From University of California-Berkeley (US): “Diamonds engage both optical microscopy and MRI for better imaging”

From University of California-Berkeley (US)

May 17, 2021
Robert Sanders
Media relations

The microdiamonds used as biological tracers are about 200 microns across, less than one-hundredth of an inch. They fluoresce red but can also be hyperpolarized, allowing them to be detected both optically — by fluorescence microscopy — and by radio-frequency NMR imaging, boosting the power of both techniques. Photo courtesy of Ashok Ajoy.

When doctors or scientists want to peer into living tissue there’s always a trade-off between how deep they can probe and how clear a picture they can get.

With light microscopes, researchers can see submicron-resolution structures inside cells or tissue, but only as deep as the millimeter or so that light can penetrate without scattering. Magnetic resonance imaging (MRI) uses radio frequencies that can reach everywhere in the body, but the technique provides low resolution — about a millimeter, or 1,000 times worse than light.

A University of California, Berkeley, researcher has now shown that microscopic diamond tracers can provide information via MRI and optical fluorescence simultaneously potentially allowing scientists to get high-quality images up to a centimeter below the surface of tissue 10 times deeper than light alone.

By using two modes of observation, the technique also could allow faster imaging.

The technique would be useful primarily for studying cells and tissue outside the body, probing blood or other fluids for chemical markers of disease, or for physiological studies in animals.

“This is perhaps the first demonstration that the same object can be imaged in optics and hyperpolarized MRI simultaneously,” said Ashok Ajoy, UC Berkeley assistant professor of chemistry. “There is a lot of information you can get in combination, because the two modes are better than the sum of their parts. This opens up many possibilities, where you can accelerate the imaging of these diamond tracers in a medium by several orders of magnitude.”

The technique, which Ajoy and his colleagues report this week in the journal PNAS, utilizes a relatively new type of biological tracer: microdiamonds that have had some of their carbon atoms kicked out and replaced by nitrogen, leaving behind empty spots in the crystal — nitrogen vacancies — that fluoresce when hit by laser light.

Ajoy exploits an isotope of carbon — carbon-13 (C-13) – that occurs naturally in the diamond particles at about 1% concentration, but also could be enriched further by replacing many of the dominant carbon atoms, carbon-12. Carbon-13 nuclei are more readily aligned, or polarized, by nearby spin-polarized vacancy centers, which become polarized at the same time they fluoresce after being illuminated with a laser. The polarized C-13 nuclei yield a stronger signal for nuclear magnetic resonance (NMR) — the technique at the heart of MRI.

The crystal lattice of a microdiamond contains gaps — nitrogen vacancies — that can be polarized (red spinning balls) and made to emit red light when illuminated by a laser. The polarized centers then hyperpolarize nearby carbon-13 atoms (blue balls), allowing them to be detected by NMR imaging. This allows the tracers to be imaged both by optical fluorescence microscopy and NMR, providing higher resolution pictures deeper inside tissue. UC Berkeley graphic by Xudong Lv and Mustafa Kamran.

As a result, these hyperpolarized diamonds can be detected both optically — because of the fluorescent nitrogen vacancy centers — and at radio frequencies, because of the spin-polarized carbon-13. This allows simultaneous imaging by two of the best techniques available, with particular benefit when looking deep inside tissues that scatter visible light.

“Optical imaging suffers greatly when you go in deep tissue. Even beyond 1 millimeter, you get a lot of optical scattering. This is a major problem,” Ajoy said. “The advantage here is that the imaging can be done in radio frequencies and optical light using the same diamond tracer. The same version of MRI that you use for imaging inside people can be used for imaging these diamond particles, even when the optical fluorescence signature is completely scattered out.”

Detecting nuclear spin

Ajoy focuses on improving NMR — a very precise way of identifying molecules — and its medical imaging counterpart, MRI, in hopes of lowering the cost and reducing the size of the machines. One limitation of NMR and MRI is that large, powerful and costly magnets are needed to align or polarize the nuclear spins of molecules inside samples or the body so that they can be detected by pulses of radio waves. But humans can’t withstand the very high magnetic fields needed to get lots of spins polarized at once, which would provide better images.

Emanuel Druga and Xudong Lv with a prototype “hyperpolarizer” for diamond particles (on table). They are standing next to a 9-tesla NMR machine. Credit: Ashok Ajoy.

One way to overcome this is to tweak the nuclear spins of the atoms you want to detect so that more of them are aligned in the same direction, instead of randomly. With more spins aligned, called hyperpolarization, the signal detected by radio is stronger, and less powerful magnets can be used.

In his latest experiments, Ajoy employed a magnetic field equivalent to that of a cheap refrigerator magnet and an inexpensive green laser to hyperpolarize the carbon-13 atoms in the crystal lattice of the microdiamonds.

“It turns out that if you shine light on these particles, you can align their spins to a very, very high degree — about three to four orders of magnitude higher than the alignment of spins in an MRI machine,” Ajoy said. “Compared to conventional hospital MRIs, which use a magnetic field of 1.5 teslas, the carbons are polarized effectively like they were in a 1,000-tesla magnetic field.”

When the diamonds are targeted to specific sites in cells or tissue — by antibodies, for example, which are often used with fluorescent tracers — they can be detected both by NMR imaging of the hyperpolarized C-13 and the fluorescence of the nitrogen vacancy centers in the diamond. The nitrogen vacancy-center diamonds are already becoming more widely used as tracers for their fluorescence alone.

In the researchers’ experiment, diamond particles arranged in a ring were imaged both optically and with magnetic resonance imaging (MRI). Credit: Ashok Ajoy.

“We show one important cool feature of these diamond particles, the fact that they spin polarize — therefore they can glow very bright in an MRI machine — but they also fluoresce optically,” he said. “The same thing that endows them with the spin polarization also allows them to fluoresce optically.”

The diamond tracers also are inexpensive and relatively easy to work with, Ajoy said. Together, these new developments could, in the future, allow for an inexpensive NMR imaging machine on every chemist’s benchtop. Today, only large hospitals can afford the million-dollar price tag for MRIs. He currently is working on other techniques to improve NMR and MRI, including using hyperpolarized diamond particles to hyperpolarize other molecules.

The experiments were led by former graduate student Xudong Lv using a home-built hyperpolarizer device constructed by staff scientist Emanuel Druga. Ajoy’s work was supported by the Office of Naval Research (N00014-20-1-2806). Other co-authors are F. Wang, A. Aguilar, T. McKnelly, R. Nazaryan and L. Wu of UC Berkeley; J. H. Walton of University of California-Davis (US); O. Shenderova of Adamas Nanotechnologies Inc., in North Carolina; D. B. Vigneron of Univerity of California-San Fransisco (US); Carlos Meriles of City University of New York (US); and professor of chemical and biomolecular engineering Jeffrey Reimer and chemistry professor Alexander Pines, both of UC Berkeley.

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The University of California-Berkeley is a public land-grant research university in Berkeley, California. Established in 1868 as the state’s first land-grant university, it was the first campus of the University of California (US) system and a founding member of the Association of American Universities (US). Its 14 colleges and schools offer over 350 degree programs and enroll some 31,000 undergraduate and 12,000 graduate students. Berkeley is ranked among the world’s top universities by major educational publications.

Berkeley hosts many leading research institutes, including the Mathematical Sciences Research Institute and the Space Sciences Laboratory. It founded and maintains close relationships with three national laboratories at DOE’s Lawrence Berkeley National Laboratory(US), DOE’s Lawrence Livermore National Laboratory(US) and DOE’s Los Alamos National Lab(US), and has played a prominent role in many scientific advances, from the Manhattan Project and the discovery of 16 chemical elements to breakthroughs in computer science and genomics. Berkeley is also known for student activism and the Free Speech Movement of the 1960s.

Berkeley alumni and faculty count among their ranks 110 Nobel laureates (34 alumni), 25 Turing Award winners (11 alumni), 14 Fields Medalists, 28 Wolf Prize winners, 103 MacArthur “Genius Grant” recipients, 30 Pulitzer Prize winners, and 19 Academy Award winners. The university has produced seven heads of state or government; five chief justices, including Chief Justice of the United States Earl Warren; 21 cabinet-level officials; 11 governors; and 25 living billionaires. It is also a leading producer of Fulbright Scholars, MacArthur Fellows, and Marshall Scholars. Berkeley alumni, widely recognized for their entrepreneurship, have founded many notable companies.

Berkeley’s athletic teams compete in Division I of the NCAA, primarily in the Pac-12 Conference, and are collectively known as the California Golden Bears. The university’s teams have won 107 national championships, and its students and alumni have won 207 Olympic medals.

Made possible by President Lincoln’s signing of the Morrill Act in 1862, the University of California was founded in 1868 as the state’s first land-grant university by inheriting certain assets and objectives of the private College of California and the public Agricultural, Mining, and Mechanical Arts College. Although this process is often incorrectly mistaken for a merger, the Organic Act created a “completely new institution” and did not actually merge the two precursor entities into the new university. The Organic Act states that the “University shall have for its design, to provide instruction and thorough and complete education in all departments of science, literature and art, industrial and professional pursuits, and general education, and also special courses of instruction in preparation for the professions”.

Ten faculty members and 40 students made up the fledgling university when it opened in Oakland in 1869. Frederick H. Billings, a trustee of the College of California, suggested that a new campus site north of Oakland be named in honor of Anglo-Irish philosopher George Berkeley. The university began admitting women the following year. In 1870, Henry Durant, founder of the College of California, became its first president. With the completion of North and South Halls in 1873, the university relocated to its Berkeley location with 167 male and 22 female students.

Beginning in 1891, Phoebe Apperson Hearst made several large gifts to Berkeley, funding a number of programs and new buildings and sponsoring, in 1898, an international competition in Antwerp, Belgium, where French architect Émile Bénard submitted the winning design for a campus master plan.

20th century

In 1905, the University Farm was established near Sacramento, ultimately becoming the University of California, Davis. In 1919, Los Angeles State Normal School became the southern branch of the University, which ultimately became the University of California, Los Angeles. By 1920s, the number of campus buildings had grown substantially and included twenty structures designed by architect John Galen Howard.

In 1917, one of the nation’s first ROTC programs was established at Berkeley and its School of Military Aeronautics began training pilots, including Gen. Jimmy Doolittle. Berkeley ROTC alumni include former Secretary of Defense Robert McNamara and Army Chief of Staff Frederick C. Weyand as well as 16 other generals. In 1926, future fleet admiral Chester W. Nimitz established the first Naval ROTC unit at Berkeley.

In the 1930s, Ernest Lawrence helped establish the Radiation Laboratory (now DOE’s Lawrence Berkeley National Laboratory (US)) and invented the cyclotron, which won him the Nobel physics prize in 1939. Using the cyclotron, Berkeley professors and Berkeley Lab researchers went on to discover 16 chemical elements—more than any other university in the world. In particular, during World War II and following Glenn Seaborg’s then-secret discovery of plutonium, Ernest Orlando Lawrence’s Radiation Laboratory began to contract with the U.S. Army to develop the atomic bomb. Physics professor J. Robert Oppenheimer was named scientific head of the Manhattan Project in 1942. Along with the Lawrence Berkeley National Laboratory, Berkeley founded and was then a partner in managing two other labs, Los Alamos National Laboratory (1943) and Lawrence Livermore National Laboratory (1952).

By 1942, the American Council on Education ranked Berkeley second only to Harvard University (US) in the number of distinguished departments.

In 1952, the University of California reorganized itself into a system of semi-autonomous campuses, with each campus given its own chancellor, and Clark Kerr became Berkeley’s first Chancellor, while Sproul remained in place as the President of the University of California.

Berkeley gained a worldwide reputation for political activism in the 1960s. In 1964, the Free Speech Movement organized student resistance to the university’s restrictions on political activities on campus—most conspicuously, student activities related to the Civil Rights Movement. The arrest in Sproul Plaza of Jack Weinberg, a recent Berkeley alumnus and chair of Campus CORE, in October 1964, prompted a series of student-led acts of formal remonstrance and civil disobedience that ultimately gave rise to the Free Speech Movement, which movement would prevail and serve as precedent for student opposition to America’s involvement in the Vietnam War.

In 1982, the Mathematical Sciences Research Institute (MSRI) was established on campus with support from the National Science Foundation and at the request of three Berkeley mathematicians — Shiing-Shen Chern, Calvin Moore and Isadore M. Singer. The institute is now widely regarded as a leading center for collaborative mathematical research, drawing thousands of visiting researchers from around the world each year.

21st century

In the current century, Berkeley has become less politically active and more focused on entrepreneurship and fundraising, especially for STEM disciplines.

Modern Berkeley students are less politically radical, with a greater percentage of moderates and conservatives than in the 1960s and 70s. Democrats outnumber Republicans on the faculty by a ratio of 9:1. On the whole, Democrats outnumber Republicans on American university campuses by a ratio of 10:1.

In 2007, the Energy Biosciences Institute was established with funding from BP and Stanley Hall, a research facility and headquarters for the California Institute for Quantitative Biosciences, opened. The next few years saw the dedication of the Center for Biomedical and Health Sciences, funded by a lead gift from billionaire Li Ka-shing; the opening of Sutardja Dai Hall, home of the Center for Information Technology Research in the Interest of Society; and the unveiling of Blum Hall, housing the Blum Center for Developing Economies. Supported by a grant from alumnus James Simons, the Simons Institute for the Theory of Computing was established in 2012. In 2014, Berkeley and its sister campus, Univerity of California-San Fransisco (US), established the Innovative Genomics Institute, and, in 2020, an anonymous donor pledged $252 million to help fund a new center for computing and data science.

Since 2000, Berkeley alumni and faculty have received 40 Nobel Prizes, behind only Harvard and Massachusetts Institute of Technology (US) among US universities; five Turing Awards, behind only MIT and Stanford; and five Fields Medals, second only to Princeton University (US). According to PitchBook, Berkeley ranks second, just behind Stanford University, in producing VC-backed entrepreneurs.

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