Light, electricity, heat, and magnetism are all important physical quantities involved in life science measurements, with optical imaging being the most widely used. With the continuous development of technology, optical imaging, especially fluorescence imaging, has greatly expanded the horizon of biomedical research. However, optical imaging is often limited by the background signal in biological samples, the instability of fluorescence signal, and the difficulty of absolute quantification, which to some extent restrict its application. Magnetic resonance imaging (MRI) is a good alternative and has a wide range of applications in some important life science scenarios, such as the examination of cranial, neurological, muscle, tendon, joint, and abdominopelvic organ lesions, due to its penetrating, low background and stability characteristics. Although MRI is expected to address the above-mentioned shortcomings of optical imaging, it is limited by low sensitivity and low spatial resolution, making it difficult to apply to imaging at the tissue level with micron to nanometer resolution.
An emerging quantum magnetic sensor developed in recent years, the nitrogen-vacancy (NV) center, a luminescent dot defect in diamond, NV center-based magnetic imaging technology enables the detection of weak magnetic signals with resolution up to the nanometer level and is non-invasive. This provides a flexible and highly compatible magnetic field measurement platform for the life sciences. It is unique for conducting tissue-level studies and clinical diagnostics in the fields of immunity and inflammation, neurodegenerative diseases, cardiovascular diseases, biomagnetic sensing, magnetic resonance contrast agents, and especially for biological tissues containing optical backgrounds, and optical transmission aberrations, and requires quantitative analysis.
Diamond NV-center Magnetic Imaging Technology
There are two main types of diamond NV-center magnetic imaging technology: scanning magnetic imaging and wide-field magnetic imaging. Scanning magnetic imaging is combined with the atomic force microscopy (AFM) technique, which uses a diamond single-color center sensor. The imaging method is a single-point scanning type of imaging, which has a very high spatial resolution and sensitivity. However, the imaging speed and imaging range limit the application of this technique in some areas. Wide-field magnetic imaging, on the other hand, uses a tethered diamond sensor with a high concentration of NV centers compared to a single NV center, which has reduced spatial resolution but shows great potential for wide-field, real-time imaging. The latter may be more appropriate for research in the field of cellular magnetic imaging.
NV center Wide-field Magnetic Imaging Technology in Cell Research
Application 1: Magnetic imaging of magnetotactic bacteria
The magnetotactic bacterium is a class of bacteria that can move directionally under the action of an external magnetic field and form magnetic nanoparticles (magnetosomes) in their bodies, mainly in soil, lakes, and oceans.
By placing the bacteria on a diamond surface and using optical methods to probe the quantum spin state of the NV center, researchers can quickly reconstruct images of the magnetic field vector components generated by the magnetosomes in the bacteria. Wide-field magnetic imaging microscopy allows simultaneous optical and magnetic imaging of multiple cells at submicron resolution and large fields of view. This work provides a new approach to imaging the biomagnetic structure within living cells under high spatial resolution conditions and will enable the mapping of a wide range of magnetic signals within cells and cellular networks.
Figure 1. Magnetic Imaging of Magnetotropic Bacteria
(Image credits: D. L. Stage et al. Optical magnetic imaging of living cells Nature, 2013, 496(7446): 486-489)
Application 2: Magnetic imaging of macrophage iron uptake
The main function of macrophages is to phagocytose (i.e., phagocytose as well as digest) cellular debris and pathogens in the form of fixed or free cells, and to activate lymphocytes or other immune cells to respond to pathogens. Macrophages are immune cells with multiple functions and are important objects for the study of cytophagy, cellular immunity, and molecular immunology.
Diamond NV center-based wide-field magnetic imaging with submicron resolution and nanotesla sensitivity was used by the researchers to image magnetic fields in cells and tissues of mouse animals, as shown in Figure 2. The utility of the technique was demonstrated by observing macrophage iron uptake and detecting iron overload in the liver tissue samples using mice as a model. In addition, the investigators detected endocytosis of magnetic particles in living cells. This approach bridges the gap between MRI voxels and their microscopic components.
Figure 2. Magnetic imaging study of macrophage iron uptake
(Image credits: H. C. Davis et al. Mapping the microscale origins of magnetic resonance image contrast with subcellular diamond magnetometry, Nature Communications, 2018, 9:131)
Application 3: Magnetic imaging of immunomagnetic labeled cells
Cancer is currently one of the most deadly diseases in humans. Research on the molecular mechanism of cancer and early & accurate clinical diagnosis are the basis for effective treatment.
Figure 3. Magnetic imaging study of lung cancer tissue
(Image credits: S. Y. Chen et al. Immunomagnetic microscopy of tumor tissues using quantum sensors in diamond, Proc. Natl. Acad. Sci. USA, 2022,119: e2118876119)
The University of Science and Technology of China (USTC) has developed a tissue-level immunomagnetic labeling method. Superparamagnetic particles were specifically labeled with target protein molecules such as PD-L1 in tumor tissues by specific recognition of antigen-antibody. Then, the tissue samples were closely attached to the diamond surface, and a layer of NV center distributed near the surface of the diamond at about one hundred nm was used as a two-dimensional quantum magnetic sensor for magnetic field imaging on a 400 nm resolution NV wide-field microscope (Figure 3), achieving micron-level spatial resolution in a millimeter field of view. Finally, the magnetic moment distribution corresponding to the magnetic field was reconstructed by a deep learning model to provide a basis for quantitative analysis.
The Harvard Smith Center for Astrophysics has used immunomagnetic labeling techniques with NV wide-field magnetic imaging. A comparison of magnetic imaging of cancer cells with healthy cells was made to characterize the utility of this imaging technique, which provides an important tool for biomedicine in the field of cellular detection.
Figure 4. Magnetic imaging study of immunomagnetic labeled cells
(Image credits: D. R. Gleen et al. Single-cell magnetic imaging using a quantum diamond microscope, Nature Methods, 2015, 12(8): 736-738.)
Application 4: Magnetic imaging of cellular ferritin
In addition to the aforementioned wide-field magnetic imaging techniques, researchers have also studied cellular magnetic imaging using NV center scanning magnetic imaging. In 2019, the USTC Key Laboratory of Microscopic Magnetic Resonance did a study on ferritin in cells. First, the researchers used a high-pressure freeze-freeze alternative method to instantly fix and embed live cells, then the cells were dissected by slicing and the surface was trimmed to nanoscale flatness using an ultrathin sectioning technique based on a diamond knife. At this point, the proteins present inside the cells are exposed to the cell dissection and can come into close contact with the diamond sensor. By scanning the sample, the researchers observed the ferritin present in the organelles inside the cell with a resolution of 10 nm.
Figure 5: NV center scanning magnetic imaging study of ferritin cells
(Image credits: P.F.Wang et al. Nanoscale magnetic imaging of ferritins in a single cell, Science advances, . 2019;5: eaau8038)
CIQTEK Quantum Diamond Series Products
CIQTEK has both Quantum Diamond Microscope and Quantum Diamond Atomic Force Microscope (AFM), and both devices can realize quantitative and non-destructive microscopic magnetic field imaging.
The Quantum Diamond Microscope has a high spatial resolution (400 nm), large field of view (1 mm*1 mm), and fast imaging speed, which is widely used in life science, geological research, chip detection, and other fields.
Quantum Diamond Microscope
The Quantum Diamond AFM with a high spatial resolution (10 nm), high sensitivity (1 T/Hz1/2), compatible with room temperature atmosphere and ultra-high vacuum environment, mainly used in magnetic domain imaging, two-dimensional materials, topological magnetic structure, superconducting magnetism, and other fields.
Quantum Diamond AFM (room temperature version, cryogenic version)