Characterizing and imaging magnetic nanoparticles by atomic magnetometry by EU Research

A magnetic vision system Magnetic nanoparticles are attracting intense research attention as a means of treating disease, yet they need to be precisely delivered to their targets to be fully effective. Professor Antoine Weis, Victor Lebedev and Vladimir Dolgovskiy tell us about their work in developing a novel imaging method to visualise magnetic fields, research which helps to localise nanoparticles in tissue Magnetometers, devices that measure the strength and orientation of a magnetic field, are increasingly used today across a range of sectors, including fundamental science, bio-medicine, and geo- and spaceexploration. Based at the University of Fribourg in Switzerland, Professor Antoine Weis and his colleagues hold deep expertise in the development of ultra-sensitive magnetometers. “Our core specialism here is making atomic magnetometers, devices that can measure very weak magnetic fields, such as the ones produced by nanoparticles, nanometre-sized magnets,” he outlines. There is a growing need for sophisticated imaging methods that can accurately represent the spatial distribution of magnetic fields, for example in biomedicine. “There has been rapid development over the past ten years regarding the use of magnetic nanoparticles in the field of biomedicine,” explains Professor Weis. “A range of applications have been identified, including using magnetic nanoparticles for targeted cancer therapy.” The idea in this approach is to inject functionalised particles into the bloodstream, which are intended to carry drugs to tumour cells, yet the delivery of these nano-drugs to their target destinations needs to be accurately www.euresearcher.com

assessed if they are to be fully effective. This is where imaging comes into play. With a suitable detection device outside the body, medical professionals can then accurately determine where the particles are inside the body, a research field that Professor Weis is investigating along several lines. “We are doing laboratory experiments, developing prototype detectors that record the magnetic field pattern generated by magnetised

Magnetic field sensing The starting point in this work is the magnetic field source, the nanoparticles themselves. These particles are magnetised in an arbitrary spatial direction, and they then produce a magnetic field with a specific pattern. “This magnetic field pattern can be measured some distance away from the particles, which is key to the noninvasive nature of the method.” says

We’re investigating at which accuracy, sensitivity and spatial resolution our detectors can visualise magnetic nanoparticles, sources of a magnetic field. This means finding out how they are distributed inside an object; what is the smallest amount we can see? nanoparticles,” he says. “From these patterns we can trace back to the particles’ positions inside an object. We’re investigating the accuracy, sensitivity and spatial resolution with which our detectors can localise the magnetic nanoparticles. This means finding out how they are distributed inside an object; what is the smallest amount we can see? The goal in this research is to develop methods to answer such questions.”

Professor Weis. The magnetic field produced by the nanoparticles has a spatial distribution; at each point in space It is described by a vector with three components, Bx, By, and Bz. “Our apparatus allows us to measure each of these components separately. This gives us full information on the magnetic field at a given point in space,” continues Professor Weis. “The idea of the project is that, from the measured strength and

Left image: The magnetic field lines from a magnetised sample intersect a layer of spin-polarised caesium (Cs) atoms. The black arrows represent the magnetic field vectors, the blue and yellow arrows being their respective components along x and y. The magnetic field perturbs the local spin polarisation in a characteristic manner. A homogeneous offset magnetic field (not shown in the figure) applied along x, y or z, allows the selective detection of the field component Bx, By or Bz. The example shown represents the distribution of the By components produced by a sample magnetised along y. Right image: Experimental realisation of the magnetic vision system. The light-emitting square layer of spin-polarised Cs atoms (imaging plane) is produced in a cubic glass cell by optical pumping. Fluorescence from this layer is detected by a camera. The camera images show characteristic patterns presented in the images below. From these intensity distributions one can infer the shape and the amount of magnetic material in the sample.

orientation of the magnetic field, we can then calculate backwards to identify where the (source) particles are located and how many of them are at a given position.” The researchers are developing a magnetic source imaging camera (MSIC) to visualise magnetic field patterns. “In the MSIC, a video camera looks at a cubic glass cell that contains a vapour of caesium (Cs) atoms that are illuminated by a sheet of laser light. The intersection of the laser beam and the cell defines a flat square volume, and the camera detects the fluorescence light emitted by this two-dimensional layer of Cs atoms (imaging plane),” explains Professor Weis. The resonant laser light spin-polarises the atoms, yielding a homogenously dark camera image. Any perturbation of the atoms by a magnetic field produces a brighter, structured pattern on the dark background. From this pattern, which reflects the magnetic field’s spatial distribution, the researchers can then calculate backwards to derive the spatial distribution of the sources that produced the magnetic perturbation. “This source

reconstruction then tells us the shape and strength of the object that produced the field, itself producing the recorded image,” says Professor Weis. Previous approaches to imaging were relatively inefficient, says Professor Weis. “You could move a very small-sized magnetometer over this square, and measure the field point-by-point. You would get the same image, but the procedure would take a very long time,” he outlines. The new sensor, by contrast, makes measurements at thousands of different points simultaneously, a much more performing approach allowing the real-time visualisation of spatial field dynamics.

Medical implications This holds important implications in terms of targeted cancer therapy. If drugcarrying nanoparticles are to be used in cancer treatment, it’s essential that the injected particles are delivered to the tumour and do not accumulate in organs, such as the liver, the spleen, or the kidneys. Patient screening by an MSIC may prove useful in both respects. This research also has a potential

diagnostic application, for example in localising lymph nodes, an important consideration in the treatment of breast cancer. A primary tumour in the breast will spread through the lymph system, which contains nodes, small, millimetresized entities. “Cancer cells moving in the lymph system will accumulate in these lymph nodes, the nodes nearest to the breast, being located in the axilla. When a patient is diagnosed with breast cancer, often doctors will surgically remove the lymph nodes in the axilla, because they may already contain cancer cells that may spread further into the body,” explains Professor Weis. However, not all lymph nodes in the axilla are connected by lymph vessels to the primary tumour. “Sometimes lymph nodes are removed in surgery unnecessarily, which has negative consequences for the patient,” continues Professor Weis. A detector showing doctors which lymph nodes contain tumour cells would therefore be highly beneficial, potentially enabling more precisely targeted treatment. It has been shown that if nanoparticles are injected into a

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tumour, they will follow the same pathway as the cancer cells and accumulate in the lymph nodes, at which point Professor Weis believes that the MSIC could play an important role. “Our camera system will help in localising the affected lymph node using the MRX method illustrated in the bottom figure,” he says. Prior to deploying nanoparticles in hospital applications, questions such as their biocompatibility and the length of time they stay in the body have to be investigated. The MSIC may prove to be useful in this context. While fully aware of the wider potential of their work, Professor Weis and his colleagues are primarily looking to improve the camera and explore its limitations. “We are trying to determine the smallest amount of nanoparticles that we can detect, and we publish our results. We will derive as many results as we can from this research, and try to do as many

proof-of-principle demonstrations as possible. We are also working on refining our algorithms for magnetic source reconstruction from the detected field patterns,” he says. The primary focus at the moment is on methodological developments. “We develop new methods and technologies, and then other people can take up our ideas and push them towards commercialisable devices,” says Professor Weis. “This has happened with our previous demonstration that an array of atomic magnetometers can produce dynamic maps of the magnetic field generated by the beating human heart.” He adds “We are confident that the MSIC method will find its way into the clinical environment. On the other hand, the device is so universal that it can image any magnetic field producing entity, with applications not only in biomedicine, but also in material screening or magnetic microscopy.”

At a glance Full Project Title Characterizing and imaging magnetic nanoparticles by atomic magnetometry Project Objectives Exploiting more than 15 years of expertise with atomic magnetometers (AM), we currently develop devices for imaging the spatial distribution of magnetic nanoparticles (MNPs) using AM detection. One device detects MNPs in fluids via their anharmonic response to a harmonic excitation. The other device images blocked MNPs, whose distribution is inferred from spatiallyresolved detection of their magnetic field. Project Funding Both projects are funded by grants from the Swiss National Science Foundation, viz., Grants No. 200020_162988 “Magnetic particle imaging (MPI) with atomic magnetometers” IZK0Z2_164165 “Atomic fluorescence imaging of magnetic fields using an imaging fiber bundle” Contact Details Project Coordinator, Professor Antoine Weis Physics Department University of Fribourg Chemin du Musée 3 CH-1700 Fribourg T: +41 (0)26 300 90 30 E: antoine.weis@unifr.ch W: physics.unifr.ch/en/page/625/

Dr Victor Lebedev (Left) Dr Vladimir Dolgovskiy (Centre) Professor Antoine Weis (Right)

Left: Anticipated magnitude distributions of the field components Bx, By, Bz (each coded by a specific colour), produced by small samples with magnetisation Mx, My or Mz. Right: Experimentally recorded distributions reproduce well the anticipated patterns.

Professor Antoine Weis got his PhD degree from ETH Zurich. He worked at MPI for Quantum Optics and was Associate Professor at the University of Bonn. Since 1999 he is Full Professor at the University of Fribourg. His current fields of interest are the development, modeling and applications of atomic magnetometers. Dr Victor Lebedev, senior research assistant with research expertise on optical magnetometry and spectroscopy of atoms, plasmas and quantum solids. Dr Vladimir Dolgovskiy, post-doctoral research assistant with background in time/frequency metrology, conducts research on weak magnetic field sensing and imaging.

Spatially-resolved magneto-relaxation (MRX): Time sequence of camera images, produced by magnetised nanoparticles, under conditions of the red-framed pattern in the figure above. The magnetising coil is switched off at t=0. The decay curve represents the characteristic (logarithmic) demagnetisation of the sample over a period of 6 minutes.