Artificially Engineered Cubic Iron Oxide Nanoparticle as a High-Performance Magnetic Particle Imaging Tracer for Stem Cell Tracking

Abstract

Stem cell therapies are increasingly recognized as the future direction of regenerative medicine, but the biological fate of the administrated stem cells remains a major concern for clinical translation, which calls for an approach to efficiently monitoring the stem cell behaviors in vivo. Magnetic particle imaging (MPI) is an emerging technology for cell tracking; however, its utility has been largely restricted due to the lack of optimal magnetic nanoparticle tracers. Herein, by controlled engineering of the size and shape of magnetic nanoparticles tailored to MPI physics theory, a specialized MPI tracer, based on cubic iron oxide nanoparticles with an edge length of 22 nm (CIONs-22), is developed. Due to the inherent lower proportion of disordered surface spins, CIONs-22 exhibit significantly larger saturation magnetization than that of spherical ones, while they possess similar saturation magnetization but smaller coercivity compared to larger-sized CIONs. These magnetic properties of CIONs-22 warrant high sensitivity and resolution of MPI. With their efficient cellular uptake, CIONs-22 exhibit superior MPI performance for stem cell labeling and tracking compared to the commercialized tracer Vivotrax. By virtue of these advantages, CIONs-22 enable real-time and prolonged monitoring of the spatiotemporal trajectory of stem cells transplanted to hindlimb ischemia mice, which demonstrates the great potential of CIONs-22 as MPI tracers to advance stem cell therapies. KEYWORDS: magnetic particle imaging, cubic iron oxide nanoparticle, bone mesenchymal stem cell, stem cell tracking, hindlimb ischemia S tem-cell-based therapies have demonstrated therapeutic potential for a wide spectrum of diseases, such as hindlimb ischemia, stroke, liver disease, and heart failure. 1,2 However, to ultimately advance this fast growing field from preclinical studies to translation, several major concerns are yet to be addressed, one of which is the poorly understood biological fate of injected stem cells, e.g., the timing and path of their migration to diseased tissues. In this regard, it is of particular relevance to monitor stem cells after administration into the body, which would provide valuable information for predicting the therapeutic efficacy, evaluating the potential risk, and optimizing treatment strategies. 3 Current technologies for in vivo stem cell tracking include optical imaging, magnetic resonance imaging (MRI), and radionuclide imaging. 4−7 Optical imaging has single-cell resolution, but its clinical translation is hindered by the poor tissue penetration of the light photon. 8 Radionuclide imaging, with excellent depth penetration, faces the disadvantage of narrow temporal window due to the short half-lives of radionuclide tracers that are also constantly questioned for toxicities. 9,10 MRI offers high spatial resolution and unlimited depth penetration without using radiotracers. 8 However, the dark signal generated by T2-weighed MRI contrast agents (CAs) (e.g., iron oxide nanoparticles (IONPs)) 11,12 can be easil...

The Reconstruction of Magnetic Particle Imaging: Current Approaches Based on the System Matrix

“…There have been some studies dedicated to improving the spatial resolution and image quality of MPI, including optimizing the particle size distribution of nanoparticles [ 46 , 47 ], simulating different scanning trajectories [ 18 , 48 ], building scanners with stronger gradient fields [ 49 ], adopting the new calibration protocol [ 50 ], and improving the reconstruction approaches [ 45 ], etc. Different SM-based reconstruction methods have been investigated in different studies.…”

Recent progress of magnetic nanoparticles in biomedical applications: A review

“…Magnetic particle imaging provides a better understanding of stem cell proliferation, migration, metabolism, and differentiation. [ 260–262 ] Lemeaster et al. [ 260 ] reported a trimodal contrast platform, magnetic particle nanobubbles facilitated ultrasound imaging, photoacuostic imaging and MPI.…”

“…[ 260 ] Moreover, Wang et al. [ 261 ] reported real‐time monitoring of migration and distribution patterns of stem cells using cubic iron oxide nanoparticles. The advantage of MPI over MRI and CT is the ability of its real‐time data acquisition within a shorter time domain and no radiation exposure compared to CT. [ 263 ] Using MPI tracer particles, it is possible to acquire crucial information on vascular anatomy, blockage of the carotid artery, differentiation of venous and arterial vessels, and the real‐time monitoring of heart rate with single beat precision.…”

Di- and tri-component spinel ferrite nanocubes: synthesis and their comparative characterization for theranostic applications

“…52 MPI is indeed an emerging imaging technique for which ferrite NCs have thus far been only partially evaluated. [53][54][55] Using a magnetic particle relaxometer, the NCs were exposed to a sinusoidal magnetic field (frequency 16.8 kHz, amplitude 16 kA m −1 ), which mimics the field free region (FFR) movement across the sample during an MPI experiment. The time dependent magnetization is inductively detected by a coil and gridded to the known instantaneous magnetic field value to generate the point spread function (PSF).…”