Advanced
Instrumentation Technology Past Projects
(Formerly Advanced Biomedical Technology)
Test for Tuberculosis —
A more rapid, sensitive, and specific tool for detecting tuberculosis to help
reduce
the spread of TB and fight the global TB epidemic.
Microblood Flow Monitor
— Remotely monitors blood flow in tissues, skin, and organs.
Microcantilever Biosensor Development — Biosensor that lets researchers and medical professionals conduct dozens of protein- and DNA-detecting tests at the same time.
Faster Test for Tuberculosis (TB)
Project Goal: To give doctors a more rapid, sensitive, and specific tool for detecting tuberculosis, reduce the spread of TB, and fight the global TB epidemic.
The World Health Organization has declared tuberculosis a global emergency. TB kills 2 million people a year. Over the next 20 years, TB could infect 1 billion people and kill 35 million. TB infection also hastens the progression of HIV/AIDS. DOE-funded scientists are developing an optical biosensor for early and rapid TB detection, particularly needed in developing countries.
Optical Biosensor
An optical biosensor is a man-made hybrid of a biological component (like
an antibody receptor) that recognizes a specific protein and a physics
component (transducer) that sends a light signal when a targeted protein
binds to the biosensor. Embedded in a disposable strip, the sensor can
detect TB infection in sputum or blood serum samples, as shown. [Image
courtesy of Dr. Basil Swanson, Los Alamos National Laboratory.]
The biosensor was developed jointly by Los Alamos National Laboratory, Johns Hopkins University, and the National Institute of Allergy and Infectious Diseases.
The 2002 Distinguished Patent Award was shared by Basil Swanson and former Los Alamos staff member Xuedong Song of the Bioscience Division for their patent of the Triggered Optical Biosensor. By amplifying specific binding events between fluorescence molecules, the biosensor can detect protein toxins, viruses, antibodies, and other biomolecules. Such sensor technology is critical to defending against threats of bioterrorism and has medical applications in diagnosing respiratory diseases like tuberculosis. The Distinguished Patent Award recognizes inventors whose work exemplifies significant technical advance, adaptability to public use, and noteworthy value to the Los Alamos National Laboratory's mission.
Miniature Blood Flow Monitor
Project Goals:
To give doctors real-time, “wireless” blood flow and oxygen measurements around
microscopic blood vessels and improve wound healing after surgery. To better
monitor patients in emergency rooms and intensive care units and help prevent
organ failure and death in hospital patients.
Lack of sufficient blood flow causes many diseases and health problems. Medical technology today does a good job of evaluating the clogged and constricted arteries that lead to heart attack and stroke. A quick look at the microcirculatory system, the networks of capillaries that feed small millimeter-sized regions of organs and muscle, reveals that it is very difficult to know if enough blood is delivering enough oxygen to surrounding tissues. DOE-funded scientists are developing a miniature, wireless implant that would send early warning signals of potential tissue damage, wound-healing problems, and organ failure.
Disease Detector: Microchip Promises Accurate Tests for Disease Markers
Principal Investigator: Thomas Thundat, Ph.D., Oak Ridge National Laboratory
This advanced biomedical technology is now moving out of DOE and into the private sector.
In the near future, doctors may test for dozens of diseases using one highly sensitive device composed of hundreds of microscopic detectors.
This remarkable device detects disease-identifying molecules by inducing them to stick to and bend a microscopic cantilever that resembles a diving board. Initial studies reveal that this technology is sensitive enough to serve as a diagnostic test for prostate-specific antigen (PSA), the protein marker characteristic of prostate cancer.
In addition, the technology shows promise for finding small variations in DNA called single nucleotide polymorphisms, or SNPs (pronounced “snips”), that result in the most common forms of biological diversity. Thanks to the Human Genome Project, scientists are identifying more and more of these DNA variations believed to underlie many aspects of health and disease.
Cantilevers Bend When Markers are Present
Teams from the University of Southern California (USC) in Los Angeles, the University of California in Berkeley (UCB), and Oak Ridge National Laboratory (ORNL) researched and developed the microcantilever technology.
UCB researchers made the cantilevers from silicon nitride using techniques identical to those used to make computer microprocessors. ORNL colleagues perfected a way to coat the cantilever's top surfaces with antibodies to detect specific proteins or single-stranded DNA sequences to detect SNPs.
The cantilever bends when proteins bind to the antibodies or a DNA strand binds with a complementary DNA strand. The higher the protein or DNA concentration that sticks to the cantilever, the greater the deflection is. The deflection is then measured with a laser.
The cantilevers are about 50 microns wide (half the width of a human hair), 200 microns long (a fifth of a millimeter), and half a micron thick. When molecules bind to the surface, the cantilever moves only about 10 to 20 nanometers—comparable to a football field bending the width of a quarter.
Sensor Flexibility, Accuracy Show Promise
Initial PSA test results are encouraging. “This technique is sensitive enough to detect levels one-twentieth the clinically relevant threshold,” said Arun Majumdar, UCB professor of mechanical engineering and one of the project scientists. “This is currently as good as and potentially better than the ELISA [enzyme-linked immunosorbent] assay, which is the standard today for detecting protein markers like PSA.”
Another advantage over existing assays is that this technique does not require the additional step of attaching fluorescent molecules (labels) to enable detection.
Other disease markers could be detected using this technology. Experiments have shown that a DNA sequence in a liquid sample binds with a complementary sequence attached to a cantilever, even if the sample sequence has one wrong base or mismatch. DNA mutations (changes) that predict diseases like breast cancer, colorectal cancer, and cystic fibrosis could be detected through these mismatches, even before patients exhibit symptoms.
“We found that a mismatch causes the cantilever to bend up instead of down,” said Thomas Thundat, senior ORNL research scientist and leader of the Nanoscale Science and Devices Group. This change in bending direction, he said, could find gene variances that contribute to disease.
“The primary advantage of the microcantilever method originates from its sensitivity, based on the ability to detect cantilever motion with subnanometer precision, as well as the ease with which it may be fabricated into a multielement sensor array,” Thundat said. “No other sensor technology offers such versatility.”
High-Impact, Low-Cost Device “Very Important”
Majumdar and his UC Berkeley colleagues have found a way to put several hundred cantilevers onto a single silicon chip and simultaneously measure the deflection of all. A single chip, with possibly hundreds of microcantilevers, could detect dozens of DNA and protein markers.
“It's not trivial to go from one cantilever to hundreds of them on a chip a millimeter apart and detecting hundreds of different biomolecules,” Majumdar said. “But that is what we need to do low-cost, high-throughput, label-free assays.”
In the near future, microcantilever chips could be used to test for dozens of disease-indicating proteins and DNA markers at a much-reduced per-test cost.
“From a discovery point of view, this is a very, very important advance,” notes Richard Cote, professor of pathology and urology at the USC Keck School of Medicine and USC Norris Comprehensive Cancer Center.
The technology has been licensed to Sense Technologies for detecting unexploded ordnance at airports and to Sarcon for infrared imaging.
Project collaborators include Thomas Thundat and Karolyn Hansen, ORNL; Arun Majumdar, UCB; and Richard Cote and Ram H. Datar, USC.
