DNA sample processing required for viral surveillance and many other biotechnology-based diagnostics can be quite similar to how packages are moved around in warehouses—both are time-consuming and labor-intensive work. In increasingly futuristic warehouses, robots the size of maintenance hole covers operationalize the movement of large and heavy packages that workers used to push manually through areas of fulfillment and sort centers, converting batch-based manual work into continuous, automated processes.
“If you think about microfluidic samples as packages that need to be processed through fixed workflows, we can reimagine the way robotics can help with diagnostics,” said Sam Emaminejad, PhD, associate professor of electrical & computer engineering at the University of California, Los Angeles (UCLA).
Emaminejad and a team of UCLA researchers have developed a technology utilizing a swarm of millimeter-sized magnets as mobile robotic agents (“ferrobots”) for precise and robust control of magnetized sample droplets and high-fidelity delivery of flexible workflows. Within a palm-sized printed circuit board-based programmable platform, various laboratory equivalent operations can execute nucleic acid amplification tests to overcome the limitations of liquid handling techniques.
“We can use magnetic robotic agents as a way of handling and processing the samples for us, rather than using one very expensive robotic arm to perform this process one sample at a time, which is not scalable,” said Emaminejad, who is a co-senior author for the article, “Ferrobotic swarms enable accessible and adaptable automated viral testing,” published in Nature.
Stopping viral spread in its tracks
The speed at which we can track a virus directly relates to the spread of a pandemic. At the onset of COVID-19, the lack of rapid, inexpensive, and automated diagnostics simply didn’t exist to take on the mass amount of tests needed to understand how the disease was sprawling. And for nucleic acid amplification-based viral testing, many steps need to be performed by a qualified technician, which is burdensome and one of the reasons test results aren’t quickly delivered. These tests are also inefficient and wasteful, requiring relatively large amounts of reagents. This is critical when it comes to pandemics, especially in the beginning when the disease being tested for is unknown.
While there are ways we can maximize the efficiency of testing through pooling, Emaminejad says that if the standard workflow for a single sample is already too much for a technician, it won’t be possible to ask that technician to process and handle a larger number of samples. And the instruments they use are bulky and incredibly expensive, requiring installation and maintenance costs. “But robotic solutions have not been able to meet our diagnostic needs,” said Emaminejad. “So, to perform complex workflows like pooled testing, we thought that miniaturizing would handle large samples and minimize the reagents.”
Mini biocompatible robotic agents
One of the goals of the microfluidics field has been to automate laboratory operations at tiny scales. One of the problems of previous approaches was centered around how to move, split, or merge droplets around at small scales—less than a microliter. “The approach we came up with using magnets relies on making magnetic droplets sizeable that magnetic fields can manipulate,” said co-senior author Dino Di Carlo, PhD, professor of bioengineering at UCLA.
Di Carlo said that the key challenges that the team was able to break through were identifying biocompatible magnetic droplets and a means to move them with magnetic fields. “One challenge is that doing assays in droplets for nucleic acid testing can be interfered with by magnetic particles,” said Di Carlo. “[A few years ago], we found a drug that’s a magnetic nanoparticle used for patients with an iron deficiency that’s a great carrier for making biocompatible droplets to perform all sorts of reactions. But, since these particles are so small—like 10 to 20 nm—they don’t have much magnetic force. So, we used electromagnets to move little magnets, which we call ‘ferrobots,’ that can drag droplets around.”
The ferrobotic testing platform that the UCLA researchers devised consists of two modules (entirely constructed by low-cost components): (1) a disposable oil-filled microfluidic chip with passive and active actuation interfaces that hosts input samples and ferrofluid or assay reagents and (2) a printed circuit board, featuring 2D arrayed coils (“navigation floor”), which can be independently activated to electromagnetically direct individual ferrobots. Before inputting the samples into the ferrobotic testing platform, samples are dropped into a multi-well plate, and a little magnetic droplet touches the sample to magnetize it. Then the sample can be inserted into the system with pipetting.
But once it’s in the platform, all sorts of operations, from splitting and pooling to colorimetric and electrochemical reading, can be done to a sample. By changing the microfluidic device design, the printed circuit board, and the analytical algorithm, all sorts of complex operations can be tested.
Parallelization and serialization
The UCLA researchers also were able to demonstrate parallelization—moving many of the ferrobots to do things at the same time. “If you think about some of the diagnostic applications, you don’t have patients coming in all simultaneously; you can streamline the patient samples, getting them processed and keep things moving,” said Di Carlo. “We envision a patient in your pharmacy or minute clinic comes in, and you can start a new reaction thread on your ferrobotic system while the others are still running.”
While the technology is a feat of engineering, both Emaminejad and Di Carlo point to the sophistication of the pooled testing algorithms they implemented. “The pooled algorithm is a demonstration of a very complex set of operations in a robust way because to do that, you can’t make a mistake in the splitting or mixing operations,” said Di Carlo. “So, it demonstrates the scale of operations that can be done in diagnostic applications and beyond. You might have processes where you take parts of samples, perform tests, and then go back to the sample and do something else.”
Emaminejad added that viral prevalence testing requires sophisticated pooling techniques, which require many operations. “Even with your dream robotic system, you cannot perform the number of operations needed for low prevalence pooled testing,” said Emaminejad. “But all of these operations are being performed on our chip.”
Ferrobotics is a promising solution to expand testing capacity for pandemic preparedness and reimagine the future automated clinical laboratory. “It’s time to decentralize testing,” said Emaminejad. “Instead of ‘point-of-care,’ we need to think about ‘point-of-person’ testing wherever people are, bringing easily translated diagnostics to people in hospitals, workplaces, schools, pharmacies, and airports and testing right on the spot. You need to know you can handle many samples to test at scale.”