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UCSC, BYU Team Developing 'Ultrasensitive' Optofluidic Antigen Test for SARS-CoV-2, Flu


NEW YORK – Last fall as fears of a double whammy of COVID-19 and the flu sent shivers through the healthcare community, diagnostic test developers such as Quidel and Roche brought to market assays capable of detecting influenza A and influenza B, as well as SARS-CoV-2.

Those fears never materialized, though, as lockdowns, social distancing, and mask wearing drove down the number of flu cases to historic lows during the 2020-2021 influenza season.

But with what to expect during the next flu season unclear — and an equally muddy picture of how the pandemic will play out during the next flu season — combo COVID-19/flu tests could be in high demand during the next fall and winter. Against this backdrop, a research team from the University of California, Santa Cruz and Brigham Young University is poised to unveil its own technology to differentiate influenza from SARS-CoV-2.

Led by Holger Schmidt, a professor of electrical and computer engineering at UCSC, the team is developing a chip-based test intended to identify both the flu viruses and SARS-CoV-2 from a single sample.

The technology, described in a paper published in Proceedings of the National Academy of Sciences earlier this month, combines microfluidics and integrated optics for optical analysis of single molecules on a chip and is based on antiresonant reflecting optical waveguides.

In the study, the researchers said they dropped two kinds of mechanical beads, one with antibodies for detecting influenza A antigens and one with antibodies for detecting SARS-CoV-2 nucleocapsid proteins, into nasal samples from the UCSC diagnostic laboratory to extract the antigens. After the beads bonded to individual antigens, Schmidt and his colleagues used bright fluorescent markers connected to a secondary antibody specific to one of the viruses to tag each antigen. Ultraviolet light was then run through the sample to release the fluorescent markers, Schmidt said.

From there, the sample liquid was then dropped onto the chip, which has small fluidic channels through which the fluorescent markers flow. The markers were hit with light from a laser beam run through an optical wave guide, and the light was captured by a photodetector, Schmidt said. Every marker that showed up via the detector was one specific type of antigen, coded by color — green for flu, red for SARS-CoV-2.

While the sample prep for this test was performed in test tubes off the chip, with the fluorescent markers added before the sample was put onto the chip, Schmidt said it would also be possible to perform every part of the process directly on a chip system. According to the paper, the optofluidic chip could be "integrated with a programmable microfluidic sample preparation chip in order to create a single, chip-scale system for rapid sample-to-answer analysis."

Doing sample prep on the chip would allow users to process larger input volumes and run those volumes through a chip to extract the needed molecules, which could then be run through the optofluidic chip at smaller volumes.

Although the team used nasal swab samples for its experiment, Schmidt noted that any kind of bodily fluid could be used, including serum and whole blood.

The technology was originally developed for use in fundamental physics, with the idea of guiding light through atomic vapors with particular properties, Schmidt said. But the researchers, who also included a group from Brigham Young University, realized that the chip could be filled with liquid and used for health and life sciences which "turned out to be the much bigger and more useful area, potentially." The team was working on adapting it for the Zika virus, but then pivoted to COVID-19 with support from the US National Institutes for Health. It has also used the technology to detect Ebola RNA.

The chip's multilayer structure has mirrors built around the liquid channel to keep the light inside. The hollow light guides are integrated with solid ones that can be used to bring the outside light source from the laser to the channel and create "very small" optical light volumes through which molecules can travel. This enables users to see each individual molecule and conduct amplification.

Adapting the technology for use with proteins was more difficult than detecting DNA and RNA molecules, Schmidt said: RNA and DNA are "quite long" and can have many fluorescent markers stuck on them to easily pick up the light, while proteins are much smaller and harder to see.

The researchers noted in the paper that "single-protein detection had remained elusive up to now because, unlike nucleic acids and virions, it was challenging to label individual targets with a sufficient number of fluorophores" for detection.

One of the challenges was to develop a new fluorescent marker to detect those smaller proteins. The marker is a hybrid between an antibody to detect a specific antigen and labeled DNA, and developing the marker was "one of the key things" to be able to directly see single antigens, according to Schmidt.

Being able to detect single antigens has led to "very high" specificity, with no false counts in the negative controls, he said, adding the sensitivity is on the lower end of the point of detection of the clinically relevant range for viral loads, with the possibility of further optimizing the test and getting the sensitivity to an even lower point. According to the paper, detection was reported at 30 ng/mL.

Brian Cunningham, a professor in the department of electrical and computer engineering at the University of Illinois at Urbana-Champaign who edited the team's paper, said the approach was seeking to overcome the "poor sensitivity" of conventional SARS-CoV-2 antigen tests that use paper test strips. He added that the optofluidic method "is simpler than a PCR test and more sensitive than a paper test strip."

There are additional steps to be taken before the test would be ready for commercial sale, such as determining the cutoff for what antigen load signifies a clinically relevant positive or negative result. But that will be the job of regulatory bodies and the startup company, Fluxus, which Schmidt is involved with, that has begun prototyping instruments to use with the chip and licensed the patents for the technology from Schmidt and his partner at BYU, Aaron Hawkins.

Peter Wagner, Fluxus' cofounder and CEO, said the company is "at a late stage product development phase," and noted that the eventual products will consist of an instrument, consumables, reagents, and software. He said that each user setting, including high volume in vitro diagnostic laboratories, research labs, and point-of-care settings, would need a different system configuration, although it would be based on the same core technology.

Wagner declined to comment on Fluxus' regulatory plans. He said the firm's commercialization strategy is "based on strategic partnerships with multinational corporations that are considered market leaders in the respective fields," although he declined to elaborate.

He said the company's target markets are IVD settings, clinical researchers, and life sciences researchers, "as well as food safety, agriculture, environmental testing, and others."

Cunningham said the approach could "be applied toward detection of nearly any protein for which a selective set of capture and detection antibodies have already been developed."

According to Wagner, the technology addresses key unmet needs in biomarker testing, including the insufficient limits of detection for clinical applications where biomarkers are at low concentrations, or sample sizes are limited, and fragmentation of bioanalytical instrumentation which requires a different instrument for each type of test.

Cunningham also noted there is "quite a lot of competition in this area with many novel approaches inspired by the needs revealed by the COVID-19 pandemic," including those based on optical detection and electronics-based detection, novel molecular biology methods that "overcome some of the limitations of PCR" for detecting nucleic acid targets specific to different viruses. He said there are also methods being developed for detecting intact viable viruses.

The technology can be applied even beyond infectious diseases, with Schmidt saying it could look for cancer biomarkers and "anything with liquid" in the health and diagnostic spaces.