The team of Du Jiangfeng of the University of Science and Technology of China uses diamond quantum sensors for cancer diagnosis
With the development of diamond nitrogen-vacancy (NV) center quantum sensors, the team of Academician Du Jiangfeng from the University of Science and Technology of China proposed and experimentally realized the micron-resolution magnetic imaging of tumor tissue in a diamond NV magnetic microscope. Magnetic imaging and quantification of tumor biomarkers were also achieved. This approach opens the door to micron-resolution magnetic resonance imaging of biological tissues and has the potential to impact cancer research and histopathology. The results will be published in the Proceedings of the National Academy of Sciences (PNAS) on February 1.
Disadvantages of traditional imaging techniques
Cancer is one of the most common and serious diseases in humans. Currently, various medical imaging techniques have been widely used in the clinical examination of tumors, and histopathological examination is the gold standard for diagnosing human cancers. Light microscopy is the most common histological examination method. However, commonly used optical microscopy imaging cannot absolutely quantify signal intensity and is often affected by background signal in the tissue.
Furthermore, it is difficult to correlate different optical imaging in the same tissue section, for example HE staining cannot be combined with other optical imaging. Due to its destructive nature, each unique tissue section in imaging mass cytometry is a single-use sample. Therefore, developing a tissue imaging method with excellent performance is still the unremitting pursuit and challenge of biologists and pathologists.
Magnetic resonance (MRI) imaging provides a powerful technique for tumor imaging. Conventional MRI has been widely used for in situ imaging ranging from biological research to clinical diagnosis of cancer. However, its low spatial resolution, such as only 60 micrometers for anatomical imaging at 9.4 T, limits its application in tissue-level imaging.
The recently developed miniature magnetic imaging technique based on diamond nitrogen-vacancy (NV) centers provides a way to break the spatial resolution limit. NV centers, which are nanoscale point defects in diamond, have been proposed as ultrasensitive quantum sensors to realize nanoscale magnetometry. Meanwhile, wide-field magnetic imaging using NV ensembles with submicron resolution is more suitable for detecting large samples.
However, micron-resolution magnetic imaging (or MRI) in biological tissues has not been achieved due to various technical obstacles. In this paper, we combined NV-based wide-field magnetic imaging with immunomagnetic labeling techniques improved by conventional immunocytochemistry (ICC) and immunofluorescence (IF) techniques to establish immunomagnetic microscopy (IMM), a novel method that can be used in approx. A method for imaging cancer biomarkers in tumor tissue at 1-micron cellular resolution and quantifying them using absolute magnetic signals.
Micron Resolution Magnetic Imaging
The researchers built an optical detection magnetic resonance (ODMR) wide-field microscope (Figure. 1A) to enable MRI of tumor tissue by detecting continuous wave (CW) spectroscopy of diamond NV centers (Figure. 1B).
On the top surface of diamond with a density of 2×1012/cm2, the volume of the NV sensor is about 1×1×0.1μm3, and the magnetic field detection sensitivity is about 10μT/√Hz. The spatial resolution is about 1 micron and the field of view (FOV) is 0.5 x 0.5 mm.
The researchers labeled tissue with target membrane proteins with 20-nanometer-sized superparamagnetic nanoparticles (MNPs) and attached the labeled tissue to the diamond surface (Figure 1C). The MNPs are magnetized by an externally applied magnetic field B0 along the NV axis, while the local magnetic field BMNP from the MNPs shifts the peak position of the CW spectrum by the order of γeBMNP (Figure. 1B). The size of BMNPs on the NV center depends on the density of BMNP and the distance from the NV. Typical magnetic signals of MNPs in cells and tissues are around 20 μT, which can be detected by this device. By detecting the magnitude of the frequency shift, the signal intensity and distribution of the target protein in the tissue can be inferred. The researchers simulated the magnetic field signal of randomly distributed MNPs on the cell surface and the magnetic pattern of MNP-labeled tissue (Figure 1D). The original expression of MNP-tagged proteins can be reconstructed by deep learning models, and the expression intensity of biomarkers can be quantified with absolute MNP density.
Figure. 1 Schematic diagram of diamond magnetic microscope and the principle of tissue magnetic imaging.
This paper reports four technological advances to enable an easy-to-use robust IMM for tumor tissue, including 1) quantifying the expression intensity of biomarkers as absolute magnetic intensity, 2) reconstructing magnetic images using deep learning algorithms, 3) using magnetic nanoscale Particles (MNPs) immunomagnetically label tissue samples, and 4) attach tissue slices over large areas close to the diamond to meet the limited detection range of NV centers.
In the IMM they developed, magnetism is used as another physical quantity besides light and mass. The IMM method is capable of accurate absolute magnetic quantification with good signal stability and negligible magnetic background. In addition, correlated IMM and HE staining are important for studying tumor microenvironment and heterogeneity. The multifunctional IMM can be extended to the histological examination of a variety of cancers and other biological processes and diseases, such as cardiac, inflammatory and neurological diseases. This work provides an attractive method for the histological examination of human disease, complementing existing tissue imaging methods and enriching magnetic resonance techniques.
In addition to pathological tissue, this NV-based magnetic microscope enables imaging, quantification, and analysis of various MRI contrast agents, magnetic particles, and magnetic molecules in animal magnetoreception at the tissue level with submicron or subcellular resolution.
Paper link：https://www.pnas.org/content/119/5/e2118876119
