Programmable Droplets Support High-Volume Alternative Tech to Microfluidic Chips

Scientists at the Massachusetts Institute of Technology (MIT) have developed a “programmable droplet” digital lab-on-a-chip technology that uses electric fields to move, mix, and stir tiny liquid droplets containing chemical or biological molecules deposited on the surface of a specially coated and inexpensive printed circuit board. MIT researcher Udayan Umapathi and colleagues claim the programmable electrowetting platform could pave the way to enabling more cost-efficient, large-scale biological experiments for drug discovery and diagnostic applications, as well as dramatically reducing use of the millions of disposable equpiment such as pipette tips, that one company's robotic liquid handling systems may use in a week. The team reports on their development in MRS Advances.

“Traditional microfluidic systems use tubes, valves, and pumps,” says lead researcher Umapathi at the MIT Media Lab. “What this means is that they are mechanical, and they break down all the time.…Biology is moving toward more and more complex processes, and we need technologies to manipulate smaller-and-smaller-volume droplets. Pumps, valves, and tubes quickly become complicated.”

Umapathi has first-hand experience building microfluidic systems and the mechanical technologies that interacted with them to deposit the samples. “I had to babysit these machines to make sure they didn’t explode,” he says. Constructing conventional microfluidic systems is also time-consuming, and the number of connections that can be generated is limited. “In the machine that I built, it took me a week to assemble 100 connections,” Umapathi comments. “Let's say you go from a scale of 100 connections to a machine with a million connections. You're not going to be able to manually assemble that.”

The new programmable electrowetting device is founded on the concept of depositing droplets of chemicals or biologic molecules onto a surface, on which they can be automatically moved around by switching on and off individual electrodes patterned onto the array that attract or repel the droplets. The technology’s software allows users to describe their experiments in relatively general terms and then automatically calculates how to move the droplets to create reaction mixes. “The operator specifies the requirements for the experiment—for example, reagent A and reagent B need to be mixed in these volumes and incubated for this amount of time and then mixed with reagent C. The operator doesn't specify how the droplets flow or where they mix. It is all precomputed by the software,” Umapathi explains.

The primary technical challenge for the team was designing a coating for the printed circuit board that would permit the liquid droplets to slide across it, and also prevent molecules from sticking to the surface and creating a contamination issue. The circuit board is patterned with an electrode array, and the MIT researchers’ prototype is coated using hydrophobic microspheres, atop of which the reaction droplets can skim across. The MIT team is also working with structures other than spheres, which may be better suited for use with specific biological materials.

Because the surface-coated microspheres are hydrophobic, the liquid droplets sitting on the top take on a spherical shape to minimize contact area. When an electrode is then charged, the droplet is flattened downward. Gradually changing the charge of adjacent electrodes can effectively pull droplets in the desired direction. 

High voltages of up to 200 volts are needed to move the droplets. In addition, 300 times a second, a charged electrode will alternate between a high-voltage, low-frequncy signal and a low, 3.3-volt, high-frequency signal. This allows the system to identify a droplet’s location and is similar to the technology used by touchscreen phones. The sensor signal can also estimate a droplet’s volume and track its progress. The technology even has the ability to automatically boost the voltage of the low-frequency signal if the droplet isn’t moving fast enough.

Umapathi hopes that digital microfluidic platform technology could dramatically cut the cost of chip-based experiments. For pharmaceutical companies who conduct many experiments in parallel, for example, liquid-handling robots may routinely get through millions of pipette tips. “If you look at drug discovery companies, one pipetting robot uses a million pipette tips in one week,” Umapathi says. “That is part of what is driving the cost of creating new drugs. I'm starting to develop some liquid assays that could reduce the number of pipetting operations 100-fold.”