May 16, 2024 | Science and technology have moved up the appearance of a high-performance point-of-care mass spectrometer to a near-term possibility, which would make it both cheaper and more convenient to monitor chronic health conditions from just about anywhere a 3D printer could be deployed—including the jungle, Antarctica, and future colonies on Mars. Researchers at the Massachusetts Institute of Technology (MIT) began from scratch on building the required hardware about a decade ago, led by Luis Fernando Velásquez-García, a principal research scientist in MIT’s Microsystems Technology Laboratories.
The critical components under development include an ionizer to give molecules in blood an electric charge before they’re analyzed, a mass filter to sort the ions based on their mass-to-charge ratio, and a vacuum pump to remove background gas molecules that would interfere with the measurement process, he says. The MIT team has already made impressive progress on the first two 3D-printed parts and continues to work on the third piece.
Most recently, they reported on an ionizer that performs twice as well as its state-of-the-art counterparts in terms of signal strength while also being more stable and less expensive (Journal of the American Association for Mass Spectrometry, DOI: 10.1021/jasms.3c00409). This comes on the heels of a study (Advanced Science, DOI: 10.1002/advs.202307665) showing how they used 3D printing to create a high-performance mass filter in the shape of “hyperbolic” chains that maximize filtering and doing so within hours versus months and for about $10 rather than $10,000.
Velásquez-García and his colleagues have a background in the fabrication of semiconductor devices, which over the past several decades has hugely improved society and individual quality of life, he notes. Since more could be done with semiconductors once they were miniaturized, the notion of a portable mass spectrometer inevitably arose.
But their attention turned to additive manufacturing because it seemed better matched to the task—and solving many of the world’s other most pressing engineering problems, Velásquez-García says. Not only are semiconductors expensive but their utility is pretty much limited to the making of transistors.
Additive manufacturing enables almost anyone to create highly complex part shapes from a variety of materials, and its seemingly limitless potential helped spawn an entirely new industry, points out Velásquez-García. Coupled with miniaturization, 3D printing can deliver small but highly intricate objects but in mass fabrication volume despite being made one batch at a time.
The technology has piqued the attention of the Empiriko Corporation, a point-of-care diagnostics company that has supported the work of the MIT team for years now. Portable mass spectrometers currently exist on the market but are manufactured using semiconductor technology where performance has been sacrificed with device downsizing, Velásquez-García says.
Mass spectrometry is the gold standard for chemical analysis because it is based on physical principles instead of a sensor and is “a lot harder to fool,” he continues. With sensors (e.g., capacitors), “you can get a signal and not know exactly what is triggering it.”
Matter is comprised of a certain number of elements that can only have certain weights, as determined by an allowable number of protons and neutrons, Velásquez-García explains. There are many possible combinations “but they are not infinite.” That greatly reduces the possibility of being misled.
Full-size mass spectrometers are expensive and require user expertise to produce reliable and valuable results. The innovation being attempted here, he says, is 3D printing an entire compact mass spectrometer that is affordable and can deliver a high level of performance with as few operational constraints as possible.
“This is really just a way to democratize technology,” says Velásquez-García, drawing a contrast with semiconductors where 90% of the chips used worldwide are produced in Taiwan. “If something happens to that island, we’re in big trouble.”
With additive manufacturing, no one country controls what is made. Products can be created just about anywhere simply by transmitting a file to a 3D printer, he says.
Traditionally, an “electrospray” technique is used to apply a high voltage to a liquid sample before a thin jet of charged particles is fired into the mass spectrometer. The more ionized the particles, the more accurate the measurement, explains Velásquez-García. The new-and-improved electrospray emitter produced by MIT researchers employs a standard 3D printing method known as binder jetting whereby a blanket of powdered material gets showered with a polymer-based glue squirted through tiny nozzles to build a stainless-steel object layer by layer.
After getting heated in an oven, the printed emitters undergo an electropolishing step. Finally, each device is coated conformally with zinc oxide nanowires that Velásquez-García likens to a glove covering all the surfaces of a hand. The “nanowire forest” resembles tiny hairs but are 1,000 times thinner than the human variety and give the emitter a level of porosity that enables it to effectively transport liquids.
The emitters were designed as solid cones with a specific angle that leverages evaporation to restrict the flow of liquid so that the sample spray contains a higher ratio of charge-carrying molecules, he continues. The size and shape of the counter-electrode that applies voltage to the sample was also optimized to prevent arcing of the electrodes so the voltage could be safely increased. A printed circuit board, with built-in digital microfluidics, enabled the ionizer to efficiently transport droplets of liquid.
In combination, these optimizations resulted in an electrospray emitter that could operate at a voltage 24% higher than state-of-the-art versions. This is what enabled their device to more than double the signal-to-noise ratio.
Semiconductor-based devices are fine for straightforward problems, such as estimating the blood-alcohol content of suspected drunk drivers by having them blow into a breathalyzer, Velásquez-García offers as an example. It’s “a whole different ballgame” with marijuana and misuse of prescription drugs, where a mass spectrometry capability is required to get reliable results.
With 3D printing, portable mass spectrometry devices can be predictably produced as personalized, one-of-a-kind products at a low cost because neither injection molding nor subtractive manufacturing is required, he says. A printer creates objects using tiny blocks called voxels (essentially 3D pixels) whether it’s making a visor clip or a reproduction of a multi-million-dollar masterpiece.
Printing of the vacuum pump, so ions can be electromagnetically manipulated without any background interferences, has been the main holdup in the creation of an entire compact mass spectrometer, he adds. The pump represents just a fraction of the cost of a mass spectrometer but is vital since it creates the necessary operating conditions.
“If I were going to do a startup on this technology tomorrow, I’d use the hardware that we have developed and pair it with what currently exists for the other components,” Velásquez-García says. “My guess is that it would be a better value proposition than what we currently have,” adding that startups currently building miniaturized mass spectrometers don’t underperform because of the pumps.
A small and inexpensive mass spectrometer would have potential utility across a range of industries, says Velásquez-García. One might be put in homes and buildings to lower the energy demands of warming up cold air or lowering humidity levels by knowing the precise indoor environmental conditions, for instance. They might similarly be placed in medical offices so diagnostic analyses can be done in situ rather than outsourced to a network of labs. For the pharmaceutical, food, and oil industries, mass spectrometry is widely embraced for process control purposes to ensure what companies intend to manufacture is what’s in fact being made.
For the portable mass spectrometer, getting from the proof-of-concept stage to having a successful product will take more than the required components, he says. A “compelling business model” is also needed given that all the legacy, chip-based devices are more expensive than full-sized machines and grossly underperform. “But for the sake of diagnostics I think a point-of-care technology that you can rely on is closer than we think.”
The expertise of the Empiriko Corporation includes mimicking the way the human body metabolizes drugs via a synthetic liver and personalized diagnostics, says Velásquez-García. If anyone is thinking about commercializing a 3D-manufactered point-of-care mass spectrometer it’s likely Empiriko, which jointly owns the intellectual property for some of the hardware with MIT but would undoubtedly need to retain the products’ inventors as consultants.
If that comes to pass, and the hardware is simple to use as well as clinically reliable, people with chronic diseases might one day soon have the means to monitor their need for and response to treatments from the comfort of home, he says. Chronic diseases currently consume the lion’s share of healthcare expenses and better addressing them would leave more money in the pot for other pressing health needs.