A Renaissance For NMRs, Big And Small

In the field of nuclear magnetic resonance (NMR) spectroscopy, bigger and more expensive have always meant better. Although that maxim is still true, a new generation of companies contends that smaller benchtop or even handheld NMRs can do much of the yeoman’s work of identifying molecular structures that room-sized NMRs do.

Makers of the smaller tools—firms such as Magritek; Thermo Fisher Scientific, which purchased start-up picoSpin in 2012; Nanalysis; T2 Biosystems; and WaveGuide—don’t expect their modestly priced machines will replace expensive high-field instruments tricked out with cryo-cooled magnets and separate operator consoles. But aided by modern electronics, improvements in permanent magnet design, and advances in software, compact-NMR makers say their small tools will become more commonplace over the next five years.

What’s more, makers of smaller NMRs say their tools will be accessible to more than just scientists skilled at using the traditional machines. Expect to see the new instruments, they say, in quality-control and teaching applications, under lab hoods monitoring reactions and verifying samples, and in hospitals diagnosing disease.

As for the two surviving makers of the larger, more complex NMRs, Bruker and JEOL, they say modern electronics and magnet design are driving development of their instruments as well. Agilent Technologies shut down its money-losing NMR operation in 2014.

Magnets are at the heart of NMR. Placed in a magnetic field, carbon- and hydrogen-containing samples give up their structural secrets when they are interrogated with pulsed radio frequencies using Fourier transform methods. Pulses of a single radio frequency are used to interrogate molecular structure in time-domain techniques.

Rare-earth-based permanent magnets have made possible compact benchtop NMRs, whereas their larger brethren use powerful helium-cooled magnets to provide more detailed information at higher magnetic fields.

Industry observers see a developing NMR landscape in which large and small machines will coexist. “An application like protein structure determination requires large and expensive high-field NMRs, and therefore they will persist,” says Stan Sýkora, an Italy-based physicist and NMR expert. “But if an application can be handled with a lower-field less costly machine, then why not?

“Simply put, the application is what matters; the instrument is secondary,” Sýkora adds. “If I were to start a company today to build an NMR, I would ask myself ‘What for?’ and not ‘What kind?’ ”

Many benchtop-NMR makers have already determined that their machines are good for the education market, points out Mark Dixon, a Thermo Fisher product manager. Small NMRs such as the firm’s picoSpin line “are plug-and-play systems for an educator” to help undergraduates get hands-on experience in analyzing samples.

But Dixon sees many other applications that suit small NMRs. A new accessory for the picoSpin line allows academic researchers and small laboratory operators to monitor chemical reactions in real time, he says.

Technology advances have made the new machines possible. “Electronics in cell phones were the inspiration behind benchtop NMRs,” Dixon explains. Whereas the big NMRs are often built with bulky printed circuit boards, the smaller NMRs depend on miniature components such as microchips and flash memory modules, he points out.

Improvements in permanent rare-earth magnets also allow makers of portable NMRs to build compact instruments that don’t have the complex magnet cooling requirements of their larger brethren. But permanent magnets currently remain limited to magnetic fields of less than 100 MHz, Dixon points out. By comparison, big helium-cooled NMRs with fields exceeding 1 GHz are now under development.

Those limitations explain the difference between the benchtop NMRs and the larger instruments. “High-field NMRs are environmentally sensitive, sophisticated to operate, and very expensive,” says Andrew Coy, chief executive officer of New Zealand-based Magritek, which makes the Spinsolve line of benchtop NMRs.

The high-field instruments excel at elucidating the structure of large molecules such as proteins typically exceeding 1,000 daltons, Coy explains. The lower magnetic fields of the smaller instruments make them more suitable to the analysis of molecules of less than 1,000 Da, he says.

Although the big high-field instruments can be set up for many different experiments, the benchtop machines are “more relevant for quick routine measurements,” Coy notes. Simpler design and intuitive software make the benchtop instruments easy to use.

“People will purchase benchtop NMRs to solve two or three specific problems,” Coy predicts.

“The market for NMR is evolving in part because of the benchtop instruments,” says Garett Leskowitz, chief technology officer of the Canadian firm Nanalysis. The education market is the “low-hanging fruit” for simple-to-use NMRs such as Nanalysis’s NMReady line of benchtops, he says.

But quality analysis and control are also developing markets, Leskowitz says. Makers of portable Raman and near-infrared spectrometers “should see us as the new competition,” he says.

NMR users have long had to line up to use high-field instruments at a specialized university center or send samples out to a commercial lab. Such delays now can be avoided, Leskowitz says, by using no-wait benchtop machines for routine analysis. As a bonus, costs to use the benchtops are much lower, he points out.

The benchtops from Thermo Fisher, Magritek, and Nanalysis all use Fourier transform techniques to characterize samples, as do the larger high-field NMRs.

Other benchtops use time-domain techniques, often for specific diagnostic tests. Among them are machines from nine-year-old T2 Biosystems, based in Lexington, Mass., which has developed a Food & Drug Administration-approved NMR diagnostic unit and test for candida fungal infections in the blood. The firm’s technology, developed by scientists at Massachusetts General Hospital and Massachusetts Institute of Technology, including Priestly Medal winner Robert Langer, is based on the activity of water molecules in a magnetic field.

According to Tom Lowery, the firm’s chief scientific officer, magnetic nanoparticles coated with an analyte-specific binding agent are mixed with a blood sample and placed in the firm’s benchtop T2Dx. The particles bind to and cluster around the pathogen, changing the microenvironment of water and altering the magnetic resonance signal. After a three-hour concentration and amplification step, a reading reveals the presence of candida, he says.

An alternative to blood cultures, which take up to five days for results, T2’s test identifies positive results 91% of the time, Lowery says. Blood cultures only do so 50 to 60% of the time, he says. The firm is now selling the system to hospitals.

Enabling the NMR reading, he adds, is a proprietary permanent magnet “about the size of a Rubik’s Cube” producing a field of 23 MHz. In addition, the firm is developing tests for pathogens associated with sepsis and Lyme disease.

Also using time-domain techniques, but for a handheld diagnostic device, is WaveGuide. Like T2 Biosystems, WaveGuide will rely on binder-coated magnetic particles to test for diseases such as tuberculosis in sputum or whole blood, says Nelson Stacks, CEO of the Cambridge, Mass.-based firm. Specifics on how the test will work are not available.

But the technology behind WaveGuide’s device is a tiny chip-based relaxometer, which measures relaxation of nuclear spin, from the lab of Donhee Ham, a Harvard University physics professor.

WaveGuide has so far raised $27 million from angel investors and has created a number of prototypes. The firm plans to hire staff and rent lab space soon to develop them.

Whereas WaveGuide is relatively new to time-domain-enabled NMR, Bruker, more often thought of as a maker of large high-field NMRs, has been active with time-domain-based benchtop NMRs for about 40 years. Many of them are targeted at specific quality-control and analysis applications, says Stefan Jehle, an applications scientist with the firm.

For instance, the firm’s minispec mq Toothpaste Analyzer measures fluorine content in toothpaste. The minispec mq7.5 Large Seed Analyzer characterizes seed oil and moisture content. “A dedicated system is cost-effective and reduces subjectivity while also speeding analysis,” Jehle says.

Bruker says it is developing a line of Fourier-transform-based benchtop NMRs, but they are not yet ready for the market. A spokesman says that “we are interested in new markets and applications.”

And Bruker is certainly interested in expanding its large-NMR offerings. It continues to develop superconducting magnets capable of operating at 1.2 GHz and plans to deliver them to customers starting next year. The largest magnet Bruker has installed to date operates at 1.0 GHz.

Although the government funding to pay for larger systems is in short supply, Clemens Anklin, vice president for NMR applications at Bruker, says they are needed to push advances in materials research, structural biology, and intrinsically disordered proteins.

So the firm has vowed to develop the new high-temperature superconducting wire that will enable higher field systems. Anklin notes that the firm owns a superconducting materials business, allowing it to stay on top of the effort to push ultra-high-field NMR.

Trying a bit of one-upmanship on Bruker, large-NMR competitor JEOL says it has plans for a spectrometer capable of operating at 1.3 GHz. The firm is collaborating on the development of a 1.3-GHz magnet with the Japan Science & Technology Agency, the National Institute for Materials Science of Japan (NIMS), and other partners. In July, the group said it successfully built a 1.02-GHz NMR magnet.

Michael Frey, a product manager for JEOL, says the firm has redesigned the electronics built into its NMRs to include “state-of-the-art digital and radio-frequency designs to greatly improve NMR experiment flexibility and data collection.” The improvements include high-speed signal and pulse generators and receivers, he says.

These advances not only have improved the instruments’ reliability but also have helped shrink the footprint of operator consoles by more than 20%, Frey says. The firm is also offering the upgraded consoles to owners of Agilent and Bruker magnets.

JEOL’s traditional strengths are in small-molecule characterization, Frey says. But the firm is now increasing its efforts “in all areas of NMR, including bio-NMR, real-time NMR, and cold probe development,” he says.

Although JEOL plans to be aggressive in big NMRs, it is leaving the development of benchtop systems to others. But whether for big or small systems, consultant Sýkora says, improvements in NMR electronics, magnets, and software have been profound.

Those improvements are not just enabling bigger and better tools for the high priests of academic science. They are also making possible simple and useful NMR gear for everyday students, bench chemists, and quality-control technicians.