NEW YORK — After the COVID-19 pandemic exposed the limits of diagnostic testing capability, a team of researchers from the University of California, Los Angeles set out to solve the problem and developed a portable diagnostic system using miniaturized robotics and microfluidics in an attempt to make molecular testing cheaper and more accessible.
The device minimizes the volume of reagents and samples needed to run an assay and automates the assay to “reimagine robotics within the framework of microfluidics,” said Sam Emaminejad, professor of electrical and computer engineering at UCLA who helped develop the system. While several diagnostic companies, such as Scope Fluidics and Standard BioTools (formerly Fluidigm), offer microfluidics-based products that move fluids, a challenge in the field of microfluidics is to keep instruments from becoming large and cumbersome, Emaminejad said. Rather than being a “lab on a chip,” microfluidic devices can instead become a “chip in the lab,” and are often not particularly scalable or accessible, he said.
Robotics are also used in many laboratories, especially for pipetting or other sample preparation steps, but they are cumbersome and difficult to use outside of laboratories. So when developing their device, the researchers wanted to find a way to integrate robotics into the system. without increasing the size. They decided to use magnetic nanoparticles, combined with tiny moving magnets they call ferrobots, to move different liquids around a circuit board to perform diagnostic tests. Dino Di Carlo, a UCLA engineering professor and member of the development team, said the researchers were able to find a nanoparticle that can magnetize a sample but doesn’t interfere with polymerase reactions.
The development and application of the device to COVID-19 testing is described in an article published in Nature Last week.
To use the device, the team adds magnetic nanoparticles to a sample and places a small drop on a microfluidic chip, which is then placed on a circuit board that controls the electromagnetic coils with the ferrobots sandwiched in between. , according to Nature paper. Once the test begins, the ferrobots are moved by the coils and magnetically attract the sample drops with them, allowing the ferrobots to move the sample, divide it into sections, merge with other reagents, or mix the sample. sample, depending on the test. For a single SARS-CoV-2 test, the sample is aliquoted to a controlled volume and moved into a reaction chamber containing reagents for an isothermal loop amplification test, then heated so that the reaction can take place, which usually takes about 30 minutes.
The presence of the ferrobots is essential, Di Carlo said, because the nanoparticles in the sample are not very magnetic and could not be moved with ordinary electromagnetic coils. By adding the ferrobots to the device, the magnetic field is strengthened and the sample droplets can be moved.
In the Nature paper, the team used a colorimetric reading to determine a positive or negative result, but Di Carlo said the reading could be changed to a fluorescent or electrochemical reading depending on the test.
The device is sample-agnostic and can be used with a variety of different fluids, including saliva and nasal swabs in transport media, Emaminejad said. The researchers also tested samples with different ionic compositions, such as varying pH levels, to make sure there was no interference from the magnets, he noted.
Beyond just individual testing with one sample, the device can also perform multiplexed testing and testing using pooled samples, Emaminejad said. Pooled testing attracted increased interest from labs and diagnostic test developers at the height of the COVID-19 pandemic as testing capacity was stretched and demand was high, but achieving group testing is “onerous” for lab technicians, Emaminejad said.
The device developed by him and his colleagues is capable of testing up to 16 samples at a time. If this pooled test is positive, the samples are split into a four-row, four-column matrix and retested – when a particular row and column are positive, this indicates that a specific patient sample at the intersection of the row and column is positive.
For a multiplexed test that tests for different diseases, such as a panel of respiratory viruses, a sample is split and each part is sent to a reaction chamber with a different LAMP solution that correlates to the virus it is being tested for. The researchers use existing LAMP tests, such as those from New England Biolabs and other diagnostics developers, so there’s no need to create their own, Di Carlo said. The team’s strategy is to figure out how it can “leverage the tests that already exist.”
The development of portable molecular diagnostic devices for infectious disease testing has boomed since the onset of the COVID-19 pandemic, and several companies have instruments in various stages of commercialization. For example, German diagnostics company Midge Medical recently received CE marking for its “palm-sized fully digital integrated rapid test system” called Minoo and a SARS-CoV-2 test, which detects the virus by amplification by recombinase polymerase reverse-transcriptase. MatMaCorp, a Nebraska-based diagnostics company, has developed its real-time analyzer for qPCR testing, and Austin, Texas-based startup Nuclein aims to bring its disposable handheld PCR system to market.
Meanwhile, Visby Medical has raised more than $230 million in private funding to support the development of additional tests on its portable single-use PCR device. The San Jose, Calif.-based company received emergency use authorization from the U.S. Food and Drug Administration for its SARS-CoV-2 test in February 2021 and was granted 510(k) clearance. ) from the agency for a multiplex test to detect Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis in August 2021.
Both Emaminejad and Di Carlo noted that one of the main innovations of their device is the ability to handle very small volumes of liquid via microfluidics so that smaller volumes of reagents can be used in each test, resulting in cost savings. There’s also no peripheral machinery required, so the footprint is smaller than many other instruments, Emaminejad said. Of the 100 clinical samples of COVID-19 that the researchers tested for the Nature study, their device missed a positive PCR sample, leading to 98% sensitivity and 100% specificity. Di Carlo noted that the sample missed by their device was also negative when tested with an RT-LAMP test outside of the device.
Mehdi Javanmard, a professor of electrical and computer engineering at Rutgers University who was not involved in the development of the device, said the field has struggled to develop small microfluidic platforms because it is difficult to “get [fluids] to move in small quantities but reliably.” Someone may have a small microfluidic chip, but the need for fluid pumps and reading instruments means that “the size of the instrument grows very rapidly.”
The device developed by the UCLA team, he said, solves this “fundamental problem” in a “very elegant, simple and scalable way”. The next step is to demonstrate that the test works reliably for the intended use, whether it is a doctor’s office, urgent care clinic, pharmacy or retail. retail, he said. If it works, the device would be a “game changer” for future pandemic preparedness and the diagnostics industry, he said.
The researchers intend to commercialize the device and have seen growing interest from potential partners since the publication of the Nature paper, says Di Carlo. However, he added that they are not yet sure what path commercialization will take – whether the technology will be licensed to another company or whether they will start their own company to take the device to the public. The intellectual property belongs to UCLA and patents have been filed, he noted.
Emaminejad said he sees the device being used at the point of care, such as a clinic, retail or pharmacy, and potentially at home. The focus is now on collecting more data to translate the device to a clinical setting, and he said researchers hope to take advantage of the world’s renewed emphasis on diagnostic testing. The team also needs to address some engineering challenges before the system can make its commercial debut, such as improving the interface and usability of the platform, he said.
Although the device’s first application was for testing SARS-CoV-2, Emaminejad said the team is considering which “key diseases could uniquely benefit” from cheap and easy testing and is focusing on “where it is most urgent”. Di Carlo added that researchers are working on additional multiplexing for larger panels for a range of applications, including infectious diseases.
“The use of magnetic forces to move fluid droplets exists, but it has never been implemented in a really robust way,” Di Carlo said. This new method “allowed many new opportunities”.
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