Diamond NV-center Immunomagnetic Microscopy Promising for Cancer Research and Diagnosis

Prof. Dr. Jiangfeng Du and Prof. Dr. Fazhan Shi of the Chinese Academy of Sciences (CAS) Key Laboratory of Microscopic Magnetic Resonance, in collaboration with Prof. Dr. Haiming Wei of the School of Life Sciences, University of Science and Technology of China (USTC), have made important progress in the biomedical application of diamond nitrogen-vacancy (NV) center quantum precision measurement technology. 

The first immunomagnetic imaging technique for tumor tissues was established to achieve magnetic imaging at the tissue level with micron resolution. It has the advantages of high stability, low background, and absolute quantification of tumor markers, and achieves both magnetic and optical multimodal imaging. 


> The research results were published in the Proceedings of the National Academy of Sciences on January 26, 2022, under the title "Immunomagnetic microscopy of tumor tissues using quantum sensors in diamond" [ Proc Natl Acad Sci U S A 119(5), e2118876119 (2022)]. 

Cancer is currently one of the most deadly diseases in humans. Research on the molecular mechanism of cancer and early and accurate clinical diagnosis is the basis for effective treatment. The imaging of tumors at the tissue level is a key part of cancer research and clinical diagnosis, especially in the diagnosis of cancer, although there are various medical imaging methods, pathological tissue testing is still the "gold standard" for cancer diagnosis. Therefore, the development of histopathological methods is of great biological and clinical importance. The current mainstream pathological tissue imaging methods include H&E staining, immunohistochemistry, and immunofluorescence, which are mainly based on optical imaging. They are susceptible to problems such as strong optical background, signal instability, inaccurate quantification, and inability to share different optical methods, which in turn affect the accuracy of histopathological detection.

Figure 1 Device and principle of immunomagnetic microscopy of tumor tissue

Figure 1 Device and principle of immunomagnetic microscopy of tumor tissue

Magnetic resonance imaging (MRI) is expected to address these shortcomings of optical imaging. However, traditional MRI is limited by low sensitivity and low spatial resolution, which makes it difficult to be applied to imaging at the tissue level with micron resolution. 

In the recent work, the research team used a newly developed quantum magnetic sensor, NV center, an atomic defect in diamond single crystals) in diamond, to build wide-field magnetic imaging equipment independently, combined with quantum precision measurement and immunomagnetic labeling technology, to achieve micron resolution tumor tissue magnetic imaging for lung cancer detection. Specifically, the research team first developed a tissue-level immunomagnetic labeling method to specifically label 20 nm diameter superparamagnetic particles with target protein molecules such as PD-L1 in tumor tissues through antigen-antibody specific recognition. The tissue samples were then tightly attached to the diamond surface, and then a layer of NV center in the diamond distributed about one hundred nm near the surface was used as a two-dimensional quantum magnetic sensor for magnetic field imaging on a 400 nm resolution magnetic microscope (Figure 1). The micron-level spatial resolution is achieved in the millimeter field of view. Finally, the magnetic moment distribution corresponding to the magnetic field is reconstructed by a deep learning model to provide a basis for quantitative analysis (Figure 2).

Figure 2 Micron-resolution magnetic imaging of lung cancer tissue

Figure 2 Micron-resolution magnetic imaging of lung cancer tissue

The new method in this study has four main advantages:

1. Absolute magnetic quantification. The signal of magnetic imaging comes from the local magnetic field of the same size nanomagnetic particles, which has a quantitative scale that can be absolutely quantified, so the calculation of magnetic field intensity can achieve absolute quantification (Figure 2B) with high accuracy.

2. It can avoid the interference of the background signals. Biological samples generally have no magnetic field background, and the spectral measurement method of magnetic imaging can effectively resist the influence of autofluorescence in tissues. Therefore, it can provide pure tumor marker information and high image contrast (generally more than 5 times higher than fluorescence methods), while contributing to the accuracy of quantification.

3. High stability of the magnetic signal. After the magnetically labeled biological samples were placed at room temperature under an atmospheric environment for one and a half years, the test revealed little change in the distribution and intensity of the magnetic field signal, which facilitates the long-term storage and repeated testing of clinical samples.

4. Magnetic and optical multimodal imaging. Magnetism and light are two different physical quantities. The magnetic imaging in this study can be coupled with conventional optical imaging to enable the detection of morphological features and tumor markers in the same tissue section. This is important for analyzing the microenvironment and heterogeneity of tumors.

In addition to tumor tissue, the study's microscopic magnetic imaging technology can also be used in other biological tissues for tissue-level studies and clinical diagnosis in the areas of immunity and inflammation, neurodegenerative diseases, cardiovascular diseases, biomagnetic sensing, magnetic resonance contrast agents, magnetic drug targeting, etc. It is particularly advantageous for biological tissues containing optical backgrounds, optical transmission aberrations, and those requiring quantitative analysis.

After achieving single-molecule magnetic resonance spectroscopy [Science 347, 1135 (2015); Nature Methods, 15, 697 (2018)] and 10-nm-class resolution cellular magnetic imaging [Sci. Adv. 5, eaau8038 (2019)], Prof. Dr. Jiangfeng Du's team achieved a quantum precision diamond NV center-based measurement technology cross-applied to the biomedical field, which is important for both cancer research and clinical diagnosis. 

Dr. Sanyou Chen, Distinguished Associate Researcher of the CAS Key Laboratory of Microscopic Magnetic Resonance, Wanhe Li, a Ph.D. student, and Dr. Xiaohu Zheng, Distinguished Professor of Prof. Dr. Haiming Wei's group, are the co-first authors of the paper, and Prof. Dr. Jiangfeng Du and Prof. Dr. Fazhan Shi are the co-corresponding authors of the paper. The research was supported by a joint grant from the National Natural Science Foundation of China, the Ministry of Science and Technology, the Chinese Academy of Sciences, Anhui Province, and the New Medicine Joint Fund of the Chinese University of Science and Technology. 

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