A perspective on a rapid and radiation-free tracer imaging modality, magnetic particle imaging, with promise for clinical translation

Abstract

Magnetic particle imaging (MPI), introduced at the beginning of the twenty-first century, is emerging as a promising diagnostic tool in addition to the current repertoire of medical imaging modalities. Using superparamagnetic iron oxide nanoparticles (SPIOs), that are available for clinical use, MPI produces high contrast and highly sensitive tomographic images with absolute quantitation, no tissue attenuation at-depth, and there are no view limitations. The MPI signal is governed by the Brownian and Néel relaxation behavior of the particles. The relaxation time constants of these particles can be utilized to map information relating to the local microenvironment, such as viscosity and temperature. Proof-of-concept pre-clinical studies have shown favourable applications of MPI for better understanding the pathophysiology associated with vascular defects, tracking cell-based therapies and nanotheranostics. Functional imaging techniques using MPI will be useful for studying the pathology related to viscosity changes such as in vascular plaques and in determining cell viability of superparamagnetic iron oxide nanoparticle labeled cells. In this review article, an overview of MPI is provided with discussions mainly focusing on MPI tracers, applications of translational capabilities ranging from diagnostics to theranostics and finally outline a promising path towards clinical translation.

Figure 1.

MPI (A) a 6.3 T m^–1 vertical bore FFL small animal imaging MPI scanner at UC Berkeley (reproduced with permission from), (B) MPI scanner produces a gradient field as shown with a FFP or FFR and saturating regions. The FFR can be electromagnetically shifted around in space. (C) SPIOs have net zero magnetization at room temperature without any external magnetic field, however, with the applied magnetic field SPIOs magnetize and saturate. Only SPIOs at the FFR can respond to excitation, thereby localizing the signal in space, while SPIOs in other regions are saturated. This figure shows an 1-D example, the magnetization of the SPIO changes rapidly as the FFR is shifted and moved over the SPIO, therefore generating a sharp inductive signal (s(x_s(t)). When two SPIOs are present, two signal peaks are generated. The timing of the peak can be spatiotemporally mapped into location of the SPIO by knowledge of FFR position in time. (Image reproduced with permission from) (D) To form an image we raster the FFR in space along the typical trajectory as shown (E) A 3D UC/Cal phantom filled with SPIOs imaged using a projection MPI scanner. (F) Experimental demonstration of magnetic CT using a FFL scanner and projection reconstruction. 3D MPI scan of Cal/ UC phantom resolving 2D plane of Cal (TOP) and UC (Bottom). Berkeley image reconstruction algorithms enable sharp, isotropic resolution MPI images (Image reproduced with permission from). 1D, one-dimensional; 2D, two-dimensional; 3D, three-dimensional; FFL, field-free line; FFP, field-free point; FFR, field-free region; MPI, magnetic particle imaging; SPIO, superparamagnetic iron oxide nanoparticle.

Figure 2.

MPI tracers core size and the surface coating play a crucial role in determining the biodistribution and pharmacokinetic behavior of the particles. The figure shows TEM images of the tracers (A) LodeSpin labs (LS017) (Adapted with permission from Yu E et al., Copyright 2017 American Chemical Society) and (B) Resovist® (Bayer-Schering). LodeSpin particles are of single core 28 nm size particle coated and stabilized with PEG, resulting in a hydrodynamic diameter of 89 nm. Resovist® is multicore MPI agents having a conglomerate of iron oxide particles, and coated with carboxydextran. Resovist has a core iron oxide diameter of 5 nm and hydrodynamic diameter of 60 nm. (C) (TOP) MPI response of Resovist™ and optimized nanoparticles of LodeSpins (UW-2), the PSF shows the LodeSpins particle have six times the intensity and two times better resolution than Resovist™ (BOTTOM) the spectrum demonstrates greater harmonics for LodeSpins particles than Resovist™ (Image reproduced with permission from) (Table 1 details the sensitivity and FWHM of various SPIOs calculated from the PSF measurement). The surface coating and the size of the core determine the biodistribution of the SPIO tracer. (D) MPI image of a rodent co-registered with a projection X-ray anatomy image demonstrate carboxydextran coated iron oxide nanoparticle such as Resovist® are taken up by the RES system while (E) PEG coated particles of LodeSpins have a longer blood circulation and behave as blood pool agents (Adapted with permission from Keselman P et al Institute of Physics and Engineering in Medicine. IOP Publishing). FWHM, full width at half maximum; MPI, magnetic particle imaging; MPS, magnetic particle spectrometer; PEG, polyethylene glycol; PSF, point spread function; TEM, transmission electron microscopy.

Figure 3.

MPI for measuring perfusion changes. (A) First in vivo MPI lung perfusion studies using SPIOs modified with macroaggregated albumin. The particles pass through the lung capillaries at 15 min and slowly get cleared to the liver. MPI is useful for imaging the lungs, where other imaging modalities tend to fail (Image adapted from Zhou X et al Institute of Physics and Engineering in Medicine. Adapted with permission of IOP Publishing.) (B) First brain perfusion study performed by Ludewig et al in a rodent stroke model. The rCBF parametric estimate show reduced perfusion of blood in the parts of the brain affected by stroke, however, the contralateral side appears well perfused (Adapted with permission from Ludewig P et al Copyright 2017, American Chemical Society). (C) Images show the first in vivo MPI gut bleed detection using long-circulating MPI tracer. The tracer accumulates in the GI lumen with time due to the occurrence of an acute bleed (Adapted with permission from Yu E et al 2017 Copyright, American Chemical Society). CBF, cerebral blood perfusion; GI, gastrointestinal; MPI, magnetic particle imaging; SPIOs, super paramagnetic iron oxide nanoparticles.

Figure 4.

First MPI perfusion studies in a tumor xenograft. The tracer distribution in the tumor over the course of time reveal well-perfused tumor periphery and poorly perfused tumor core. The MPI tracer distributes in the tumor and is cleared eventually (Images adapted with permission from Yu E et al 2017 Copyright, American Chemical Society). MPI, magnetic particle imaging.

Figure 5.

MPI angiograms. (A) A 4D flow image of aneurysm phantom obtained by Sedlacik J et al using a Bruker BioSpin GmbH preclinical MPI scanner (Reproduced under creative commons attribution license from), the part of the phantom having aneurysm shows a decreased flow rate. (B) MPI angiogram showing a stenosis (50% occlusion) in an internal carotid artery phantom obtained by Lu K et al from University of California Berkeley (Adapted with permission from Lu K et al IEEE). (C) MPI angiogram of a rodent head showing blood vessels constituting to the CBV acquired using a FFP scanner at UC Berkeley (Reproduced with permission for Zheng B et al Copyright Springer Nature). 4D, four-dimensional; CBV, cerebral blood volume; FFP, field-free point; MPI, magnetic particle imaging.

Figure 6.

Tracking of SPIO-labeled cells provide vital information in regenerative medicine. (A) 87 days of tracking SPIO-tagged NPCs in the forebrain of a rodent. The labeled cells migrated into the ventricle of the brain (B) as shown by Prussian blue staining of SPIO-labeled cells (Figure adopted with permission from Zheng B et al Springer Nature). (C) MPI image of SPIO-labeled pancreatic islet cells transplanted under the kidney capsule; the transplanted labeled cells were functional as indicated by (D) immunofluorescence staining (red, insulin; green, dextran, blue, cell nucleus) (Reproduced with permission from). MPI, magnetic particle imaging; NPC, neuronal progenitor cell; SPIO, super paramagnetic iron oxide nanoparticle.

Figure 7.

MPI can be used as a theranostic platform, for diagnosis and treatment of cancer using hyperthermia.^– MPI enables image-guided therapy where a new approach of using the MPI gradient field to localize thermal dose deposition at-depth with margins of 7 mm using a 2.35 T m^–1 gradient and 2 mm using a 7 T m^–1 gradient. Using MPI images, Tay et al (A) predicted the heat deposition to tumor, and by using gradients and high excitation frequency (B) was able to spatially-selectively deposit thermal dose in a phantom and in a dual tumor xenograft model, (C) where the bottom tumor was selectively treated but not the tumor in the top (Reproduced with permission from, 2018 Copyright, American Chemical Society). MPI, magnetic particle imaging.

Figure 8.

MPI sensitivity dependence on various parameters. Equation assumes limit of detection at SNR = 1 for a 1 s scan, and sensor coil noise dominance (body noise negligible and ideal noise matching to pre-amplifiers). Parameters: ρ = density of SPIO, k_B = Boltzmann constant, T = temperature of sensor coil, NF = noise figure of the preamplifier, R_coil = resistance of coil, B_coil = sensitivity of coil, H_sat = applied field H needed to achieve M_sat, M_sat = magnetization value at saturation, BW = final receive bandwidth used (after windowing), ω = 2π* excitation frequency, H_ampl = excitation amplitude. The derivation estimates peak dM/dt can be approximated by m_sat/(Δt necessary to go from H = 0 to H = H_sat), where m_sat = M_sat*V_nanoparticle, m represents magnetic moment. MPI, magnetic particle imaging; SNR, signal-to-noise ratio.

Figure 9.

Future of MPI scanner. (A) An integrated MPI-MRI system designed by Bruker BioSpin GmbH and University of RWTH, Achen. Image shows a cavity phantom with MRI image in greyscale and MPI image rendered in red scale. (Adapted with permission from) (B) A human scale head MPI scanner design demonstrating the FFL region using a x-z gradient of 1 T m^–1 (Reproduced under the creative common license from). (C) Magnetostimulation limit and SAR estimate in human torso (graph reproduced with permission from), PNS is the dominant safety concern for MPI at drive field frequency <42 kHz. FFL, field-free line; MPI, magnetic particle imaging; PNS, peripheral nerve stimulation.