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With $1.8M NIH Grant, Researchers Developing 10-Minute Test for Neurotoxins in Blood, Water

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NEW YORK (360Dx) – With a three-year, $1.8 million grant from the US National Institutes of Health, researchers from the University of Cincinnati and the University of Illinois at Chicago are collaborating to develop a portable microscale platform to detect toxic metals in a drop of blood within around 10 minutes.

The platform would allow for rapid detection of metals such as manganese and lead, neurotoxins that can affect cognitive development and neuromotor function.

With the NIH grant, the researchers are focused on completing fabrication of their platform and doing clinical validation in children suspected of having been exposed to high levels of manganese in Chicago. Longer term, they hope to launch a commercial diagnostic test that can be used at the point of care to test for manganese and lead in blood and water.

The platform uses a method called cathodic stripping voltammetry that detects trace elements of blood-based manganese attracted to electrodes that are part of silicon chips. Manganese, a metal that is required by the body in tiny amounts, can be toxic at elevated levels, particularly in children. Researchers have noted that adverse neurological outcomes, such as declines in cognitive and motor function, are associated with occupational exposures and environmental exposures among people who have been exposed to the metal at high levels.

There are currently no point-of-care sensors to detect manganese, and subjects participating in epidemiological research have had to wait up to nine months to receive results when they send samples to central laboratories, Ian Papautsky, a professor of bioengineering at the UIC College of Engineering and a principal investigator on the grant, said in an interview.

That was too long for ongoing research initiated in 2009 by Erin Haynes, a professor of environmental health at the University of Cincinnatti, that is examining the levels of manganese in the blood of children near a ferromanganese refinery in Marietta, Ohio, owned by Eramet Marietta.

"The community was concerned about emissions from the facility," said Haynes, who is a second principal investigator on the NIH grant for development of the point-of-care test. "Parents were eager to know if manganese was affecting their kids."

In a study published in 2017 in the journal Science of The Total Environment, Haynes and her colleagues used structural equation modeling to examine routes of exposure to manganese among children residing near the firm's refinery. They said that the results provide a potential framework for understanding the inhalation exposure pathway for children exposed to ambient air manganese, who live in proximity to an industrial emission source.

In addition to soil and air contamination, well water can be contaminated with high levels of manganese, researchers have previously noted.

Point-of-care tests, such as those being developed by Papautsky and Haynes "would be extremely valuable for many parts of the world…where manganese concentrations in well water can be orders of magnitude higher than the suggested limit set by the World Health Organization," Samantha Ying, a lead author and assistant professor of environmental sciences in the University of California, Riverside's College of Natural and Agricultural Sciences, said in an interview.

Because of the presence of high levels of manganese, especially at shallow depths, underground drinking water sources in parts of the US and three Asian countries may not be as safe as previously thought, according to a study conducted by Ying and her colleagues at UCR and Stanford University, published last year in Environmental Science & Technology.

According to Haynes, the NIH-sponsored point-of-care tests could also provide a way to speed up testing and treatment. Central labs conducting testing on samples use inductively coupled plasma mass spectrometry (ICPMS), which ionizes the sample and then uses a mass spectrometer to separate and quantify the ions.

In their research project, labs required around 50 samples before they would run a test, Haynes said. Part of the delay came from being able to collect only a few samples per week until they had enough to send to the lab. If a patient attends a clinic, they can get a result in 24 hours, because clinics order large enough volumes of tests, she said, but the process is quite different for people doing research.

Further, although the researchers were sending 5 milliliter tubes to the central labs, which are smaller than samples normally used in central lab testing, the volume of blood still made it difficult to do repeat testing on the children in the near term, the researchers noted. Getting a single drop of blood from a child is a lot easier, Papautsky said.

Prior to the current award, Papautsky, Haynes, and colleagues had received two NIH grants totaling more than $2 million to begin and continue developing a diagnostic device, based on point-of-care sensors, to assess the presence of manganese in subjects' samples. Since 2010, they have developed and tested the proof-of-concept prototype on around 12 samples and found that the platform had performance levels that match that of central lab testing, Papautsky said.

The recent award permits broader validation of the point-of-care platform and assay by enabling testing of an extended range of samples from 150 children recruited from southeast Chicago neighborhoods, and the researchers aim to validate the diagnostic platform by comparing its results with those obtained from matching blood samples sent for traditional lab processing.

By expanding the study to Chicago, the researchers are also tracking the activities of a company operating in both Ohio and Illinois. Although Haynes and her colleagues began their epidemiological work in Marietta, they found a second facility in East Liverpool, Ohio, owned by SH Bell that had high levels of manganese in the air near its facility.

They conducted a study of the impact of air manganese on child neurodevelopment in East Liverpool and published it in NeuroToxicology last year, reporting that IQ scores for children aged 7 to 9 were negatively associated with elevated levels of manganese found in their systems.

The US Environmental Protection Agency in August 2017 issued a notice of violation against SH Bell for excessive manganese emissions from the company’s facility in southeast Chicago. "The NIH-sponsored project is focused on testing children that live near that SH Bell facility," Haynes said.

The point-of-care device uses a sensing approach based on electrochemistry. In a 2017 study published in Electroanalysis, Papautsky and his colleagues described the development of the device, a microscale electrochemical sensor with platinum thin film electrodes for analysis of manganese in water.

The researchers reported that the sensor enables on-site monitoring of manganese in environmental samples when it is coupled with portable instrumentation, and it could be used for biological samples with appropriate sample preparation.

Central to its operation, Papautsky said, is a one-centimeter-squared sensor chip that consists of electrodes. A portable potentistat controls current in the sensor, and a tablet enables reading results.

"A combination of buffers leads to deposits of manganese ions on a working electrode," Papautsky said. Using a technique called stripping voltammetry, the researchers bias the electrode to attract metal ions from the sample. By changing the electric potential, the system converts manganese metal to metal ions, and during the phase transition, the material donates electrons that generate current. The system recognizes current peaks and produces a curve on an electronic reader, whose amplitude reflects the concentration of metal deposited from the sample onto the electrode.

The researchers are investigating using the platform to also detect lead, and to detect both manganese and lead in water as well as in blood.

Being able to quickly detect high concentrations of these heavy metals would enable quicker and more effective treatment of subjects and accelerate remediation efforts to remove the metals from the environment, Papautsky said.

The study conducted by Ying and her colleagues describes manganese levels that exceed guidelines in groundwater wells in Bangladesh, Cambodia, China, and the Glacial Aquifer, which spans 26 states in the northern US and provides drinking water to more than 41 million Americans.

In particular, people in south, southeast, and east Asia, such as central China, who are exposed to such high levels of manganese are in rural areas where access to clinics or other facilities that can draw large amounts of blood safely are unavailable, Ying said, adding that "a more portable unit that only requires a drop of blood would facilitate monitoring."

"Some families are likely drinking from wells that have extremely high manganese concentrations and have no idea the well is contaminated," Ying said.

Papautsky, Haynes, and their co-researchers anticipate eventually launching a CLIA-waived blood test available in doctors' clinics. Their vision is to also produce a portable device made available to test levels of metals in water in homes.

Other than validating the platform under the NIH grant, the researchers will work to integrate several parts of the system — the chip on which a drop of blood or water is placed, the equipment that sends current through the chip to separate out the metal, software to process the results, and the user interface that displays the results.

"In terms of licensing our technology versus establishing a startup to launch a product and take it through regulatory review, we are considering both options," Papautsky said.

Ultimately, they want the sensor to be easy for anyone to use and the results easy to interpret, and to make disposable sensors available at about $10 each, Papautsky said.

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