Magnetic particle imaging with tailored iron oxide nanoparticle tracers

Abstract

Magnetic particle imaging (MPI) shows promise for medical imaging, particularly in angiography of patients with chronic kidney disease. As the first biomedical imaging technique that truly depends on nanoscale materials properties, MPI requires highly optimized magnetic nanoparticle tracers to generate quality images. Until now, researchers have relied on tracers optimized for MRI T2(∗) -weighted imaging that are sub-optimal for MPI. Here, we describe new tracers tailored to MPI's unique physics, synthesized using an organic-phase process and functionalized to ensure biocompatibility and adequate in vivo circulation time. Tailored tracers showed up to 3 × greater signal-to-noise ratio and better spatial resolution than existing commercial tracers in MPI images of phantoms.

Figure 1

Schematic illustration of MPI detection and size-dependent tracer magnetic properties. (a) The characteristic nonlinear magnetic response (m(t) and its derivative m’(t)) of superparamagnetic nanoparticles to an applied field, H. (b, c) As the field free point sweeps over a location that contains MNPs, b’(t) changes rapidly, generating a signal that reveals the MNP location. In (b) and (c), m’′(t) (black curve) is shown for all time t< t_n, while the FFP, which is moving from left to right with time, is represented at t = t_n, where n = 1 or 2. MPS signals: (d) m’(H), the tracer response, determines the point spread function (PSF, m’(G_x)) when the system field gradient, G, is known; (e) the harmonic spectrum, F(m’), is used to evaluate tracers for System Matrix MPI reconstruction.

Figure 2

MNP size characterization of LS-1. (a) Bright field TEM image of magnetite particles. In this example, median crystal diameter was determined to be 26 nm from statistical analysis of TEM images (6000 particle counts), assuming a log-normal distribution. (b) Median magnetic core diameter was determined to be 28 nm by fitting M(H) data to the Langevin function and assuming a log-normal size distribution. (c) Hydrodynamic diameter (~72 nm, Z-average) was measured using dynamic light scattering.

Figure 3

MNP magnetic properties. (a) Measured M(H) loops for water-suspended MNPs of the specified median diameter and distribution width, σ. (b) Measured harmonic spectra, showing only odd harmonics. The system noise floor is also shown (solid line). (c) Measured tracer response, scaled by iron content and normalized to 1 for comparison of FWHM (inset). Only scans of increasing H are shown in the figure.

Figure 4

MPI performance is determined largely by MNP core size and size distribution. Here, key performance metrics measured by MPS are presented for different tracer formulations produced during optimization, with both spot size and color proportional to the relevant metric: (a) Spatial resolution (FWHM of tracer response, in mT/μ₀, smallest diameter is best) and (b) Normalized intensity (max intensity of tracer response, in m³/kgFe, largest diameter is best). According to both metrics, MPI performance improves with increasing core size, provided that size distribution remains narrow.

Figure 5

MPS measurements (f₀ = 25kHz, H_max = 16 mT/μ₀) of optimized MNPs (UW-2) and Resovist^®: (a) MNP response, m’′(H). Forward (low to high field) and reverse (high to low field) scans are shown. Signal intensity, measured by the m’(H) maximum, of UW-2 was 0.030 m³/kgFe, 6x greater than Resovist^® (0.005 m³/kgFe). Full width at half maximum resolution was 4.7 (mT/μ₀) for UW-2, half that of Resovist^®. (b) Harmonic spectra of UW-2 and Resovist^®. UW-2 showed greater harmonic intensity for all harmonics; 3.5x, 12.1x, and 9.8x greater at the 3rd, 19th, 39th harmonics, respectively.

Figure 6

Fast system matrix MPI imaging of phantoms containing equivalent iron concentrations of UW-2 (b, top) and Resovist^® (b, bottom), acquired with Philips pre-clinical demonstrator imaging system. Acquisition time was 0.129 s, with an additional 0.431 s of latency built into the acquisition sequence. (a) photograph of phantom filled with tracer. Tubing inner diameter was 1.5 mm. (b) Comparison of reconstructed MPI images, after scaling intensities with the noise levels of the images. (c) Intensity profiles obtained from phantom images.

Figure 7

x-space phantom imaging experiments at the UC Berkeley 3D MPI scanner. (a) Native (i.e., undeconvolved) MPI images of the phantoms. Channels were 1.5 mm wide and 1.5 mm deep. (b) MPI images of the phantoms, where UW-1 shows improved signal intensity and spatial resolution. Images are maximum intensity projections after mild Weiner deconvolution, with absolute intensity scaling. The imaging FOV was 4.5 × 4.5 × 14 cm³. (c) Photograph of laser-cut acrylic phantoms containing UW-1 (top) and Resovist^® (bottom) (top) mid-line cross-sections (bottom) of native

Figure 8

Resolution phantoms. Native MPI images (maximum intensity projections) of phantoms containing LS-1 (a) and Resovist (b); blue circles were overlaid for emphasis (c) cross sections. (d) photograph of the LS-1 phantom. Edge to edge separation between adjacent point sources (0.56 mm diameter) was 3.8, 2.7, 1.7, and 0.6 mm, respectively.