Scott Manalis holds in his palm a thin microchip about the size of a fingernail. To the naked eye, it looks similar to the chips you might find in your cell phone or iPod. What’s different is buried in the chip and hidden from sight: a suspended vibrating microchannel carved out of silicon.
It is, says Manalis, “to our knowledge, the world’s most sensitive way to measure the mass of biomolecules or the mass of cells in an aqueous environment.”
Pointing to a micrograph showing a cross section of the chip, Manalis, who developed the sensor with then graduate student Thomas Burg, explains how the technology works. The key is the microchannel, which is 300 micrometers long, 50 micrometers wide, and a few micrometers thick. It acts like a tiny diving board; once its inner surface is chemically treated, specific proteins or other biomolecules selectively bind to it, and the added weight changes the frequency of its vibrations. That change, which can be measured either electronically or with a laser, corresponds directly with the mass of the binding molecules.
Manalis, a professor of biological and mechanical engineering at MIT’s Media Lab, believes the technology could provide not only an extremely sensitive but also a highly practical method for detecting everything from viruses to cells to protein biomarkers. Indeed, this fall Manalis received a five-year, $3.2 million grant from the National Cancer Institute to develop a sensor for sniffing out the rare proteins that can be the telltale signs of cancer. His first target: prostate cancer.
With standard techniques, detecting biomolecules generally requires labeling them with fluorescent tags. The glow of the tags can be measured with an optical reader to determine whether a particular molecule is present and, if so, in what quantities. This technology has become one of the workhorse tools of biotechnology and is used, for example, in DNA microarrays for genetic testing.
But fluorescence-based devices have two severe limitations: first, because they require chemical labels and precise optical equipment, they are often inconvenient to use and fragile; and second, they can’t easily be shrunk and integrated into a microchip.
Manalis says his method for the direct detection of biomolecules does not suffer those drawbacks. Because it doesn’t use fluorescence, it doesn’t use an optical reader. That, says Manalis, makes it “much more robust. You can drop it.”
And because its manufacture relies on the same basic process as any other silicon microchip’s, the detector can be easily miniaturized and combined with other silicon components. A series of tiny, nearly identical microchannels could be fabricated alongside each other, yielding a device capable of rapidly measuring many different types of samples.
A Liquid Asset
The ease of integrating the silicon detector with other components should make it useful in microfluidics, a hot area of biomedical research. In microfluidics, the various steps involved in preparing and testing a sample are executed on a microchip. The liquid in, say, a blood sample moves through microscopic channels, where procedures such as bursting open cells, separating their component molecules, and running tests on those molecules all happen in tiny channels.
Manalis says the silicon microchannels built by his lab can be easily incorporated into such a microfluidic scheme. His detectors, he points out, determine the contents of an extremely small volume of liquid, about 10 picoliters – roughly the volume of a single cell.
Other physicists have shown that microscopic vibrating cantilevers could be an extremely sensitive method for detecting mass, explains Manalis. “If you talk to physicists, their favorite quantity to measure is vibrational frequency because it is very easy to measure. It’s very robust, and it is very hard to interfere with.”
But previous work had encountered a seemingly insurmountable practical problem when it came to detecting biomolecules: the cantilevers had to operate in a dry environment, preferably in a vacuum. In water or any other liquid, the delicate vibrations would be instantly damped. That’s a problem, says Manalis, because the biomolecules that scientists want to detect – viruses, for example – are found in aqueous environments, such as a blood sample. In biology, he points out, “everything happens wet.”
It is here that Manalis came up with an ingenious solution. He and his colleagues hollowed out a tiny channel inside the cantilever so that small volumes of the sample would flow into it; the targeted biomolecules bind to the inner walls. The vibrations of the suspended resonator are still affected by the mass of the binding molecules, but there is no longer any surrounding fluid to damp them.
Of course, it’s one thing to design such a device; it’s quite another to get it working reliably at the limits of its sensitivity. Burg, now a postdoc, developed the device for his doctoral thesis and has solved many of the problems of how the tiny suspended microchannel interacts with the outside world.
Manalis and Burg hope one day to build the detector into a small handheld device that could be used to detect pathogenic viruses or for a quick and easy cancer test in a doctor’s office.
But for now, the chip that Burg is testing is hooked up to a tangle of electrical wires and held tightly by several small clamps at the end of a lab bench. A laser is aimed at the chip to measure precisely the vibrational frequency of the suspended microchannels. Plastic tubes protrude from holes dotting the chip and run to an automated liquid-handling instrument.
For physicists like Manalis and Burg, who are used to working with precise semiconductor technology, optimizing the chemistry and the flow of the liquids is the trickiest part of the experiments. The researchers first treat the inner walls of the microchannel with specific antibodies that will selectively bind to the target biomolecules, such as a particular type of protein.
The chemistry is not novel, says Burg, but because it’s affected by temperature and other factors, it’s unpredictable. For that reason, the group gathers seemingly endless data (the automated experiment runs through the night) to ensure that the microchannel is accurately and consistently detecting the targeted biomolecules.
If all goes well, though, within the next year the experimental device could move from all-nighters in the MIT lab to testing out in the real world. At that point, Innovative Micro Technology, a foundry in Santa Barbara, CA, will take over the production of standardized versions of the highly sensitive detectors.
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