Single-cell analysis inspired by microchips

US and Korean researchers have developed a device, similar to a random-access memory (RAM) chip, which moves cells rather than electrons. The device could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes.

The researchers, from Duke University and Daegu Gyeongbuk Institute of Science and Technology (DGIST), hope the cell sorting system will allow the fast, efficient control and separation of individual cells that could then be studied in vast numbers. Their work has been published in the journal Nature Communications.

Benjamin Yellen, associate professor of mechanical engineering and materials science.

“Most experiments grind up a bunch of cells and analyse genetic activity by averaging the population of an entire tissue rather than looking at the differences between single cells within that population,” said Benjamin Yellen, an associate professor of mechanical engineering and materials science at Duke’s Pratt School of Engineering. “That’s like taking the eye colour of everyone in a room and finding that the average colour is grey, when not a single person in the room has grey eyes. You need to be able to study individual cells to understand and appreciate small but significant differences in a similar population.”

Drawing inspiration from general circuit theory and magnetic bubble technology, Yellen and his collaborator, Cheol Gi Kim of DGIST, printed thin electromagnetic components like those found on microchips onto a slide. These patterns create magnetic tracks and elements like switches, transistors and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin liquid film. Like a series of small conveyer belts, localised rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip.

“The integrated circuits are constructed from lithographically defined, overlaid patterns of magnetic film and current lines,” the researchers said. “The magnetic patterns passively control particles similar to electrical conductors, diodes and capacitors. The current lines actively switch particles between different tracks similar to gated electrical transistors. When combined into arrays and driven by a rotating magnetic field clock, these integrated circuits have general multiplexing properties and enable the precise control of magnetisable objects.”

The researchers demonstrated a 3-by-3 grid of compartments that allow magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied and retrieved. In a RAM chip, similar logic circuits manipulate electrons on a nanometre scale, controlling billions of compartments in a square inch. As cells are much larger than electrons, the new device is limited to hundreds of thousands of storage spaces per square inch.

“You need to analyse thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” said Yellen. “And if you’re looking for cells exhibiting rare behaviour, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”

For example, said Yellen, in diseases like HIV or cancer, most afflicted cells are active and can be targeted by therapeutics. A few rare cells, however, remain dormant, avoiding destruction before activating and bringing the disease out of remission. With the new technology, the researchers hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them and analyse their genetic activity.

“So this is of importance to the field of biology because in medicine there is an urgent need to understand the needle in the haystack; the rare responses in biology that are doing something different than the rest of the cells,” said Yellen.

The researchers now plan to demonstrate a larger grid of 8-by-8 or 16-by-16 compartments with cells, and then to scale it up to hundreds of thousands of compartments. If successful, their technology could give scientists around the world access to single-cell experimentation.

“Our idea is a simple one,” said Kim. “Because it is a system similar to electronics and is based on the same technology, it would be easy to fabricate. That makes the system relevant to commercialisation.”

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