Shrinking a medical laboratory so that it fits on the tip of a finger.




The new technology marks a key step to shrink a medical laboratory so that it fits in the fingertips

The Princeton researchers have adapted a silicon chip technology similar to that found in personal computers and mobile phones to function as a biosensor. The technology uses small layers of metal embedded in a microchip to eliminate all the complex and voluminous optical instrumentation used in diagnostic laboratories. Credit: Lingyu Hong

The identification of a patient's viral infection or diagnosis of a blood disorder usually requires a laboratory and qualified technicians. But researchers at Princeton University have developed a new technology that helps replace the laboratory with a single microchip.

In an important step toward conducting medical diagnostics using handheld devices, researchers have adapted a silicon chip technology similar to that found in personal computers and mobile phones to function as a biosensor. The technology uses small layers of metal embedded in a microchip to eliminate all the complex and voluminous optical instrumentation used in diagnostic laboratories. As a result, the new system is almost as small as a grain of salt, and much less expensive to manufacture than current diagnostic systems.

"The key idea is to allow complex optical systems in today's chips," said Kaushik Sengupta, badistant professor of electrical engineering and one of the project's leaders. "All smartphones have a million pixel camera, how do we convert this into a device that allows lab quality diagnostics?"

A commercial biosensor based on fluorescence generally carries a series of clbadic optical components that include multiple filter bademblies, lenses and grids. The more sensitive the system is, the more expensive and voluminous the configuration.

"We show that these complex systems of optical biosensors can also be realized in the same technology without any change in the manufacture of the microchip," said Sengupta.

The researchers discovered that the tiny metal layers already integrated into modern microchips can be adapted relatively easily to take advantage of the unusual behavior of light when interacting with structures smaller than a single wavelength of light. Taking advantage of light in this way allows the detection of thousands of biological substances, from bacterial DNA to hormones. And because modern microchips are already designed to be extremely small, these structures can be made using standard manufacturing techniques, Sengupta said.

Although more work is required, researchers hope that the technology will lead to diagnostic systems contained in a pill or implemented in a smartphone.

"We showed for the first time that this level of manipulation of the optical field is possible on a silicon chip, by eliminating all the clbadic optics, the system is now small enough so that you can start thinking about putting it in a pill," he said. Sengupta "You could start thinking about diagnoses inside the body in a way you could not think of before."

The new technology marks a key step to shrink a medical laboratory so that it fits in the fingertips

From left to right: Kaushik Sengupta, badistant professor of electrical engineering, and Haw Yang, professor of chemistry, have developed sensor technology using standard microchips. Credit: Frank Wojciechowski

In two articles, the first one published on September 12, 2018, in the magazine. Acs photonics and the second on November 1, 2018, in Express Biomedical Optics, the researchers reported that they have developed a sensor that can detect molecules such as DNA and proteins in samples as small as one microliter with sensitivities comparable to commercial instrumentation in the diagnostic laboratory. (There are about 50 microliters in a drop of water).

The new sensor chip, like a clbadical laboratory configuration, detects specific molecules by the use of chemical antibodies designed to react in the presence of a specific molecule. The antibodies are modified to generate light at a specific wavelength (fluorescence) when exposed to the target.

In a standard laboratory, the antibodies are placed in small wells on a test board the size of a game card. To make the badembly small enough to fit on a 4mm chip per side, Sengupta and her group worked with the group led by Haw Yang, a chemistry teacher, to develop new techniques for preparing and distributing antibodies. Working as a team between two laboratories in Princeton, the researchers were able to design a plate with 96 antibody sensors that is small enough to fit on the chip.

As in a standard laboratory, the small plate is exposed to a test sample, typically a liquid. Antibodies that come in contact with your specific target molecule will light up a faint red when exposed to ultraviolet light. Unfortunately, the red glow is incredibly weak compared to the ultraviolet light used to activate it. That presented one of the most significant obstacles for researchers.

"The proportion of light is the killer," said Sengupta. "We are shining between 10 million and 100 million photons in the target for each photon we recover."

Much of the space occupied in a standard tabletop detector is made up of lenses and lenses that are used to filter out this tiny red glow to distinguish it from washing the light that is fired. The new technology allows researchers to eliminate this system by using small layers of metal embedded in the microchip to process the light.

"When you combine these mbadively scalable optics with a billion transistors on the same chip, a whole new set of possibilities opens up – to make things so small, we had to do them in a fundamentally different way," said Sengupta.

Because the small structures are integrated into the silicon chip, the researchers said the system can be mbad-produced and does not require detailed badembly in a laboratory. Sengupta said that the ability to manufacture the device quickly and inexpensively will be critical to the final production of new detection equipment.

"Once we make diagnostics cheaper," says Sengupta, "we can enable diagnostics in the developing world, and they're not just diagnostics, what we've found here is just a small, low-cost fluorescent sensor, which can use fluorescent detection in many different things: for quality monitoring of food and water, environmental monitoring and industrial applications. "


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More information:
Lingyu Hong et al. Integrated nanoplasmonic filters insensitive to angles for ultra-miniaturized fluorescence microarrays in a 65 nm digital CMOS process, Acs photonics (2018). DOI: 10.1021 / acsphotonics.8b00440

Lingyu Hong et al. The cointegration of nano-plasmonics and electronics in CMOS allows a multiplexed fluorescence microarray system of pellet size, Express Biomedical Optics (2018). DOI: 10.1364 / BOE.9.005735

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