Nobody expects cutting-edge biomedical technology to come cheap. Magnetic-resonance imaging (MRI) machines that create detailed images of the organs and tissues within your body will typically set you back over a million dollars, while CT X-ray scanners cost hundreds of thousands. But researchers are hoping that some of these medical tests will become dirt cheap, even throwaway. They’ll need no fancy equipment, merely a sheet of paper and an office printer.
The latest step in this direction comes from a US team led by Daniel Ratner at the University of Washington in Seattle. They have shown how to attach biological markers for disease like genes or antibodies to the cellulose fibres of paper via secure chemical bonds. This has enabled the researchers to make a paper-based test simply by adapting an inkjet printer like the one standing on your desk, so that it prints with biochemical molecules in place of ink. These might not only lower medical costs and make clinical diagnoses quicker and easier, but could allow developing countries to start using low-cost medical tools that are currently too expensive.
In a typical so-called bioassay test, for instance, one that detects antibodies raised in response to a particular pathogen or chemicals released in response to an incipient tumour, a liquid sample – blood or urine, say – is directed along tiny channels so that it flows over little patches coated with particular biomolecules. These biomolecules grab hold of or react with particular ingredients of interest in the sample, and when that happens, the patch might be designed to change colour or become fluorescent, glowing under a light source of the right colour. A scientist or doctor can then identify whether or not the sample contains the corresponding ingredients, and determine whether a test is positive or negative.
The idea of manufacturing these tests on paper has been around for several years. In 2007 a team at Harvard University in Massachusetts imprinted paper with flow channels by depositing a water-repelling polymer through a patterned mask – a method usually used to etch channels in integrated circuits on silicon chips.
The fibrous structure of paper means that liquids get soaked up automatically by capillary action – in the same way that coffee-stained water rises up a paper coffee filter. The Harvard group used their patterned paper to detect glucose in urine, a system that could potentially be used to monitor and diagnose diabetes.
To make paper bioassays that will remain useable for a long time, though, the “sensing” biomolecules in the test patches have to be securely bound to the paper. Some molecules will just stick by physical attraction, for example, because bits of the molecules with positive electrical charge are attracted to regions of negative electrical charge in cellulose molecules. Often, however, this physical adhesion is weak – the molecules either won’t stick at all or will be easily washed off.
It’s far better to forge a strong chemical bond holding the molecules to the cellulose. Several groups have already found strategies for doing that, using linker molecules that will bind both to cellulose and to common bioassay molecules such as enzymes or DNA.
Even so, say Ratner and his colleagues, the methods are often far from ideal. They might work only for a small range of molecules, or they might require several laborious and costly chemical steps to fit everything in place, perhaps using flammable or toxic solvents. Ratner’s team has been exploring a linker molecule called divinyl sulfone (DVS), which has two “sticky ends” – one to stick to the paper, the other to the assay molecule. Studies have shown that DVS will link up with carbohydrate molecules similar to cellulose, and Ratner and colleagues have used them previously to stick biomolecules to gold and silicon.
Now they have succeeded in carrying out both sticky acts simultaneously. It’s a simple process. First the researchers coat a sheet of paper with DVS, giving it lots of “hooks” on which biomolecules like proteins and DNA can be hung. Next, they use an Epson inkjet printer to create patches of biomolecule, filling empty refill ink cartridges with the appropriate reagent. In alkaline solution, the molecules spontaneously form chemical bonds with the sole remaining ‘sticky end’ of the DVS linkers. The position and shape of these patches can be controlled with an accuracy of less than a millimetre.
When a sample meets the coated paper, its ingredients will stick to the respective patches tailored to capture them and, depending on the design, change colour or become fluorescent. The paper bioassays still work after being stored for at least 30 days in dry air.
One of the next steps will be to combine the printing of patches with the printing of flow channels that can convey particular samples to specific parts of the assay. If this is successful, it would allow complex diagnoses to be made quickly and cheaply on a single sheet of paper. As throwaway ideas go, paper-based diagnostic tests could be one of our most valuable ones yet.
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