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What does the crystal signify?

Weizmann Institute of Science scientists have developed nanocrystals of calcium fluoride which can be used as a marker in MRI scans, and enable the detection of inflammatory conditions in the body in early stages 

Fluorite crystal - the mineral is mentioned in writings from the 16th century, is used, among other things, for ornamental purposes and is considered one of the most colorful minerals in the world. Photo: Rob Lavinsky, iRocks.com – CC-BY-SA-3.0
Fluorite crystal - the mineral is mentioned in writings from the 16th century, is used, among other things, for ornamental purposes and is considered one of the most colorful minerals in the world. Photo: Rob Lavinsky, iRocks.com – CC-BY-SA-3.0

It all started with a beautiful picture in the book: a photograph of a purple crystal known as fluorite, whose spectacular color caught the eye of Dr. Amnon Bar-Shir From the Department of Organic Chemistry at the Weizmann Institute of Science. The impressive crystal, which is composed of the elements calcium and fluorine, reminded Dr. Bar-Shir, who studies magnetic resonance imaging (MRI), of the conventional wisdom that fluorine-based markers may enable higher resolution MRI scans.

Despite the promise inherent in fluorine-containing materials for MRI applications, the idea of ​​using a fluorite (calcium fluoride) crystal does not seem promising at first glance. Due to its solid crystalline structure, it would be expected that it would not be seen in the MRI machine, since this machine maps signals of soft tissues, fluids, or small soluble molecules. The main clinical use of it is for imaging the water molecules in our body; Or, to be precise, images of the hydrogen atoms in water whose nuclear spins are adjusted under the influence of the device's strong magnet. Fluorine atoms return a nuclear magnetic signal very similar to that of hydrogen atoms in water, although they do so at a different frequency. Therefore, fluorine-based markers are in principle suitable for use in the existing systems.

From the right: Dr. Amnon Bar-Shir, Dr. Hila Elosh-Arnon and Dr. Idan Ashur. It all started with a beautiful picture in the book
From the right: Dr. Amnon Bar-Shir, Dr. Hila Elosh-Arnon and Dr. Idan Ashur. It all started with a beautiful picture in a book

Unlike water, fluorine does not exist naturally in the soft tissues of the body. Therefore, injecting a fluorine-based tracer into a target organ or tissue may give a high-quality image without the "background noise" of the water. But, as mentioned, in order to create a signal in an MRI scanner, the marker must be liquid, or, in the words of Dr. Bar-Shir: "It must be able to move around its axis in solution freely, that is, without the mobility limitation of a normal solid."

"Then a crazy idea popped into my head," recalls Dr. Bar-Shir. "What if it were possible to produce calcium fluoride nanocrystals that would be small enough so that they could move around their axis at high speed, thus giving them the mobility needed to generate their own unique MRI signal?" As is the way of far-reaching thoughts, the idea remained "on a small fire", while Dr. Bar-Shir turned to look for other, more accessible directions for the development of research in the field of magnetic resonance. But when Dr. Idan Ashur came to Dr. Bar-Shir's laboratory, the idea popped up again. "Dr. Ashur has never worked with MRI or any biological imaging before," says Dr. Bar-Shir. "But he had a lot of experience in a very relevant field in this case - the creation of nanoparticles. We agreed that he would try my 'impossible' idea - magnetic resonance imaging with calcium fluoride nanocrystals, and that if it didn't work, he would be free to move to another lab."

In the end, Dr. Ashur did not have to look for another laboratory, because the results were nothing short of amazing: the tiny nanocrystals he created from calcium fluoride returned strong MRI signals when placed in a solution in a test tube. The crystals, four or five nanometers in diameter, were apparently small enough to move in solution around their axis and produce a signal.

Nanocrystals for detecting inflammation

Following the success, the research team, in collaboration with the post-doctoral researcher Dr. Hila Elosh-Arnon, turned to adapting the nanocrystals for biological imaging. To this end, the researchers applied technology from the field of the pharmaceutical industry, which is used to extend the life cycle of small drug molecules or nanoparticles for injection. The method, pegylation, involves coating nanoparticles with a biologically adapted material called polyethylene glycol (or PEG for short), which increases their stability in a biological substrate.

Admittedly, creating coated nanocrystals involves a complex process, but in the end it turned out to be worthwhile. After the researchers injected the new nanocrystal into mice, they were able to map and locate extensive inflammatory processes in the lymph nodes in an intact animal. Another study showed that the nanocrystals were "swallowed" and transported to the lymph nodes by macrophages - cells of the immune system that serve as the body's "cleaning team". When an inflammatory process takes place in the body, there are many macrophages in the bloodstream, and thanks to their large number, the lymph nodes were highlighted in the MRI scan.

In follow-up experiments, the research team tested other fluorine-based compounds, and showed that they can also be used in the form of nanocrystals. For example, they created nanocrystals of strontium fluoride, and found that their MRI signal was different from that of calcium fluoride crystals. Taking advantage of this fact, and by using two types of nanocrystals, the researchers were able to create multi-colored images; In this way, it will be possible in the future to monitor several biological targets at the same time. The results of these experiments were published recently in the scientific journal applied Chemistry.

A calcium fluoride nanocrystal as seen under an electron microscope (right) and a schematic illustration of a pegylated nanocrystal (left)
A calcium fluoride nanocrystal as seen under an electron microscope (right) and a schematic illustration of a pegylated nanocrystal (left)
A calcium fluoride nanocrystal as seen under an electron microscope (right) and a schematic illustration of a pegylated nanocrystal (left)

One impossible idea - many possible applications

Contrast agents specially designed for detecting early stages of inflammation may serve as a basis for powerful diagnostic tools in various pathological conditions, including outbreaks of diseases such as Alzheimer's, Parkinson's, multiple sclerosis, and even cancer. Theoretically, it is also possible to attach additional molecules to the nanocrystals, such as antibodies directed against specific cell types, thereby further expanding the capabilities of MRI. The nanocrystals themselves may also pave new ways in material engineering, as they have properties of both solid crystals and small molecules.

"As far as I know, this is the first time that magnetic resonance signals have been received from elements inside nanocrystals when they are in solution," says Dr. Bar-Shir. "We went with the initial impossible idea all the way, until we demonstrated its effectiveness in living tissue."

"ידע", the applications arm of the Weizmann Institute of Science, is working with Dr. Bar-Shir's research group to translate this technology into commercial use.

The diameter of a calcium fluoride nanocrystal (about 5 nm) is 44,000,000 times smaller than a football, and contains about 25,000 fluorine atoms.

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