A tiny microscope that employs the same kind of chip used in digital cameras can produce high-resolution images of cells without the expensive, space-hogging lenses that have been part of microscope design for centuries. Researchers at Caltech, who developed the revolutionary imaging system, say that the devices could be mass-produced at a cost of $10 each and incorporated into large arrays, enabling high-throughput imaging in biology labs. The device could also broaden access to imaging technology: incorporated into PDA-size devices, for example, the microscopes could enable rural doctors to carry sophisticated imaging systems in their pockets.
The Caltech device uses a system of tiny fluid channels called microfluidics to direct cells and even microscopic animals over a light-sensing chip. The chip, an off-the-shelf sensor identical to those found in digital cameras, is covered with a thin layer of metal that blocks out most of the pixels. A few hundred tiny apertures punched in the metal along the fluid channel let light in. As the sample flows through the microscope, each aperture captures an image. One version of the microscope uses gravity to control the flow of the sample across the apertures. Another version, which allows for much better control, uses an electrical potential to drive the flow of cells.
The 100 to 200 images are then combined using simple image-processing software. The processing power in a PDA is more than sufficient to perform the calculations, says Caltech engineer Changhuei Yang, who designed the microscope. The microscope must be illuminated from above, but sunlight is sufficient. The resolution of the microscope is similar to that of a conventional light microscope–about one micrometer–and is limited by the size of the apertures.
Yang’s device is part of a new revolution in microscopy, says Michael Feld, a physicist at MIT. “Regular microscopes are no longer the only game in town,” he says. Other recent advances have included sophisticated technologies for overcoming long-standing physical limitations on the resolution of light microscopes and improving their penetration into tissue. Yang’s tiny microscope, however, takes the technology in another, simpler direction. It is “cheap, compact, and elegant,” says Feld.
Yang says that the microscopes could be manufactured using conventional fabrication techniques employed in the semiconducting industry and grouped in arrays of hundreds or even thousands for high-throughput, automated imaging. Additional image-processing software could alert researchers to cells of interest in a sample, freeing up their time to do something else while the experiment proceeds.
The miniature microscopes have a multitude of potential uses. Because they’re cheap and compact, Yang hopes that they’ll be used in portable devices in the developing world. “The gold standard for detecting malaria is examining a blood sample under a high-power microscope,” he says. However, conventional microscopes are too fragile, cumbersome, and power hungry to be implemented in many places where the blood parasite is prevalent. Ten-dollar microscopes could be inserted into PDA-size devices that display the images on a small screen. Such a device would probably cost about $100; the microscope systems could be replaced like printer cartridges when they show wear and tear.
The devices might also be useful for tracking cancer. Yang recently began a collaboration with Richard Cote, a urologist at the University of Southern California who is developing devices for real-time monitoring of cancer therapies. Cote’s technology uses filters to pluck large, wandering cancer cells from the blood. Doctors need to look at the cells to determine whether a patient’s cancer is spreading, but putting the cells onto a microscope slide simply isn’t practical. “Lenses are the limiting proposition,” and Yang’s system eliminates them, says Cote. Yang also envisions implantable microscopes that search for wandering cancer cells and identify a subset of images for a clinician to examine manually.
High-throughput imaging will be a boon for pharmaceutical companies, says Peter So, head of the Bioinstrumentation Engineering, Analysis, and Microscopy Lab at MIT. During drug development, hundreds of versions of the same compound are first tested in cells. The current state of the art involves plating cells in tiny wells and then exposing them to drugs, then testing their response using a combination of technologies, including microscopy. Microfluidic systems for handling cells would require smaller samples and would speed the process, but they haven’t been widely implemented because until the Caltech advance, there hasn’t been a way to integrate imaging into these devices, says So.
Yang says that he is talking with several companies about commercializing the microscope on a chip, and he hopes that it will be on the market in five years. He’s also working on modifications to the system to enable fluorescence imaging–the microscopes currently can’t detect colors–and to increase the scopes’ resolution.
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