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Tufts University Demonstrates Use of 3-D Paper Microfluidic, Sees Broad POC Potential

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NEW YORK (360Dx) – Researchers at Tufts University have opted for wax paper and screen printing in the design and manufacture of a diagnostic testing platform that they said could someday be commercially available to test for several diseases at the point of care in low-resource settings.

Diagnostic tests being developed for these locations often need to operate where there are no laboratory test facilities, preventing clinicians from sending patient samples for central processing. In such settings, these types of diagnostic tests frequently must work in ambient temperatures, while also being inexpensive.

"We wanted to develop what I call a do-it yourself, low-cost diagnostic test that almost anyone could build and that can target multiple analytes," Sameer Sonkusale, one of the platform's developers and a professor of electrical and computer engineering at Tufts University, said in an interview.

He and his colleagues described the technology in a paper published last week in the journal Analyst.  

In their study, they demonstrated the sensitivity of the technology in testing three clinical parameters — glucose, dopamine, and PH, but the concept can be extended to many other biomarkers, limited only by the type of antibody that can be integrated with the platform, Sonkusale said.

For example, the researchers see potential for the test in diagnosis of stomach cancers, and for use in cardiovascular, liver, and kidney disease testing and monitoring, he said, adding the time to complete a test from sample preparation to receiving a result is less than five minutes.

"The work in this paper seems very promising in that it shows a novel combination of paper-based microfluidics and an approach to target detection using electrochemical processes," Tej Patel, a co-founder of FluxErgy, which is developing a portable microfluidic diagnostics system, said in an e-mail. "Different detection processes will allow for hopefully higher accuracy from paper-based microfluidic systems."

Although the development of paper-based microfluidics is not new, two-dimensional devices have suffered from variability that has hampered sensitivity and adoption, Sonkusale said. The cause of variability is often an irregular electroactive sensing area that the analyte contacts as it flows over a paper substrate. This sensing area, at the interface of screen-printed electrodes and the paper surface, varies widely from sensor to sensor, the researchers said, and analyte absorption onto the substrate’s cellulosic-fibers leads to varying analyte volumes.

In their paper, the Tufts researchers described an analytical device that uses a hollow 3-D fluid reservoir that allows for use of a uniform electroactive sensing area.

"Normally, plasma flows through a paper channel, but here sensing happens in a reservoir sitting on the paper substrate, and the top surface of the electrode interacts with the sample," Sonkusale said.

Because of this design tweak, the team is seeing greater uniformity from one test to the next that makes the platform more reliable and sensitive, he noted, adding that it also enables targeting a broader array of analytes.

"With accurate electrochemical-based detection, we can add multiple targets," create diagnostic tests for several disease areas, and measure the presence of several markers at once while testing for one disease, he said.

The researchers noted that they demonstrated the versatility of their device by doing voltammetric, amperometric, and potentiometric measurements of dopamine, glucose, and pH.

They said that in measuring pH, the platform exhibited a sensitivity of -45.0mV/pH, and in measuring dopamine, it showed linearity over the measured clinical range of 5mM to 17.5 mM with a sensitivity of 0.34µA/mM.

Meera Punjiy, a researcher at Tufts and the study's lead author, developed a customized silicon chip accessory that provides an electronic readout for the platform. It eliminates the need for a handheld or benchtop reader, she said in an interview.

The research group is also looking to integrate an automated and compact method of sample preparation, she said, to separate plasma from blood.

The team at Tufts is not alone in its quest to become a new entrant into clinical testing markets. Other researchers are investigating paper-based microfluidic tests for clinical applications.

In August 2017, for example, in the journal Advanced Materials Technologies, Purdue University researchers described fabricating a microfluidic test prototype using paper that could eventually be used at the point of care to detect biomarkers such as glucose, uric acid, L-lactate, ketones, and white blood cells that are used in the clinical analysis of liver and kidney function, malnutrition, and anemia.

The test could be particularly suitable for use in remote locations without electricity or clean water, and it has been designed to be easy enough to operate even by untrained people, the researchers said.

In March 2017, a separate team of Purdue University researchers said that they had developed a new biosensing method using impedimetric sensors and applied it to mosquito-borne viruses in proof-of-principle studies.

Their goal is to combine the technique with a rapid, paper-based sample prep method employing thermally actuated wax valves to create a point-of-care system to detect viruses such as Zika and dengue in human and mosquito vector samples.

Commercial entities are also investigating non-paper-based microfluidic tests that may have use in low-resource settings. They include startup MFluiDx, which is developing a tool called the Simple Chip that can process whole blood with on-chip sample prep. Also, Alveo Technologies is developing a POC diagnostic platform that combines nucleic acid detection with molecular biochemistry for infectious disease testing. The firm recently announced the completion of a $38 million Series A financing round.

And another startup FluxErgy, in Irvine, California, is developing a portable microfluidic diagnostic system that it hopes will ultimately be used in low-resource settings around the world and in in physician offices.

"There are multiple players working towards paper-based microfluidic technologies all with the focus on low-cost diagnostic assays," FluxErgy's Patel said. He noted that most groups seem to be primarily operating in academic settings.

"Until there is a significant dedication of resources to developing manufacturing processes at scale, we most likely won’t see approved paper-based microfluidic diagnostic test for at least a few more years," he said.

Developers of microfluidic technology need to bring their manufacturing scale and cost of goods sold to where they can offer a price point per test of between $1 and $2, or "there really will be limited uptake of their product," he said.  

The Tufts University researchers noted in their paper that although the field is promising, there are still several challenges that need to be addressed for wide spread usage of paper-based devices.

They will next need to evaluate the test on patient samples in large-scale clinical trials, and depending on those results, they would then decide whether to commercialize the test, Sonkusale said.

The researcher noted, however, that the test platform — because it is inexpensive to mass manufacture and eliminates the need for use of a cleanroom — would be cost-competitive with existing strip-based tests. Should the team eventually commercialize a glucose test, they would release it at a price similar to existing glucose testing strips, he said.

And now that the researchers have completed a lab-on-a-chip demonstration, they intend to develop and test the platform with additional disease markers, Sonkusale said.