March 19, 2012 — Researchers at Columbia Engineering and University of Pennsylvania, led by Columbia Engineering professor Ken Shepard, developed a way measure nanopores with less error, designing a custom integrated circuit (IC) using commercial semiconductor technology and building the nanopore measurement around the new amplifier chip.

The researchers put the amplifier chip directly into the liquid chamber next to the nanopore, for a cleaner signal. The team could observe single molecules passing through the pore in 1ms, said Jacob Rosenstein, a Ph.D. candidate in electrical engineering at Columbia Engineering and lead author of the study. "Previously, scientists could only see molecules that stay in the pore for more than 10ms," he explained. Shepard’s group is continuing to improve these techniques, aiming for 10X improvement in the next generation, measuring things that last only 100ns.

Photo. The Columbia Engineering team’s custom multichannel CMOS preamplifier chip, wire bonded to a circuit board with gold wire. SOURCE: Columbia Engineering.

The electronic single-molecule measurement method allows observations in the range of billions of signals per second, as compared to a few thousand photons per second with fluorescent-molecule optical techniques. With optical techniques, "you can’t see anything that happens faster than a few milliseconds, because any image you could take would be too dim," explained Shepard. With electronic measurements, "there is no equivalent to a fluorescent wavelength filter, so even though the signal comes through, it is often buried in background noise."

Classical electrophysiology amplifiers are mostly optimized for slower measurements, noted Shepard, so the team designed its own IC. Rosenstein designed the new electronics and performed related lab work.

The nanopore sensor method took shape with the help of Marija Drndic, a professor of physics at the University of Pennsylvania, who gave a seminar at Columbia Engineering in 2009. Drndic’s group at the University of Pennsylvania fabricated the nanopores that the team then measured in their new system.

Instead of slowing down the DNA, the researchers built faster electronics, combining sensitive electronics with the most sensitive solid-state nanopores, Drndic said. The result is a simple, portable set up that could be used for significantly lower-cost DNA sequencing or other medical applications.

The lab is also working with other electronic single-molecule techniques based on carbon nanotube transistors.

This research was funded by the National Institutes of Health, the Semiconductor Research Corporation (SRC), and the Office of Naval Research.

Results were published in the Advance Online Publication on Nature Methods’ website on March 18.