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UCLA Team Uses Magnets, Microfluidics to Create Handheld Molecular Dx System


NEW YORK – After the COVID-19 pandemic revealed limits in diagnostic testing capacity, a team of researchers from the University of California, Los Angeles set out to address the issue and have developed a handheld 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 sample needed to run a test and automates the test to "reimagine robotics in the framework of microfluidics," said Sam Emaminejad, a professor of electrical and computer engineering at UCLA who helped develop the system. While multiple diagnostic companies, such as Scope Fluidics and Standard BioTools (formerly Fluidigm), have products based on microfluidics that move fluid around, a challenge in the microfluidics field is keeping instruments from becoming large and unwieldy, Emaminejad said. Rather than being a "lab-on-a-chip," microfluidic devices can instead become a "chip in the lab," and often aren't particularly scalable or accessible, he said. 

Robotics are also used in many laboratories, particularly for pipetting or other sample preparation steps, but they are bulky and difficult to use in non-laboratory settings, so when developing their device the researchers wanted to figure out a way to integrate robotics into the system without increasing the size. They decided to use magnetic nanoparticles, combined with tiny mobile magnets they call ferrobots, to move different liquids around a circuit board to conduct diagnostic tests. Dino Di Carlo, a fellow UCLA professor of engineering and member of the development team, said that the researchers were able to find a nanoparticle that can magnetize a sample but doesn't interfere with polymerase reactions. 

The device's development and application to COVID-19 testing is described in a paper published in Nature last week.

To use the device, the team adds magnetic nanoparticles to a sample and places a small drop onto a microfluidic chip, which is then put on a circuit board that controls electromagnetic coils with the ferrobots sandwiched in between, according to the Nature paper. Once the test begins, the ferrobots are moved by the coils and magnetically draw the sample drops along with them, allowing the ferrobots to move the sample, split it into sections, merge with other reagents, or mix the sample, depending on the test. For a single SARS-CoV-2 test, the sample is aliquoted to obtain a controlled volume and moved into a reaction chamber containing reagents for a loop-mediated isothermal amplification test and then heated so 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 aren't very magnetic and couldn't be moved with regular electromagnetic coils. By adding the ferrobots to the device, the magnetic field is strengthened and the sample droplets can be moved around.

In the Nature paper, the team used a colorimetric readout to determine a positive or negative result, but Di Carlo said that the readout could be changed to a fluorescent or electrochemical readout 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 ensure there was no interference with the magnets, he noted. 

Beyond just an individual test with one sample, the device can also perform multiplexed tests and tests using pooled samples, Emaminejad said. Pooled testing gained increased interest from laboratories and diagnostic test developers during the height of the COVID-19 pandemic, since testing capacity was strained and demand was high, but conducting pooled testing is "onerous" for laboratory technicians, Emaminejad said. 

The device developed by him and his colleagues is able to test up to 16 samples at a time. If that pooled test is positive, the samples are divided into a matrix of four rows and four columns and tested again – when a particular row and column is positive, it indicates that a specific patient sample at the intersection of the row and column is positive.

For a multiplexed assay that is testing for different diseases, such as a respiratory virus panel, a sample is divided, and each part is sent into a reaction chamber with a different LAMP solution correlating to the virus for which it's being tested. The researchers use existing LAMP assays, such as those from New England Biolabs and other diagnostic developers, so there's no need to create their own, Di Carlo said. The team's strategy is to determine how it can "leverage the assays that are already in existence."  

The development of handheld molecular diagnostic devices for infectious disease testing has seen a boom since the COVID-19 pandemic began, and multiple companies have instruments in varying stages of commercialization. For example, German diagnostics firm Midge Medical recently received CE marking for its "palm-size, fully digital integrated rapid test system" called Minoo and a SARS-CoV-2 test, which detects the virus via reverse-transcriptase recombinase polymerase amplification. MatMaCorp, a Nebraska-based diagnostics company, has developed its My Real-Time Analyzer for qPCR testing, and Austin, Texas-headquartered startup Nuclein is aiming to commercialize its disposable handheld PCR system.

Visby Medical, meantime, has raised more than $230 million in private financing to support the development of additional tests on its single-use handheld PCR device. The San Jose, California-based company received Emergency Use Authorization from the US Food and Drug Administration for its SARS-CoV-2 test in February 2021 and nabbed 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 key innovations in their device is the ability to handle very small liquid volumes via the microfluidics so 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 COVID-19 samples the researchers tested for the Nature study, their device missed one PCR-positive sample, leading to a sensitivity of 98 percent and specificity of 100 percent. 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 device's development, said that the field has struggled when developing small microfluidics platforms because it is hard to "get [fluids] to move around in small quantities but in a reliable way." Someone may have a small microfluidic chip, but the need for fluid pumps and readout instruments means that the "size of the instrument grows very rapidly." 

The device developed by the UCLA team, he said, addresses this "fundamental problem" in a "very elegant, simple, and scalable manner." The next step is to demonstrate the test works reliably for the indicated use, whether that's a doctor's office, urgent care clinic, pharmacy, or retail setting, he said. If it does work, 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 increasing interest from potential partners since the publication of the Nature paper, Di Carlo said. However, he added that they're not yet sure what path the commercialization will take – whether the technology will be licensed to another company, or whether they'll start their own firm to take the device public. The intellectual property is owned by 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 setting, and potentially at home. The emphasis right now is to gather more data to translate the device into clinical settings, and he said that the researchers hope to take advantage of the world's renewed emphasis on diagnostic testing. The team must also address some engineering challenges before the system can make its commercial debut, such as improving the interface and making the platform more user friendly, he said. 

Although the first application of the device has been for SARS-CoV-2 testing, Emaminejad said that the team is considering what "key diseases could uniquely benefit" from cheap and easy testing and focusing on "where it's needed most urgently." Di Carlo added that the researchers are working on further multiplexing for broader panels for a range of applications, including infectious diseases. 

"Using magnetic forces to move droplets of fluid has been around but it has never been implemented in a way that was actually robust," Di Carlo said. This new method "has enabled a lot of new opportunities."