'Programmable droplets' could replace pipettes

19:00 EST 15 Feb 2018 | Australian Life Scientist

Now, researchers from the Massachusetts Institute of Technology (MIT) are replacing the humble pipette with lab-on-a-chip technology that uses electric fields to move droplets of biological solutions around a surface, mixing them in ways that could be used to test thousands of reactions in parallel.

“Biologists in a lab spend on average 30–50% of their time manually moving fluids, and this task is not only tedious, but is also error-prone,” said Udayan Umapathi, a researcher at the MIT Media Lab. “On top of that, each of these labs produce massive amounts of hazardous trash in the form of pipette tips.

“Of course you can replace the human with a pipetting robot, but each of these machines have their own definition for what a protocol is and there are multiple research laboratories developing their own standard.”

Furthermore, Umapathi said, pipetting robots do not solve the problem of pipette waste, with pharmaceutical companies in particular guilty of employing robots equipped with dozens or even hundreds of pipettes.

“If you look at drug discovery companies, one pipetting robot uses a million pipette tips in one week,” he said. “That is part of what is driving the cost of creating new drugs.”

Another alternative to pipetting is microfluidic devices, in which biological solutions are pumped through microscopic channels connected by mechanical valves. Umapathi noted that traditional microfluidic systems that use tubes, valves and pumps are mechanical — which means they have a tendency to break down.

“I noticed this problem three years ago, when I was at a synthetic biology company where I built some of these microfluidic systems and mechanical machines that interact with them. I had to babysit these machines to make sure they didn’t explode.

“Biology is moving toward more and more complex processes, and we need technologies to manipulate smaller and smaller volume droplets,” Umapathi continued. “Pumps, valves and tubes quickly become complicated. In the machine that I built, it took me a week to assemble 100 connections. 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.”

Seeking a solution to this problem, Umapathi and his team have been developing lab-on-a-chip technology based on a physical principle called electrowetting, whereby electric fields are used to move, merge, stir and analyse tiny biological samples. Their research has been described in the journal MRS Advances.

“So fundamentally what we are doing in our chip is to charge and discharge tiny metal plates,” Umapathi explained. “This charging and discharging of these metal plates attracts and repels tiny droplets. And by sequentially turning on and off these metal electrodes, you can gently shuttle a drop from one location to another. We developed a new surface coating that prevents droplets from leaving a trail behind and thus preventing contamination between droplets which could cross each other.”

Dispensing a biological sample on to the programmable chip via pipette. This can then be used in a dilution process, or to include a new reagent in an experiment. Image courtesy of MIT Media Lab/Jimmy Day under CC-BY-NC-ND 4.0

Thousands of droplets could be deposited on the surface of Umapathi’s device, automatically moving around in computationally prescribed patterns in order to carry out experiments efficiently, cost-effectively and at large scales. The system includes software that allows users to describe the experiments they wish to conduct, before automatically calculating droplets’ paths across the surface and coordinating the timing of successive operations.

“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,” Umapathi said. “The operator doesn’t specify how the droplets flow or where they mix. It is all precomputed by the software.”

Two droplets before and after being merged programmatically. Images courtesy of Udayan Umapathi/MIT Media Lab under CC-BY-NC-ND 4.0

The MIT group is not the first to venture into the field of ‘digital microfluidics’, with various research groups experimenting with the electrical manipulation of droplets over the past 10 years. However, previous chips have been manufactured using high-end etching techniques that require controlled environments known as clean rooms.

Umapathi and his colleagues have instead focused on getting costs down, with their prototype making use of a printed circuit board (PCB) — a plastic board with copper wiring deposited on top of it — patterned with an array of electrodes. Their chief technical challenge was to design a coating for the surface of the PCB that would a) reduce friction, enabling droplets to slide across it, and b) prevent biological or chemical molecules from sticking to it, so they won’t contaminate future experiments.

Birds-eye view of the programmable chip with various droplets. Image courtesy of MIT Media Lab/Jimmy Day under CC-BY-NC-ND 4.0

In the prototype, the researchers coated the board with a dense array of tiny spheres, only a micrometre high, made from a water-repellent material that causes droplets to skate across the tops of the spheres. The researchers are also experimenting with structures other than spheres, which may work better with particular biological materials.

Because the board’s surface is hydrophobic, droplets deposited atop it naturally try to assume a spherical shape. Charging an electrode pulls the droplet downward, flattening it out. If the electrode below a flattened droplet is gradually turned off, while the electrode next to it is gradually turned on, the hydrophobic material will drive the droplet towards the charged electrode.

Three hundred times a second, a charged electrode in the researchers’ device alternates between a high-voltage, low-frequency (1 kHz) signal and a 3.3 V high-frequency (200 kHz) signal. The high-frequency signal enables the system to determine a droplet’s location, using essentially the same technology as touch-screen phones. If the droplet isn’t moving rapidly enough, the system will automatically boost the voltage of the low-frequency signal. The sensor signal additionally enables the system to estimate a droplet’s volume, which, together with location information, allows it to track a reaction’s progress.

A side view of the programmable chip shows the wiring that supports the actuation and sensing of droplets, allowing for movement and combination of droplets. Image courtesy of MIT Media Lab/Jimmy Day under CC-BY-NC-ND 4.0

Umapathi believes that digital microfluidics could drastically cut the cost of experimental procedures common in industrial biology, removing the need for specialty machines and the use of disposables such as pipette tips. He and his colleagues have been running various experiments on their chip to reduce their dependency on pipettes by over 10-fold, and they are even working on liquid assays that could reduce pipetting operations 100-fold.

The team’s work has also been noticed by BioBright, a company that develops information systems to manage the wealth of data generated by high-volume biological experiments. BioBright founder and CEO Charles Fracchia described Umapathi’s digital microfluidics system as “effectively a cheaper version” of the smaller-volume systems employed by pharmaceutical industry over the past 15–20 years.

“I don’t want to call it DIY bio, but it’s lower cost, simpler instrumentation, easier access,” said Fracchia. “It’s exciting that he’s managed to do it with lower voltage, and it’s exciting that he can do it with a single electrode.”

Ultimately, Umapathi hopes his technology will enable existing machines to manipulate over a million samples on a single chip, thus leading to the discovery of new drugs and markers for disease.

“Modern healthcare testing facilities around the world do not scale economically to provide affordable health care,” he said. “My hope is that we can bring affordable health care through lab-on-chip technologies to billions of people around the world.”

Top image caption: A programmed experiment on the programmable chip with large volumes of biological fluids. Image courtesy of MIT Media Lab/Jimmy Day under CC-BY-NC-ND 4.0

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