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Background:
Magnetic Particle Imaging (MPI) is a highly sensitive biomedical imaging modality that quantitatively images superparamagnetic iron oxide (SPIO) nanoparticle tracers in the body [1]. With zero radiation, no depth attenuation, and no background signal from the body, MPI has shown great promise in many applications including GI bleed imaging (Fig. 1a) [2], cell tracking (Fig. 1b) [3], pulmonary embolism imaging [4], stroke detection [5], and cancer imaging [6]. The primary hurdle in clinical translation of MPI is its relatively poor resolution, which is proportional to the magnetic resolution of the tracer divided by the gradient strength [7], [8]. Preclinical MPI scanners can only achieve roughly 1.5 mm resolution with current SPIO tracers. Several recent studies have shown that under specific conditions, nanoparticles can spontaneously form chains and exhibit superferromagnetism [9], [10], [11]. These superferromagnetic iron oxide (SFMIO) nanoparticles experimentally demonstrate up to 28-fold linear resolution improvement for MPI in vitro [11].
Hypothesis/Objective:
For clinical translation, SFMIO chains must work in water and blood, but all synthetic SFMIOs published to date work only in nonpolar solvents. Hydration layers push nanoparticles apart, preventing superferromagnetic chain formation [11]. Larger nanoparticles can overcome this challenge because the dipole fields extend further than the hydration layer. Multicore nanoparticles up to 100 nm diameter have been synthesized [12], [13], [14], [15]. This study aims to create multicore SFMIOs (mc-SFMIOs) that achieve high MPI resolution in aqueous media for the first time.
Methods:
Multicore nanoparticles (also referred to as nanoclusters or nanoflowers) consist of small single domain magnetite cores aggregated into clusters. A hydrothermal polyol synthesis was used to create polyacrylic acid (PAA) coated multicore nanoparticles. For this study, one batch was synthesized with 92 ± 19 nm cluster diameter and another batch with 31 ± 6 nm cluster diameter. The cores within the clusters had 6.0 ± 0.1 nm diameter. Particle size and chain formation were validated using transmission electron microscopy (TEM). MPI point-spread functions (PSFs) were obtained using a custom arbitrary waveform relaxometer, and MPI images were obtained on a field-free line (FFL) MPI scanner with 6.5 T/m gradient and 40 mT drive field amplitude.
Results:
TEM results confirm that 92 nm multicore nanoparticles formed linear chains in water after brief exposure to a uniform magnetic field (Fig. 1c). Their PSF showed 4-fold linear resolution improvement over ferucarbotran, the current gold standard SPIO for MPI (Fig. 2d). The mc-SFMIO PSF also shows notable coercivity, a hallmark of superferromagnetic behavior. Using a low frequency 2 kHz transmit field (Fig. 2e) improved the resolution an additional 2-fold, achieving an unprecedented 1.3 mT full-width at half maximum (FWHM). This represents a 10-fold improvement in linear resolution over ferucarbotran. The 31 nm multicore nanoparticles did not spontaneously form chains in water. However, dispersing them in a 1x PBS buffer solution showed noticeable superferromagnetic behavior (Fig. 1f), with identical resolution to the 92 nm mc-SFMIOs. MPI phantom images confirm the impressive resolution improvement now possible in aqueous media using multicore SFMIOs (Fig. g-h).
Conclusion:
This study presents the first observation of synthetic SFMIOs in aqueous media, enabling 4-fold MPI resolution improvement in each dimension, a genuine breakthrough. SFMIO chain formation in aqueous media removes a major hurdle in encapsulating these chains for in vivo use. Chain encapsulation methods will be studied further [16], [17], [18]. Given the promising data with PBS, our group also hopes to optimize surface charge for ideal SNR and resolution.
Image/Figure:
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Image/Figure Caption:
Figure 1. Magnetic Particle Imaging (MPI) has proven effective for numerous imaging applications such as (A) GI bleed imaging [2] and (B) quantitative cell tracking [3]. (C) TEM images show spontaneous chain formation of multicore SFMIO nanoparticles in aqueous. (D) MPI point-spread functions (PSFs) measured at 20 kHz drive field frequency. Chain formation enables an experimental 4-fold resolution improvement in aqueous media over ferucarbotran. (E) Using a low-frequency 2 kHz drive field yields a further 2-fold resolution improvement, reaching 1.3 mT full-width at half maximum (FWHM). (F) Buffering the solvent with 1x PBS allows 31 nm multicore particles to become SFMIOs. Images of (G) ferucarbotran and (H) chained multicore SFMIOs taken on a field-free line (FFL) MPI scanner.
Author
Justin Garlepp
University of California, Berkeley