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Diagnostics

Prototype diagnostic patch picks up on a chemical below the skin

Combining microneedles and nanoparticle-laden paper produces a device that directly detects a compound in rat interstitial fluid

by Sarah Webb, special to C&EN
May 24, 2019

 

20190524lnp2-figure3.jpg
Credit: ACS Sens.
Marrying microneedles and plasmonic paper allowed researchers to sample interstitial fluid (ISF) from rat skin (right) and detect a dye using surface-enhanced Raman spectroscopy, without having to extract the dye in a separate step.

One day doctors might replace some blood tests with a small microneedle skin patch followed by a quick scan of the sample. As a step toward that goal, researchers have demonstrated a simple prototype device that combines microneedles and sensor-laden paper to sample fluid from below the skin (ACS Sens. 2019, DOI: 10.1021/acssensors.9b00258). The researchers can directly detect a dye infused into rats by collecting interstitial fluid with the device and analyzing it with surface-enhanced Raman spectroscopy (SERS).

Mark R. Prausnitz and his colleagues at the Georgia Institute of Technology have been studying the idea of using arrays of tiny needles to deliver drugs and vaccines below the skin’s surface, avoiding both uncomfortable injections and hypodermic needle waste. Recently they have extended this work toward developing microneedles that can sample interstitial fluid —the clear, nonclotting liquid that the body’s cells bathe in—to do diagnostics. But extracting and analyzing chemicals from this fluid can be complicated and inconvenient. These steps dilute the sample and can lead to analyte loss.

While at Georgia Tech as a graduate student, Chandana Kolluru wondered if they could make a simple device that skips the extraction steps. She read about plasmonic paper developed by Srikanth Singamaneni of Washington University in St. Louis, for embedding nanoparticles into paper, which boosts the Raman signal from adhered molecules (ACS Appl. Mater. Interfaces 2010, DOI: 10.1021/am1009875). Singamaneni’s team has detected trace amounts of molecules as diverse as explosives with SERS and cancer biomarkers with localized surface plasmon resonance.

Kolluru contacted Singamaneni and soon the teams were collaborating, marrying microneedles with plasmonic paper. “Can we integrate some kind of sensing element into the paper so we can do the analysis directly on the paper?” Singamaneni asks.

As a proof-of-concept, they built a device for detecting rhodamine 6G, a positively charged fluorescent dye, that they administered to rats. First, they grew gold nanoparticles and coated them with negatively charged poly(4-styrenesulfonic acid). Then they concentrated the coated nanoparticles into an ink and placed it in a ballpoint pen cartridge. They wrote the ink onto a 1 mm by 7 mm strip of filter paper and attached it to a strip of nine steel microneedles 650 µm long.

To collect interstitial fluid, researchers applied patches to six hairless rats who had been infused with 10 mg/mL of the dye for 30 min. They allowed the paper sensor strip to become saturated and successfully detected the dye in the collected fluid using SERS. Handheld SERS instruments are now available, which means such tests could be done outside a laboratory.

Other groups have used microneedle devices to directly detect glucose or optically detect drugs, says Ronen Polsky of Sandia National Laboratories, who was not involved in the research. But it’s the first time that researchers have combined interstitial fluid extraction with microneedles and SERS detection. If the team can demonstrate that the paper-backed microneedles can detect a drug or biomarker using SERS, he adds, such a device would be “extremely valuable.”

Singamaneni agrees that a major challenge will be functionalizing the nanoparticles with antigens that bind specifically to biomarker targets. In addition, researchers need more information about how biomarker concentrations in interstitial fluid correlate with levels in blood, he says. “Most diagnostics are based on blood,” he says. “We need a better understanding of what’s going on in interstitial fluid.” Prausnitz is the founder of microneedle company Micron Biomedical. His Georgia Tech team is continuing to work toward a human diagnostic, Kolluru says.

CORRECTION

This story was updated on May 30, 2019, to reflect that the microneedles used in the patch are not hollow.

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