The “Citation Classic” That Redefined Microfluidics

Just over a decade ago, researchers at Duke University revolutionized the field of microfluidics by demonstrating a digital lab-on-a-chip for the first time.

Since the inception of the field, the manipulation of liquids on a microscopic scale was almost exclusively based on continuous fluid flows in tiny channels. Imagine the complex series of pipes, reservoirs and pumps found in any boiler room, but miniaturized onto the surface of a microchip.

While useful, this setup has many drawbacks, such as offering little flexibility in terms of scaling the systems up, reconfiguring the networks for different tests and manipulating delicate biological fluids. These systems were also a one-way street, making it impossible to move liquids in reverse through the channels.

But in 2004, all of that changed when Richard Fair, the Lord-Chandran Professor of Engineering at Duke University and his students, published a paper demonstrating the world’s first integrated digital microfluidic platform, essentially manipulating drops of fluids like electrons on a microchip (V. Srinivasan, V.K. Pamula, and R.B. Fair, Lab Chip, 4,310 (2004)). Originally appearing in the journal Lab on a Chip, the study has been cited more than 546 times to date—and was recently highlighted as a “Citation Classic” in the journal Clinical Chemistry.

“We set out to design high-density microfluidic chips that were reusable based on the success of microchips,” said Fair. “After burning a year on pursuing continuous flow technology, we realized we needed a ‘digital’ system that would let us manipulate individual droplets of liquid. But we had no idea how to do it!”

The solution came from a Russian instrument maker and former Duke postdoc in cell biology by the name of Alex Shenderov. He had a notion of how to move droplets on a hydrophobic surface under voltage control—a process called electrowetting on dielectric, which Fair had never heard of before.

Imagine a sphere of liquid sitting on top of a hydrophobic insulator surface. If an electric charge is built up at the bottom of the droplet by applying voltage to a buried electrode, it changes the surface energy of the liquid. This causes the liquid sphere to wet the insulator surface and to sag along its edges, resembling more of a melting scoop of ice cream.

Then, if a voltage is applied to an adjacent buried electrode while the original electrode voltage is removed, the droplet will move to the new location of the applied voltage.  The droplet follows the applied voltage, because the droplet would prefer to stay in its “melted” or wetted state caused by the resulting charge at the droplet/insulator interface. By activating a series of charges between droplets and a flat hydrophobic surface, individual droplets can be moved in any direction or pattern desired.

“We showed that we could move a droplet containing DNA back and forth on a Teflon surface 40,000 times without leaving behind so much as a molecule,” said Fair.

The paper also demonstrated that the researchers could pull droplets out of a reservoir in precise volumes. Combined with the ability to move them anywhere on the chip, they demonstrated the first digital microfluidic lab-on-a-chip that could combine, mix and test fluids. The initial tests measured blood glucose, but the theory could be used for most anything.

The digital microfluidic technology was spun out of Fair’s lab by members of his original research team. Advanced Liquid Logic was formed in 2004 and was acquired by Illumina in 2013. Today, the technology is in use in products of three different companies.  Illumina now produces machines that automate the time-consuming, complicated process of preparing DNA for sequencing. “Instead of a highly trained specialist taking the better part of a day to prepare a sample, you can just put some blood in the machine overnight and it’ll be ready the next morning,” said Fair.

GenMark bought a license to the technology to amplify genetic material from individual drops of blood. The company Babies in Research Triangle Park uses the technology to screen infants for 48 different genetic diseases using only a few microliters of blood. 

Check out more amazing videos at the Duke Microfluidics Laboratory website.