyung Suk Yang, a graduate
research assistant also working in the Nanotechnology Research Center.
Without the separation, the types of materials and processes that can be
used to fabricate the sensors are severely limited.

The sensitivity of the tiny electronic sensors can often be greater than
current systems, potentially allowing diseases to be detected earlier.
Because the sample wells will be substantially smaller than those of
current microplates -- allowing a smaller form factor -- they could
permit more testing to be done with a given sample volume.

The technology could also facilitate use of ligand-based sensing that
recognizes specific genetic sequences in DNA or messenger RNA. "This
would very quickly give us an indication of the proteins that are being
expressed by that patient, which gives us knowledge of the disease state
at the point-of-care," explained Ken Scarberry, a postdoctoral fellow
in McDonald's lab.

So far, the researchers have demonstrated a biosensing system with
silicon nanowire sensors in a 16-well device built on a one-centimeter
by one-centimeter chip. The nanowires, just 50 by 70 nanometers,
differentiated between ovarian cancer cells and healthy ovarian
epithelial cells at a variety of cell densities.

Silicon nanowire sensor technology can be used to simultaneously detect
large numbers of different cells and biomaterials without labels.
Beyond that versatile technology, the biosensing platform could
accommodate a broad range of other sensors -- including technologies
that may not exist yet. Ultimately, hundreds of thousands of different
sensors could be included on each chip, enough to rapidly detect markers
for a broad range of diseases.

"Our platform idea is really sensor agnostic," said Ravindran. "It
could be used with a lot of different sensors that people are
developing. It would give us an opportunity to bring together a lot of
different kinds of sensors in a single chip."

Genetic mutations can lead to a large number of different disease states
that can affect a patient's response to disease or medication, but
current labeled sensing methods are limited in their ability to detect
large numbers of different markers simultaneously.

Mapping single nucleotide polymorphisms (SNPs), variations that account
for approximately 90 percent of human genetic variation, could be used
to determine a patient's propensity for a disease, or their likelihood
of benefitting from a particular intervention. The new biosensing
technology could enable caregivers to produce and analyze SNP maps at
the point-of-care.

Though many technical challenges remain, the ability to screen for
thousands of disease markers in real-time has biomedical scientists like
McDonald excited.

"With enough sensors in there, you could theoretically put all possible
combinations on the array," he said. "This has not been considered
possible until now because making an array large enough to detect them
all with current technology is probably not feasible. But with
microelectronics technology, you can easily include all the possible
combinations, and that changes things."

Papers describing the biosensing device were presented at the Electronic
Components and Technology Conference and the International Interconnect
Technology conference in June 2010. The research has been supported in
part by the National Nanotechnology Infrastructure Network (NNIN),
Georgia Tech's Integrative BioSystems Institute (IBSI) and the
Semiconductor Research Corporation.


Additional Photos

Comparing old and new microplates

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Last revised May 15, 2020