Immunomagnetic microscopy of tumor tissues using quantum sensors in diamond

Abstract

Histological imaging is essential for the biomedical research and clinical diagnosis of human cancer. Although optical microscopy provides a standard method, it is a persistent goal to develop new imaging methods for more precise histological examination. Here, we use nitrogen-vacancy centers in diamond as quantum sensors and demonstrate micrometer-resolution immunomagnetic microscopy (IMM) for human tumor tissues. We immunomagnetically labeled cancer biomarkers in tumor tissues with magnetic nanoparticles and imaged them in a 400-nm resolution diamond-based magnetic microscope. There is barely magnetic background in tissues, and the IMM can resist the impact of a light background. The distribution of biomarkers in the high-contrast magnetic images was reconstructed as that of the magnetic moment of magnetic nanoparticles by employing deep-learning algorithms. In the reconstructed magnetic images, the expression intensity of the biomarkers was quantified with the absolute magnetic signal. The IMM has excellent signal stability, and the magnetic signal in our samples had not changed after more than 1.5 y under ambient conditions. Furthermore, we realized multimodal imaging of tumor tissues by combining IMM with hematoxylin-eosin staining, immunohistochemistry, or immunofluorescence microscopy in the same tissue section. Overall, our study provides a different histological method for both molecular mechanism research and accurate diagnosis of human cancer.

Recent Development of Fluorescent Nanodiamonds for Optical Biosensing and Disease Diagnosis

“…This notion has been widely exploited for optical magnetometry using a single and an ensemble of NV centers [ 27 , 108 ]. A diamond spin magnetic microscope enabling wide-field imaging of tumors with a spatial resolution of 1 µm in a 0.5 mm 2 field of view has been reported using a bulk diamond crystal [ 109 ]. The target tissues labeled with 20 nm superparamagnetic nanoparticles (SMNPs) were deposited on the diamond surface for magnetic sensing with a spatial resolution of 400 nm.…”

“…Under the influence of alternating magnetic fields, the SMNPs flip their magnetization, causing noticeable shifts in the NV-ODMR spectra within an NV-sensing volume of 0.1 µm 3 . The ODMR shift is then interpreted using a deep-learning algorithm to estimate the target protein distribution in immunomagnetic images [ 109 ]. The experiments were carried out using human lung tumors by labeling the proteins (EGFR, TfR, Ep-CAM, Ki67, and PD-L1) as cancer biomarkers exhibiting an SPMNs density of 300–600/µm 2 in the magnetic images, which were further processed for cell segmentation and quantification.…”

“…ML algorithms have been empowering FNDs for intracellular magnetic microscopy [ 109 ]. Deep-learning algorithms enable the high-contrast reconstruction of magnetic images from optical images.…”

Bayesian-Based Hybrid Method for Rapid Optimization of NV Center Sensors

“…The nitrogen-vacancy (NV) center in diamond shows bright prospects in the quantum sensing of magnetic fields [ 1 , 2 , 3 ], electric fields [ 4 ], temperature [ 5 ] and strain [ 6 ]. In these areas, research on NV center-based ultrasensitive magnetometry has achieved fast development [ 7 , 8 ] and is on the road to practical and commercial applications in biomedicine and diagnostics [ 9 , 10 , 11 , 12 ]. Inhomogeneous broadening due to ambient nuclear spins and external bias fields is one of the main obstacles to further improving the sensitivity of sensors.…”

Digital Magnetic Detection of Biomolecular Interactions with Single Nanoparticles

“…The NV sensor has already presented powerful capabilities in the high-sensitivity detection of magnetic fields. − Moreover, the biocompatibility of diamond and sensing capabilities under ambient conditions render NV centers ideal sensors for applications in biomedical systems. These features and advances have attracted much interest in single-molecule structure research, − single-cell imaging, − tumor tissue imaging, , biomagnetism sensing, and DNA assay, indicating the prospects of NV-based magnetic sensing in extensive biomedical fields. In particular, a 15 pT/Hz 1/2 sensitivity and a 10 nm-scale spatial resolution have been achieved.…”