Scott J. Kemp

Magnetic Particle Imaging With Tailored Iron Oxide Nanoparticle Tracers

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 MPIs 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.

Magnetic Particle Imaging: A Novel in vivo Imaging Platform for Cancer Detection.

Cancer remains one of the leading causes of death worldwide. Biomedical imaging plays a crucial role in all phases of cancer management. Physicians often need to choose the ideal diagnostic imaging modality for each clinical presentation based on complex trade-offs among spatial resolution, sensitivity, contrast, access, cost, and safety. Magnetic particle imaging (MPI) is an emerging tracer imaging modality that detects superparamagnetic iron oxide (SPIO) nanoparticle tracer with high image contrast (zero tissue background signal), high sensitivity (200 nM Fe) with linear quantitation, and zero signal depth attenuation. MPI is also safe in that it uses safe, in some cases even clinically approved, tracers and no ionizing radiation. The superb contrast, sensitivity, safety, and ability to image anywhere in the body lends MPI great promise for cancer imaging. In this study, we show for the first time the use of MPI for in vivo cancer imaging with systemic tracer administration. Here, long circulating MPI-tailored SPIOs were created and administered intravenously in tumor bearing rats. The tumor was highlighted with tumor-to-background ratio of up to 50. The nanoparticle dynamics in the tumor was also well-appreciated, with initial wash-in on the tumor rim, peak uptake at 6 h, and eventual clearance beyond 48 h. Lastly, we demonstrate the quantitative nature of MPI through compartmental fitting in vivo.

Monodisperse magnetite nanoparticles with nearly ideal saturation magnetization

We present a scalable thermolysis and high temperature oxidation procedure for synthesizing monodisperse magnetite nanoparticles with saturation magnetization of up to 80 emu g−1 (412 kA m−1), 92% of bulk magnetite. Diameters in the 15–30 nm size range are produced from iron oleate via the thermolysis method at 324 °C and varying oleic acid ratios for size control (6.7–7.6 equivalents per Fe). The influence of the iron oleate synthesis procedure on the quality of resulting nanoparticles is examined and the structure of the iron oleate is proposed to have a triironoxonium core [Fe3O+] based on magnetic susceptibility measurements. The thermolysis method is shown to initially give wustite nanoparticles, which are oxidized in situ at 318 °C using 1% oxygen in argon to form highly magnetic magnetite nanoparticles. The use of 1% oxygen offers broad application as a safe and efficient reagent for the high temperature oxidation of nanoparticles. Special consideration to the reproducibility of nanoparticle diameter and monodispersity has uncovered critical factors. Additionally, the reduction of Fe(III) to Fe(II) is shown to occur during the heat up stage of thermolysis, beginning at less than 180 °C and being complete by 320 °C. Evidence for the reduction occurring by the oxidative decarboxylation of oleic acid is presented. Decomposition of the remaining oleic acid is shown to occur by a ketonization reaction producing oleone. The nucleation event and growth of particles is examined by TEM. Comparison of the solvents 1-octadecene and octadecane are presented demonstrating the effect on the reduction of Fe(III) during heat up, the large difference in particle size, and effects on the oxidation rate of iron oxide nanoparticles. Determination of Fe(II) content in magnetic iron oxide nanoparticles by titration is presented.

Drive-Field Frequency Dependent MPI Performance of Single-Core Magnetite Nanoparticle Tracers

The drive-field frequency of magnetic particle imaging (MPI) systems plays an important role for system design, safety requirements, and tracer selection. Because the commonly utilized MPI drive-field frequency of 25 kHz might be increased in future system generations to avoid peripheral nerve stimulation, a performance evaluation of tracers at higher frequencies is desirable. We have studied single-core magnetite nanoparticles that were optimized for MPI applications, utilizing magnetic particle spectrometers (MPS) with drive-field frequencies in the range from 1 to 100 kHz. The particles have core diameters of 25 nm and a hydrodynamic size of 77 nm. Measurements in the frequency range above 5 kHz were carried out with a newly designed MPS system. In addition, to exclude possible particle interaction, samples of different concentrations were characterized and compared.

Tracking short-term biodistribution and long-term clearance of SPIO tracers in magnetic particle imaging

Magnetic particle imaging (MPI) is an emerging tracer-based medical imaging modality that images non-radioactive, kidney-safe superparamagnetic iron oxide (SPIO) tracers. MPI offers quantitative, high-contrast and high-SNR images, so MPI has exceptional promise for applications such as cell tracking, angiography, brain perfusion, cancer detection, traumatic brain injury and pulmonary imaging. In assessing MPIs utility for applications mentioned above, it is important to be able to assess tracer short-term biodistribution as well as long-term clearance from the body. Here, we describe the biodistribution and clearance for two commonly used tracers in MPI: Ferucarbotran (Meito Sangyo Co., Japan) and LS-oo8 (LodeSpin Labs, Seattle, WA). We successfully demonstrate that 3D MPI is able to quantitatively assess short-term biodistribution, as well as long-term tracking and clearance of these tracers in vivo.

First in vivo traumatic brain injury imaging via magnetic particle imaging

Emergency room visits due to traumatic brain injury (TBI) is common, but classifying the severity of the injury remains an open challenge. Some subjective methods such as the Glasgow Coma Scale attempt to classify traumatic brain injuries, as well as some imaging based modalities such as computed tomography and magnetic resonance imaging. However, to date it is still difficult to detect and monitor mild to moderate injuries. In this report, we demonstrate that the magnetic particle imaging (MPI) modality can be applied to imaging TBI events with excellent contrast. MPI can monitor injected iron nanoparticles over long time scales without signal loss, allowing researchers and clinicians to monitor the change in blood pools as the wound heals.

Variation of Magnetic Particle Imaging Tracer Performance With Amplitude and Frequency of the Applied Magnetic Field

The magnetic response of magnetic particle imaging (MPI) tracers varies with the slew rate of the applied magnetic field, as well as with the tracers average magnetic core size. Currently, 25 kHz and 20 mT/μ0 drive fields are common in MPI, but lower field amplitudes may be necessary for patient safety in future designs. We studied how several different sizes of monodisperse MPI tracers behaved under different drive field amplitude and frequency, using magnetic particle spectrometry and ac hysteresis for drive field conditions at 16, 26, and 40 kHz, with field amplitudes from 5 to 40 mT/μ0. We observed that both field amplitude and frequency can influence the tracer behavior, but that the magnetic behavior is consistent when the slew rate (the product of field amplitude and frequency) is consistent. However, smaller amplitudes provide a correspondingly smaller field of view, sometimes resulting in excitation of a minor hysteresis loop.

In vitro and in vivo comparison of a tailored magnetic particle imaging blood pool tracer with resovist.

Optimizing tracers for individual imaging techniques is an active field of research. The purpose of this study was to perform in vitro and in vivo magnetic particle imaging (MPI) measurements using a new monodisperse and size-optimized tracer, LS-008, and to compare it with the performance of Resovist, the standard MPI tracer. Magnetic particle spectroscopy (MPS) and in vitro MPI measurements were performed in concerns of concentration and amount of tracer in a phantom. In vivo studies were carried out in healthy FVB mice. The first group (n  =  3) received 60 µl LS-008 (87 mM) and the second (n  =  3) diluted Resovist of the same concentration and volume. Tracer injections were performed with a syringe pump during a dynamic MPI scan. For anatomic referencing MRI was applied beforehand of the MPI measurements. Summing up MPS examinations and in vitro MPI experiments, LS-008 showed better sensitivity and spatial resolution than Resovist. In vivo both tracers can visualize the propagation of the bolus through the inferior vena cava. MPI with LS-008 did show less temporal fluctuation artifacts and the pulsation of blood due to respiratory and cardiac cycle was detectable. With LS-008 the aorta was distinguishable from the caval vein while with Resovist this failed. A liver vessel and a vessel structure leading cranially could only be observed with LS-008 and not with Resovist. Beside these structural advantages both tracers showed very different blood half-life. For LS-008 we found 88 min. Resovist did show a fast liver accumulation and a half-life of 13 min. Only with LS-008 the perfusion fraction in liver and kidney was measureable. MPI for angiography can be significantly improved by applying more effective tracers. LS-008 shows a clear improvement concerning the delineation while resolving a larger number of vessels in comparison to Resovist. Therefore, in aspects of quality and quantity LS-008 is clearly favorable for angiographic and perfusion studies.

Magnetic Particle Imaging for Highly Sensitive, Quantitative, and Safe in Vivo Gut Bleed Detection in a Murine Model

Gastrointestinal (GI) bleeding causes more than 300 000 hospitalizations per year in the United States. Imaging plays a crucial role in accurately locating the source of the bleed for timely intervention. Magnetic particle imaging (MPI) is an emerging clinically translatable imaging modality that images superparamagnetic iron-oxide (SPIO) tracers with extraordinary contrast and sensitivity. This linearly quantitative modality has zero background tissue signal and zero signal depth attenuation. MPI is also safe: there is zero ionizing radiation exposure to the patient and clinically approved tracers can be used with MPI. In this study, we demonstrate the use of MPI along with long-circulating, PEG-stabilized SPIOs for rapid in vivo detection and quantification of GI bleed. A mouse model genetically predisposed to GI polyp development (ApcMin/+) was used for this study, and heparin was used as an anticoagulant to induce acute GI bleeding. We then injected MPI-tailored, long-circulating SPIOs through the tail vein, and tracked the tracer biodistribution over time using our custom-built high resolution field-free line (FFL) MPI scanner. Dynamic MPI projection images captured tracer accumulation in the lower GI tract with excellent contrast. Quantitative analysis of the MPI images show that the mice experienced GI bleed rates between 1 and 5 μL/min. Although there are currently no human scale MPI systems, and MPI-tailored SPIOs need to undergo further development and evaluation, clinical translation of the technique is achievable. The robust contrast, sensitivity, safety, ability to image anywhere in the body, along with long-circulating SPIOs lends MPI outstanding promise as a clinical diagnostic tool for GI bleeding.

Generic multi-purpose multi-modality phantom kit design

Phantoms are well-established tools for the characterization of imaging systems with regard to resolution, sensitivity, geometric distortions, or flow detection [1]. For the MPI community, the availability of standard phantoms is highly desirable to facilitate direct comparisons between the different MPI scanner designs that have emerged since the inception of this novel imaging modality [2-7]. To be stable over longer times, such phantoms require a sealed containment for liquid contrast agents to prevent leakage or solvent evaporation. As MPI typically requires a second modality for providing morphological reference, it is desirable to use phantoms that also exhibit a good contrast in other modalities such as MRI or μCT. As the spatial resolution of MPI scanners is typically anisotropic, it is desirable to allow different phantom alignments. In this study, we evaluate our new generic kit for building compact phantoms that meet the above requirements.