The setting: a doctor’s office. A patient delivers a litany of symptoms, complaining of a headache and a fever. “It’s probably the flu,” the doctor might say, and prescribe bed rest and acetaminophen for the ache. But perhaps the patient is suffering from something far more serious — like meningitis. And if the patient is wrongly diagnosed because his physical symptoms aren’t clear enough for diagnosis, death is a distinct possibility.
Though this scenario may be less likely to occur in US, misdiagnosis in rural and underdeveloped parts of the world, where medical resources are much more scarce. But what if this could be avoided? What if the doctor could simply take a blood sample, place it into a tiny machine, and deliver an electronic diagnosis within minutes? According to a report published this week in Nano Letters, Yale scientists have found a way to do just that. Staff Reporter Divya Subrahmanyam reports on a novel nanotechnology diagnostic tool making big waves at the Yale School of Medicine.
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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 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, but also from a technological one.
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 OCR 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.