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MIT Researchers Develop Modular Paperfluidics Kits for Dx Design


NEW YORK (360Dx) – Researchers at the Massachusetts Institute of Technology have developed a set of modular paperfluidic blocks for use in the prototyping and development of point-of-care diagnostic devices.

Called Ampli (asynchronous modular paperfluidic linear instrument-free) blocks, the system is inspired by the electronic breadboards that are commonly used to prototype electronic devices, said Jose Gomez-Marquez, co-director of MIT's Little Devices Lab and leader of the effort.

Paper-based microfluidic devices have been in use for at least a decade at this point, Gomez-Marquez said, finding applications in areas like biomarker and environmental testing. In theory, such devices could enable clinicians, particularly in resource-constrained settings, to easily and cheaply build POC devices for a variety of testing purposes.

Gomez-Marquez cited the medical laboratories in Honduras, where he grew up. "You would go in and get checked for everything from parasites to your glucose levels," he said. "They didn't have much, but they have maybe a spectrophotometer and some microscopes, and so it is a safe, clean place where you could create small [devices] to run small assays."

"And our inspiration was, if we've taught a whole generation of people how to take malaria samples, how to do microscopy, how to take smears, why can't we teach them how to make paper tests?" he said.

However, while development of paper tests is simple in theory, becoming good at the manual steps involved in building such test takes considerable practice.

"You are dealing with things that are just millimeters wide, and you have to learn to place things very gingerly, Gomez-Marquez said. "It's almost like model ship building. It's a skill that you can acquire, but it's not something that you have automatically. In our lab it takes postdocs months to get up and running with these skills, to really get good at."

That challenge led the MIT team to consider the breadboard concept, in which the components for device development come already made.

"If you're a scientist working on a new [electronics] project, you certainly don't start by spinning your own capacitors," he said. "You have the pre-fabricated components and then you put them together."

"You didn't have that for biology," Gomez-Marquez noted. "You didn't have that for paper tests. If you changed your mind about the antibody in a sequence or the label or the dye, you had to start again from scratch. We just thought there was a better way."

The researchers described the Ampli system in a paper published last week in Advanced Healthcare Materials. It consists of 3D printed plastic blocks containing one or more laser-cut microfluidic membranes that can be connected to each other via complementary slots. Different blocks allow for different flow patterns or functionalization with different reagents like antibodies or dyes.

Gomez-Marquez and his colleagues estimated that a set of four blocks including reagents and dyes would cost in the $7 to $9 range. Keeping the price modest is key to enabling the sort of experimentation the system is designed to facilitate, he said, noting that subtle differences in the material used can significantly impact a test's performance.

"Sometimes just using [a membrane] with a pore size slightly different from another can make or break your test. It can mess with the evaporation rates and that sort of stuff," he said. Additionally, he noted, it can be difficult to determine precisely what reagents are being used in premade tests, which can further hamper the ability of researchers and clinicians to construct their own.

"For instance, if I buy an Ebola test, it's often very hard to understand exactly what antibodies they are using," he said. "What we want is to generate a transparent library [of components] so people can know what's on the block, which one works better than others, which one is more expensive, and understand the trade-offs. And you can't really do that today with [existing] rapid tests that come already impregnated with the reagents."

The open nature of the system also allows researchers to customize the blocks with their own reagents, Gomez-Marquez said, "because the most exciting reagents are the ones that the user generates locally that I may never get access to."

In a proof of concept, the MIT team used the blocks to build a simple glucose test, using a block functionalized with potassium iodide (KI) for detection. They then swapped out the KI block for one functionalized with o-toluidine, which generated a much stronger colorimetric signal, demonstrating how users can use different components to fine-tune an assay's readout.

The researchers also built a lateral flow immunoassay (LFI) for dinitrophenyl-biotin peptide as well as a four-channel multiplexed LFI. They noted that the ability to easily change test multiplexing levels could potentially save resources by allowing clinicians to customize tests more appropriately.

"For instance," the wrote, "while STD–pregnancy test combinations may be useful for female patients, 50 percent of that test is wasted on a male patient. With dynamic multiplexing the pregnancy test branch could be deleted and saved for later, while still caring for the male patient."

A key challenge the researchers faced in developing the system was bringing it down to a more practical size, said Gomez-Marquez.

"The first versions of these systems, when we gave them to people for user testing, they generated these channels that were almost three-and-a-half-feet long," he said. "That immediately taught us that that was going to require a lot of sample and a lot of buffer to get it all the way across. So we had to miniaturize a lot of things."

"It became a process of determining what is the best way to miniaturize it and defeat things like the natural surface tension of some of these liquids that are flowing through tiny spaces, and then at the same time battling things like the fact that if [the channel] is really small and there is not a lot of [sample] how do you make sure it doesn't evaporate?" he said. "It's a lot of the usual tuning that you would do in a traditional test."

Having developed the system, Gomez-Marquez and his colleagues are now distributing them to interested scientists around the world. "We've sent them to Chile, to Nicaragua, to Europe. We're getting ready to send them to Honduras, where I'm from, and a handful of other countries," he said.

The researchers are also developing a program called Open Diagnostics that will allow interested parties to apply for access to the Ampli tools. Gomez-Marquez said he ultimately hopes to turn the blocks into a commercial product people can order much as they would other scientific supplies.