Discovering Drugs with Bubbles

Using tiny bubbles to perform logical operations could lead to smart lab-on-a-chip devices for drug discovery and chemical and biological analyses.

Lab-on-a-chip devices that manipulate tiny volumes of liquid in microscopic channels promise to speed up drug discovery, medical diagnostics, and genomic analysis. But current lab-on-a-chip devices use bulky external pumps and valves to control the liquids. An innovation by MIT researchers could eliminate the need for external pumps and valves and lead to cheaper, larger-scale systems for sorting through vast numbers of possible chemical combinations.

Bubbles enter the parallel channels of a ladder-shaped synchronizer at different times. Liquid flows from one channel to the other through the rungs of the ladder, changing the speed of the bubbles until the lagging bubble catches up, ensuring that the bubbles reach their destination at the right time.

The researchers have designed complex intersecting channels that direct tiny bubbles to various locations on the microfluidics chip. Several types of intersections act as different types of logic gates, like those on computer chips. “One of the biggest limitations of microfluidics is, you have beautiful little devices with channels and reactions, but there’s no room for the control systems required to make them work,” says Neil Gershenfeld, director of MIT’s Center for Bits and Atoms, who reported this work with his graduate student Manu Prakash in Science last week. “With our new work, the controls are part of the microfluidic system itself.”

This is a smart design for controlling droplets on a chip, says Mathieu Joanicot, who does microfluidics research at chemical company Rhodia’s Laboratory of the Future, in Pessac, France. “Because you will no longer need the pumps and valves outside the chip for control, it makes [lab-on-a-chip devices] more robust and compact,” he says.

In one type of microfluidic logic gate, two channels approach an intersection, and two exit it, with exit A being slightly wider than exit B. If bubbles approach the intersection one at a time, they always leave through exit A because it offers less resistance. But if two bubbles from opposite channels reach an intersection at the same time, one will take path A and the other will be forced to take exit B.

The researchers have also designed small chambers that temporarily hold bubbles until another bubble arrives, as well as ladder-shaped channels that synchronize the flow of two bubbles so that they can arrive at a logic gate or at a reaction site at the same time. Electronic devices control the frequency with which bubbles enter the microfluidic chip.

By controlling the timing of the bubbles and the types of logic gates used, researchers can design circuits on microfluidic chips for a variety of tasks. The idea is eventually to enclose biological samples inside the bubbles or replace the bubbles with chemical droplets. Then the bubble logic circuits will make it possible to test hundreds of reagents on a DNA sample, for example, or make all possible combinations of 20 different chemicals to discover possible drugs, Gershenfeld says.

With the new devices, a microfluidics chip could have reservoirs of the chemicals stored on the chip–something like information stored in a computer’s memory. Just as information is retrieved from your computer’s memory, a bubble logic circuit would address the memory. Then a counter would dispense a specific number of the sample’s droplets, and a logic circuit would guide the droplets to reaction sites on the chip.

Stephen Quake, an applied physicist at Stanford, says that this work provides “a powerful general set of tools to manipulate microfluids,” even though it might be too early to say what the best application will be. Quake has designed tiny valves and pumps that can be integrated into a microfluidics chip to move fluid samples around. He says that the MIT work is “another general solution by using bubbles to do the manipulation instead of integrated valves.”

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