Lab-on-a-Chip Made of Paper

Color coding: This prototype of a new paper diagnostic test from Harvard University analyzes the glucose (left well) and protein (right well) content of urine; the top well is a control for the glucose assay. The beige part of the test paper has been treated with a hydrophobic polymer that channels the liquid into the wells. In this test, the paper was dipped in an artificial urine solution that contained glucose and a protein extracted from cow blood.
Credit: Andres W. Martinez

By taking advantage of the natural movement of liquid through paper, researchers at Harvard's Whitesides Research Group may have found a way to make microfluidics technology much cheaper. The result could be disposable diagnostic tests simple and abundant enough for use in the developing world.

The field of microfluidics deals with the precise manipulation of tiny quantities of liquid. One of its most promising applications is the so-called lab-on-a-chip, which can work with much smaller fluid samples than larger devices require, potentially allowing for more portable diagnostic tools. But existing microfluidic chips are generally made from comparatively expensive materials like silicon, glass, or plastic and have tiny pumps and valves that can be difficult to manufacture.

Now, Harvard's George Whitesides and his team have built a microfluidic device on a square of paper the size of a pinky fingernail. "It's the first example I've heard of paper microfluidics," says Albert Folch, a bioengineer at the University of Washington who works on microfabrication. "It's really clever because it uses paper as a substrate, which is universally available."

While larger paper tests (like those for pregnancy) are common, shrinking the paper and minimizing the quantity of the required chemical reagents reduces manufacturing costs. The ability to direct the sample to particular regions of the paper enables the simultaneous performance of several tests, to look for multiple symptoms of a condition, like kidney failure or infectious disease, says Whitesides. And reducing sample size is a particular advantage in developing countries, where noninvasively gathering small amounts of fluids avoids the need for syringes, which can be hard to clean and dispose of.

A pinprick of blood or drop of urine soaked up at the edge of the Whitesides device moves naturally through the paper, in much the way that wine will spread through a paper napkin. But the paper is treated with a hydrophobic polymer, which directs the liquid along prescribed channels. Once the liquid reaches the wells at the ends of the channels, it interacts with reagents, turning the paper different colors. The colors can be matched to those on a color key, much as they are in a pH test. One test design that looks like a miniature, three-branched, geometric tree might have wells at the end of two branches for a glucose assay and one at the end of the third for a protein assay, for example.

The design dispenses with expensive components common in conventional microfluidic devices: chemical reactions that color parts of the paper replace sophisticated sensors and analyzers, while using paper's natural capillary action to absorb liquids avoids the need for external pumps or power sources. Diagnostics for All--a spinoff cofounded by Whitesides and Harvard visiting scholar Hayat Sindi, with the support of partners from MIT--is commercializing the technology.

Instead of etching channels into a material, as most microfluidics designers do, Whitesides and Sindi were able to take advantage of the network of channels inherent in paper; the hydrophobic polymer simply seals off the channels that the researchers don't want to use. "What's really clever about this system is that they've actually patterned the whole volume of the substrate," Folch explains. "The paper itself forms a network of capillaries."

One disadvantage Folch notes is that, because of the paper tests' limited pumping action, they probably won't be able to perform more-complex chemical reactions.

Aside from making the devices cheaper, the designers kept in mind other characteristics that would make them more practical in the developing world. The test's light weight and resistance to breaking make it more portable than tests patterned on easily shattered glass surfaces. The paper chip is also easily disposable, by incineration, a key consideration in developing countries concerned with maintaining public health, says Whitesides. "The kinds of things we're developing here are intended to be useful for screening public health in the developing world," he says. Instead of "taking first-world medicine and trying to downsize it," the team began designing the technology with developing countries in mind, concentrating on ease of use, affordability, and portability, says Whitesides.

In order to optimize the device for developing countries, the team plans to combine the paper tests with a system of cell phones for off-site diagnosis, minimizing the level of expertise needed to use the tests. "It's primarily a way of conserving the valuable time and limited resources of health-care folk," says Whitesides. The team envisions that, in rural areas where doctors are limited, people who are trained only to conduct the tests carry them out "and send them back to a central facility where a doctor looks at that information and [recommends] diagnosis and treatment without having to actually be there," says Whitesides.

As of now, Whiteside and his colleagues have tested the paper diagnostic tool using artificial urine. In a paper published last month, they analyzed the paper results remotely, via phone cameras, and found that the results were "comparable in accuracy" to on-the-spot analysis, says Whitesides.

The next step is a clinical trial and deployment somewhere in Africa, says Sindi. Right now, the team is testing the device under harsh conditions, she says, such as high pressure, temperature, and humidity. So far, the test does not seem to be adversely affected, says Whitesides. The team eventually hopes to move beyond human diagnostics, developing devices for testing water, livestock, and other food sources.

"The kinds of diagnostic assays you want to do and the kinds of problems you want to solve are very diverse in the real world," says Mehmet Fatih Yanik, an assistant professor at the Research Laboratory of Electronics at MIT. "The nice thing about paper is that it's a very flexible platform for conducting a variety of assays." He adds that making microfluidic devices like the Whitesides group's is a lot cheaper than making bulk diagnostic machines. "The combination of the two low-cost systems--the paper-based fluidics and cell phones, which are quite ubiquitous in the developing world--that's a novel idea," says Yanik.

"It really brings a tool that will have a big impact on the implementation of microfluidics," a technology that usually requires a lot of hardware and expertise to use, Folch says. "They've lowered the barrier and are able to bring microfluidics to the masses, so to speak."

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