Microelectronic sensors could replace multi-welled microplate in
23 Sept 2010
The multi-welled microplate, long a standard tool in
biomedical research and diagnostic laboratories, could be replaced by
new electronic biosensing technology on a chip developed by a team of
microelectronics engineers and biomedical scientists at the Georgia
Institute of Technology.
Microplates, which are arrays of small test tubes, have been used
for decades to simultaneously test multiple samples for their
responses to chemicals, living organisms or antibodies. Fluorescence
or colour changes in labels associated with compounds on the plates
can signal the presence of particular proteins or gene sequences.
The microplates themselves have been progressively shrinking over
the years, but the marriage of electronics with biotechnology could
see them replaced altogether — along with the associated laboratory
equipment used to analyse their contents automatically and capture
the resulting data.
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.
Associate professor Muhannad Bakir (left) holds
electronic microplate, while Professor John McDonald
an example of the conventional microplate it will replace.
“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
“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
“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
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
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
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.”