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Microfluidic Diagnostics at the Point of Care: The Power of Paper

Patrick Beattie, 2014 SLAS Innovation Award winner and former director of operations for Diagnostics for All (DFA), recently took the next step on his journey to improve global health when he was named a Skoll Scholar by the Skoll Centre for Social Entrepreneurship. He credits “the incredible work that has been done by the entire DFA team over the past six years” as instrumental to his selection for this honor.

In 2008, Beattie became the first DFA employee, selected by George Whitesides, Ph.D., and Carmichael Roberts, Ph.D., when the two cofounders decided to hire someone to work for the nascent nonprofit organization. Beattie had spent two years as a Peace Corps volunteer teaching math and chemistry in Gambia, and an additional year as a chemistry teacher in Guinea. “I really enjoyed my work in West Africa, but decided to come back to the U.S. to rekindle the lab work I had been doing while earning a chemical engineering degree at Princeton,” he recalls.

The DFA opportunity “was perfect,” Beattie says. “The nonprofit was formed around a new technology—paper microfluidics—and the cofounders were committed to using it for global good. It combined what I had been doing in the field with what I had been missing, which was the science—in particular, working at the intersection of engineering and biology. I couldn’t think of a better job, and luckily, they couldn’t think of a better person for it.
Why Paper?
Paper is an ideal “fundamental material” for diagnostics for the developing world because the resulting tests are “inexpensive, functional, portable and usable by people who are not necessarily skilled in U.S. diagnostics,” Whitesides explains in an MIT video created shortly after the launch of DFA. Paper also is “compatible with biological systems” and, after use, can be disposed of simply by incineration. When conceptualizing the technology, he says, “we asked, ‘what is the least expensive way we can start, in order to provide the function we need?'”

The team began by taking advantage of the fact that paper is hydrophilic and wicks fluids. Beattie explains: “Say you spill some wine on a table, and soak it up with a paper towel. You’ll notice when you put the paper towel onto the spill that the fluid naturally wicks into the paper. If you think about it, this means the fluid moves on its own, without the assistance of any kind of internal pump,” he says. “But the one big drawback is that you can’t control where that wicking happens. The wine essentially wicks throughout the paper.”

The paper microfluidics technology developed in the Whitesides Research Group changed all that. “It allowed us to create polymer walls, or channels, within the paper, in a very simple, low cost way, that then enabled us to control how the fluid wicks through,” Beattie explains. The result is “patterned paper,” comprised of paper, which is hydrophilic, bounded by the hydrophobic polymer.

“We’ve patterned everything from toilet paper to lab wipes to high quality nitrocellulose,” Beattie continues. Two-dimensional patterning and flow within a plain sheet of paper gave way to prototype three-dimensional microfluidic devices “in which we weren’t just controlling fluid flow in the X-Y direction, but also in the Z direction between layers of patterned paper stacked together with double-sided adhesive tape. This offered the ability to distribute fluids vertically and laterally, and for streams of fluid to cross one another without mixing—none of which could have been done in a two-dimensional format.”

Specifically, unlike traditional microfluidics systems made from glass or plastic, the 3D paper-based devices could guide fluid samples from a single inlet on the top layer through networks of 3D channels into an array of spots or “detection zones” on the bottom layer, Beattie explains. The spots were pretreated with reagents that could detect multiple analytes simultaneously, changing color in the presence of particular analytes. The first prototype device tested four different samples for four different analytes and displayed the results side by side. [Ed. note: Andres Martinez provides a detailed explanation of the how two- and three-dimensional patterned paper is made and works in a video, “Making Paper Diagnostic Tests,” made while he was working in the Whitesides Research Group.

From Lab to the Field
DFA was founded to create paper-based microfluidics products that would have an impact in the field, particularly in resource-poor settings, Beattie stresses. Around the time that he was hired, DFA and Harvard University entered into an agreement that gave DFA the option to exclusively license the diagnostic technology from Harvard royalty-free for not-for-profit purposes. “Whereas the Whitesides lab was doing—and continues to do—a tremendous amount of interesting innovation, DFA was charged with identifying which of those innovations would make useful products in the field, and then driving their development.”

“My experience living and working in West Africa turned out to be a huge benefit, in that it enabled us to identify needs that actually exist, and areas where the technology could actually be used,” Beattie continues. “The reason I became so enamored with DFA was that it was based on the first technology I’d seen since being back in the U.S. that made me think immediately of people I knew in the villages where I had lived and taught. I thought, ‘I can really see them using this type of diagnostic. It’s simple enough and robust enough that it can be used in those areas.’ And I became very excited.”

Most of DFA’s products are in various stages of development, Beattie observes. The product that is furthest along is a paper-based point-of-care finger stick transaminase test, used to monitor liver function. “While it’s great that people in developing countries now have increased access to therapies for HIV, tuberculosis and other infectious diseases, the ability to monitor for drug-induced liver toxicity is limited,” Beattie says. DFA’s prototype device, which provides an assessment of liver health within 15 minutes from a single drop of blood, “has undergone significant field testing over the past few years, and is now ready for commercialization. Getting this test out into the market so it can start to affect people’s lives is a huge next step that everyone is excited about.”

Beattie was involved with other DFA projects that are now undergoing further development and testing. For example, through a grant from the Bill & Melinda Gates Foundation, the organization is using its paper-based microfluidics technology to create a rapid diagnostic test for immune markers of successful vaccination against measles and tetanus in children. This will enable developing countries to monitor the efficacy of vaccination campaigns and identify areas with low coverage.

Other DFA projects aim to assist farmers in rural parts of sub-Saharan Africa and elsewhere. A grant from the Bill & Melinda Gates Foundation and the UK’s Department for International Development is enabling the organization to investigate “two opportunities with respect to livestock, recognizing that low-cost diagnostics can play a role in helping farmers to maximize their income,” Beattie says. “One is a bovine estrus detection test that enables farmers to determine the optimal time to inseminate cows to keep them in a high milk-producing state.” (DFA recently received a second grant to help finalize development of the estrus diagnostic and assess its performance in field tests.) “The other is a milk spoilage diagnostic to test milk coming into a processing plant to make sure it hasn’t spoiled. If one batch is spoiled, it can contaminate an entire pool of milk and depress the prices processors are willing to pay.” The milk spoilage diagnostic is in collaboration with Sam Nugen at the University of Massachusetts, Amherst.

A third project involves detecting aflatoxin in maize samples. “What DFA is really trying to do with this diagnostic is enable farmers whose maize is aflatoxin-free to prove it, and thereby access the higher margin markets that demand that quality assurance,” Beattie explains.

DFA also is supporting child nutrition in developing countries, where prolonged deficiencies of micronutrients can harm mental function and immune response, and cause serious birth defects and death. Through another Bill & Melinda Gates grant, DFA is partnering with MC10, a Boston-area company that has a flexible electronics platform. According to DFA, the collaboration “will enable an entirely new class of low-cost diagnostics, capable of highly quantitative analysis, all without a reader, enabling accurate monitoring of micronutrient levels in rural settings and at low cost.”

Looking Ahead
Going forward, DFA is concentrating its efforts on various classes of diagnostics, says Beattie. “Our first application was the enzymatic assay for liver function. It wasn’t a huge shift to think of using the technology for immunoassays, because that’s what’s typically done on pregnancy tests. We did it in a different way, but really that was a clear next step,” Beattie says. “But more recently, DFA has developed true point-of-care nucleic acid amplification testing. That’s a major step because until now, that kind of testing has required some sort of cartridge and box model. Using the paper microfluidics platform, we were able to develop a 100 percent disposable nucleic acid test.”

The prototype is now in early stages, but the group recently was nominated for a $250K seed grant through the United States Agency for International Development to develop an HIV test based on this technology, Beattie notes. The equipment-free, qualitative test for infants would reduce the turnaround time for results from over one month to under an hour.

Has the recent Ebola outbreak had an impact on product development at DFA? “I think it highlights the benefit of both anticipating where emerging threats are coming from and making sure that vulnerable healthcare systems have appropriate tools for dealing with those threats,” Beattie says. “That’s not necessarily a new area for the organization, but it underscores the fact that healthcare in other countries is not always the kind of centralized system that we have here in the U.S. Therefore, centralized tools and centralized interventions are unlikely to be effective. The outbreak really has demonstrated some of the struggles healthcare systems in the developing world are up against, and the need for tools that work in those environments.”

As he prepares to move on to Oxford, Beattie reviewed his DFA experience. “For me, what has made DFA such an interesting organization to work for is that it doesn’t just focus on global health. It also works on global development, as was highlighted with the agriculture test,” he says. “The goal always has been to find any way that low-cost diagnostics can improve people’s lives. When it turns out that something that’s being created for the developing world happens to have utility in the developed world, DFA uses agreements with partners who are interested in commercializing the product in high margin markets to create royalty revenue that comes back into the organization and supports the developing world work.”

Although he will miss his colleagues and work at DFA, he is looking forward to his year (2014-2015) as a “Skollar.” “Being chosen as a Skoll Scholar is a great honor,” Beattie says. “It is a highly competitive award that was given to only four individuals this year. While the award is partly in recognition of my focus on using technological innovation for social benefit and my desire to continue fighting for improved global health, it also a validation of DFA’s mission—to take innovations typically used for strictly developed world purposes and focus those innovations on improving healthcare delivery to those most in need. I am incredibly excited about the Skoll Centre’s support and the opportunity to interact with the greater Oxford community to identify and implement new opportunities to improve global health, especially with partners not traditionally involved in international development,” he concludes.

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