Real-time multi-contrast magnetic particle imaging for the detection of gastrointestinal bleeding.

Gastrointestinal bleeding, as a potentially life-threatening condition, is typically diagnosed by radiation-based imaging modalities like computed tomography or more invasively catheter-based angiography. Endoscopy enables examination of the upper gastrointestinal tract and the colon but not of the entire small bowel. Magnetic Particle Imaging (MPI) enables non-invasive, volumetric imaging without ionizing radiation. The aim of this study was to evaluate the feasibility of detecting gastrointestinal bleeding by single- and multi-contrast MPI using human-sized organs. A 3D-printed small bowel phantom and porcine small bowel specimens were prepared with a defect within the bowel wall as the source of a bleeding. For multi-contrast MPI, the bowel lumen was filled with an intestinal tracer representing an orally administered tracer. MPI was performed to evaluate the fluid exchange between the vascular compartment of the bowel wall and the lumen while a blood pool tracer was applied. Leakage of the blood pool tracer was observed to the bowel lumen. Multi-contrast MPI enabled co-registration of both tracers at the same location within the bowel lumen indicating gastrointestinal bleeding. Single- and multi-contrast MPI are feasible to visualize gastrointestinal bleeding. Therefore, MPI might emerge as a useful tool for radiation-free detection of bleeding within the entire gastrointestinal tract.

Comparative Modeling of Frequency Mixing Measurements of Magnetic Nanoparticles Using Micromagnetic Simulations and Langevin Theory.

Dual frequency magnetic excitation of magnetic nanoparticles (MNP) enables enhanced biosensing applications. This was studied from an experimental and theoretical perspective: nonlinear sum-frequency components of MNP exposed to dual-frequency magnetic excitation were measured as a function of static magnetic offset field. The Langevin model in thermodynamic equilibrium was fitted to the experimental data to derive parameters of the lognormal core size distribution. These parameters were subsequently used as inputs for micromagnetic Monte-Carlo (MC)-simulations. From the hysteresis loops obtained from MC-simulations, sum-frequency components were numerically demodulated and compared with both experiment and Langevin model predictions. From the latter, we derived that approximately 90% of the frequency mixing magnetic response signal is generated by the largest 10% of MNP. We therefore suggest that small particles do not contribute to the frequency mixing signal, which is supported by MC-simulation results. Both theoretical approaches describe the experimental signal shapes well, but with notable differences between experiment and micromagnetic simulations. These deviations could result from Brownian relaxations which are, albeit experimentally inhibited, included in MC-simulation, or (yet unconsidered) cluster-effects of MNP, or inaccurately derived input for MC-simulations, because the largest particles dominate the experimental signal but concurrently do not fulfill the precondition of thermodynamic equilibrium required by Langevin theory.

Configurable Artificial Spin Ice with Site-Specific Local Magnetic Fields.

We demonstrate ground state tunability for a hybrid artificial spin ice composed of Fe nanomagnets which are subject to site-specific exchange-bias fields, applied in integer multiples of the lattice along one sublattice of the classic square artificial spin ice. By varying this period, three distinct magnetic textures are identified: a striped ferromagnetic phase; an antiferromagnetic phase attainable through an external field protocol alone; and an unconventional ground state with magnetically charged pairs embedded in an antiferromagnetic matrix. Monte Carlo simulations support the results of field protocols and demonstrate that the pinning tunes relaxation timescales and their critical behavior.

Nonequilibrium Dynamics of Magnetic Nanoparticles with Applications in Biomedicine.

Magnetic nanoparticles are currently the focus of investigation for a wide range of biomedical applications that fall into the categories of imaging, sensing, and therapeutics. A deep understanding of nanoparticle magnetization dynamics is fundamental to optimization and further development of these applications. Here, a summary of theoretical models of nanoparticle dynamics is presented, and computational nonequilibrium models are outlined, which currently represent the most sophisticated methods for modeling nanoparticle dynamics. Nanoparticle magnetization response is explored in depth; the effect of applied field amplitude, as well as nanoparticle size, on the resulting rotation mechanism and timescale is investigated. Two applications in biomedicine, magnetic particle imaging and magnetic fluid hyperthermia, are highlighted.

Observing the colloidal stability of iron oxide nanoparticles in situ.

Colloidal processes such as nucleation, growth, ripening, and dissolution are fundamental to the synthesis and application of engineered nanoparticles, as well as numerous natural systems. In nanocolloids consisting of a dispersion of nanoparticles in solution, colloidal stability is influenced by factors including the particle surface facet and capping layer, and local temperature, chemistry, and acidity. In this paper, we investigate colloidal stability through the real-time manipulation of nanoparticles using in situ liquid cell Scanning Transmission Electron Microscopy (STEM). In a distribution of uniform iron oxide nanoparticles, we use the electron beam to precisely control the local chemistry of the solution and observe the critical role that surface chemistry plays in nanoparticle stability. By functionalizing the nanoparticle surfaces with charged amino acids and peptides, stability can be tuned to promote dissolution, growth, or agglomeration, either permanently or reversibly. STEM imaging is used to quantify kinetics of individual nanoparticles subject to local variations in chemistry. These measurements of dissolution and growth rates of iron oxide nanoparticles provide insights into nanoparticle stability relevant to synthesis and functionalization for biomedical applications.

Intracellular dynamics of superparamagnetic iron oxide nanoparticles for magnetic particle imaging.

Superparamagnetic iron oxide nanoparticles (SPIONs) are a foundational platform for a variety of biomedical applications. Of particular interest is Magnetic Particle Imaging (MPI), which is a growing area of research and development due to its advantages including high resolution and sensitivity with positive contrast. There has been significant work in the area of in vivo optimization of SPIONs for MPI as well as their biodistribution in and clearance from the body. However, little is known about the dynamics of SPIONs following cellular internalization which may limit their usefulness in a variety of potential imaging and treatment applications. This work shows a clear 20% decrease in magnetic performance of SPIONs, as observed by Magnetic Particle Spectroscopy (MPS), after internalization and systematic consideration of applicable factors that affect SPION signal generation, including microstructure, environment, and interparticle interactions. There is no observed change to SPION microstructure after internalization, and the surrounding environment plays little to no role in magnetic response for the SPIONs studied here. Interparticle interactions described by dipole-dipole coupling of SPIONs held close to one another after internalization are shown to be the dominant cause of decreased magnetic performance in cells. These conclusions were drawn from transmission electron microscopy (TEM) image analysis at relevant length scales, experimentally prepared and characterized SPIONs in varied environmental conditions, and theoretical modeling with Monte Carlo simulations.

Discriminating nanoparticle core size using multi-contrast MPI.

Magnetic particle imaging (MPI) is an imaging modality that detects the response of a distribution of magnetic nanoparticle tracers to alternating magnetic fields. There has recently been exploration into multi-contrast MPI, in which the signal from different tracer materials or environments is separately reconstructed, resulting in multi-channel images that could enable temperature or viscosity quantification. In this work, we apply a multi-contrast reconstruction technique to discriminate between nanoparticle tracers of different core sizes. Three nanoparticle types with core diameters of 21.9 nm, 25.3 nm and 27.7 nm were each imaged at 21 different locations within the scanner field of view. Multi-channel images were reconstructed for each sample and location, with each channel corresponding to one of the three core sizes. For each image, signal weight vectors were calculated, which were then used to classify each image by core size. With a block averaging length of 10 000, the median signal-to-noise ratio was 40 or higher for all three sample types, and a correct prediction rate of 96.7% was achieved, indicating that core size can effectively be predicted using signal weight vector classification with close to 100% accuracy while retaining high MPI image quality. The discrimination of the core size was reliable even when multiple samples of different core sizes were placed in the measuring field.

Moving table magnetic particle imaging: a stepwise approach preserving high spatio-temporal resolution.

Magnetic particle imaging (MPI) is a highly sensitive imaging method that enables the visualization of magnetic tracer materials with a temporal resolution of more than 46 volumes per second. In MPI, the size of the field of view (FoV) scales with the strengths of the applied magnetic fields. In clinical applications, those strengths are limited by peripheral nerve stimulation, specific absorption rates, and the requirement to acquire images of high spatial resolution. Therefore, the size of the FoV is usually a few cubic centimeters. To bypass this limitation, additional focus fields and/or external object movements can be applied. The latter approach is investigated. An object is moved through the scanner bore one step at a time, whereas the MPI scanner continuously acquires data from its static FoV. Using a 3-D phantom and dynamic 3-D in vivo data, it is shown that the data from such a moving table experiment can be jointly reconstructed after reordering the data with respect to the stepwise object shifts and heart beat phases.

Evaluating size-dependent relaxivity of PEGylated-USPIOs to develop gadolinium-free T1 contrast agents for vascular imaging.

Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles provide a safer alternative to gadolinium-based contrast agents (GBCAs) in T1-weighted MR imaging. MRI contrast behavior of USPIOs depends on their magnetic properties, which in turn depend on their physicochemical composition. Identifying and tailoring USPIO structural characteristics that influence proton relaxation in MRI is crucial to developing effective gadolinium-free T1 contrast agents. Here, we present a systematic empirical evaluation of the relationship between USPIO size and MRI relaxivity (r1 and r2 values). Monodisperse USPIO cores, with precisely controlled core diameter (dC ) were synthesized via the thermal decomposition of iron(III)-oleate precursor. USPIOs with dC = 6.34, 7.58, 8.58, and 9.50nm, were dispersed in aqueous phase via ligand exchange with silane or dopamine-modified polyethylene glycol (PEG) polymers. Relaxivity characterization in a 1.5 T clinical MRI scanner showed the r2 /r1 ratio increased linearly with USPIO core diameter (R2 = 0.95), but varied little with both hydrodynamic diameter (dH ) and PEG molecular weight. One sample, DOPA-6-20 (6.34nm USPIO cores coated with 20 kDa dopamine-modified PEG), provided the lowest r2 /r1 value (3.44) and thus promise as a potential T1 contrast agent. In a preliminary study, we evaluated DOPA-6-20 for in vivo angiography imaging in a mouse with a 7 T scanner and observed strong T1-weighted enhancement of the mouse blood pool. Key anatomical features in the vascular network were visible even 5 min after intravenous administration. Using empirical data, we have presented the basis of a structure-property relationship that can help develop optimized USPIO-based T1 contrast agents. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2440-2447, 2018.

Improved HER Catalysis through Facile, Aqueous Electrochemical Activation of Nanoscale WSe2.

In the search for nonprecious metal catalysts for the hydrogen evolution reaction (HER), transition metal dichalcogenides (TMDCs) have been proposed as promising candidates. Here, we present a facile method for significantly decreasing the overpotential required for catalyzing the HER with colloidally synthesized WSe2. Solution phase deposition of 2H WSe2 nanoflowers (NFs) onto carbon fiber electrodes results in low catalytic activity in 0.5 M H2SO4 with an overpotential at -10 mA/cm2 of greater than 600 mV. However, two postdeposition electrode processing steps significantly reduce the overpotential. First, a room-temperature treatment of the prepared electrodes with a dilute solution of the alkylating agent Meerwein's salt ([Et3O][BF4]) results in a reduction in overpotential by approximately 130 mV at -10 mA/cm2. Second, we observe a decrease in overpotential of approximately 200-300 mV when the TMDC electrode is exposed to H+, Li+, Na+, or K+ ions under a reducing potential. The combined effect of ligand removal and electrochemical activation results in an improvement in overpotential by as much as 400 mV. Notably, the Li+ activated WSe2 NF deposited carbon fiber electrode requires an overpotential of only 243 mV to generate a current density of -10 mA/cm2. Measurement of changes in the material work function and charge transfer resistance ultimately provide rationale for the catalytic improvement.

Tomographic magnetic particle imaging of cancer targeted nanoparticles.

Magnetic Particle Imaging (MPI) is an emerging, whole body biomedical imaging technique, with sub-millimeter spatial resolution and high sensitivity to a biocompatible contrast agent consisting of an iron oxide nanoparticle core and a biofunctionalized shell. Successful application of MPI for imaging of cancer depends on the nanoparticles (NPs) accumulating at tumors at sufficient levels relative to other sites. NPs' physiochemical properties such as size, crystallographic structure and uniformity, surface coating, stability, blood circulation time and magnetization determine the efficacy of their tumor accumulation and MPI signal generation. Here, we address these criteria by presenting strategies for the synthesis and surface functionalization of efficient MPI tracers, that can target a typical murine brain cancer model and generate three dimensional images of these tumors with very high signal-to-noise ratios (SNR). Our results showed high contrast agent sensitivities that enabled us to detect 1.1 ng of iron (SNR ∼ 3.9) and enhance the spatial resolution to about 600 µm. The biodistribution of these NPs was also studied using near-infrared fluorescence (NIRF) and single-photon emission computed tomography (SPECT) imaging. NPs were mainly accumulated in the liver and spleen and did not show any renal clearance. This first pre-clinical study of cancer targeted NPs imaged using a tomographic MPI system in an animal model paves the way to explore new nanomedicine strategies for cancer diagnosis and therapy, using clinically safe magnetic iron oxide nanoparticles and MPI.

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.

Magnetic Particle Imaging for Real-Time Perfusion Imaging in Acute Stroke.

The fast and accurate assessment of cerebral perfusion is fundamental for the diagnosis and successful treatment of stroke patients. Magnetic particle imaging (MPI) is a new radiation-free tomographic imaging method with a superior temporal resolution, compared to other conventional imaging methods. In addition, MPI scanners can be built as prehospital mobile devices, which require less complex infrastructure than computed tomography (CT) and magnetic resonance imaging (MRI). With these advantages, MPI could accelerate the stroke diagnosis and treatment, thereby improving outcomes. Our objective was to investigate the capabilities of MPI to detect perfusion deficits in a murine model of ischemic stroke. Cerebral ischemia was induced by inserting of a microfilament in the internal carotid artery in C57BL/6 mice, thereby blocking the blood flow into the medial cerebral artery. After the injection of a contrast agent (superparamagnetic iron oxide nanoparticles) specifically tailored for MPI, cerebral perfusion and vascular anatomy were assessed by the MPI scanner within seconds. To validate and compare our MPI data, we performed perfusion imaging with a small animal MRI scanner. MPI detected the perfusion deficits in the ischemic brain, which were comparable to those with MRI but in real-time. For the first time, we showed that MPI could be used as a diagnostic tool for relevant diseases in vivo, such as an ischemic stroke. Due to its shorter image acquisition times and increased temporal resolution compared to that of MRI or CT, we expect that MPI offers the potential to improve stroke imaging and treatment.

Towards Picogram Detection of Superparamagnetic Iron-Oxide Particles Using a Gradiometric Receive Coil.

Superparamagnetic iron-oxide nanoparticles can be used in medical applications like vascular or targeted imaging. Magnetic particle imaging (MPI) is a promising tomographic imaging technique that allows visualizing the 3D nanoparticle distribution concentration in a non-invasive manner. The two main strengths of MPI are high temporal resolution and high sensitivity. While the first has been proven in the assessment of dynamic processes like cardiac imaging, it is unknown how far the detection limit of MPI can be lowered. Within this work, we will present a highly sensitive gradiometric receive-coil unit combined with a noise-matching network tailored for the imaging of mice. The setup is capable of detecting 5 ng of iron in-vitro with an acquisition time of 2.14 sec. In terms of iron concentration we are able to detect 156 µg/L marking the lowest value that has been reported for an MPI scanner so far. In-vivo MPI mouse images of a 512 ng bolus and a 21.5 ms acquisition time allow for capturing the flow of an intravenously injected tracer through the heart of a mouse. Since it has been rather difficult to compare detection limits across MPI publications we propose guidelines to improve the comparability of future MPI studies.

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.

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.

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 MPI's 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.

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.

Detection of Cancer-Specific Proteases Using Magnetic Relaxation of Peptide-Conjugated Nanoparticles in Biological Environment.

Protease expression is closely linked to malignant phenotypes of different solid tumors; as such, their detection is promising for diagnosis and treatment of cancers, Alzheimer's, and vascular diseases. Here, we describe a new method for detecting proteases by sensitively monitoring the magnetic relaxation of monodisperse iron oxide nanoparticles (IONPs) using magnetic particle spectrometer (MPS). In this assay, tailored peptides functioning as activatable nanosensors link magnetic nanoparticles and possess selective sites that are recognizeable and cleaveable by specific proteases. When these linker peptides, labeled with biotin at N- and C-terminals, are added to the neutravidin functionalized IONPs, nanoparticles aggregate, resulting in well-defined changes in the MPS signal. However, as designed, in the presence of proteases these peptides are cleaved at predetermined sites, redispersing IONPs, and returning the MPS signal(s) close to its preaggregation state. These changes observed in all aspects of the MPS signal (peak intensity, its position as a function of field amplitude, and full width at half-maximum-when combined, these three also eliminate false positives), help to detect specific proteases, relying only on the magnetic relaxation characteristics of the functionalized nanoparticles. We demonstrate the general utility of this assay by detecting one each from the two general classes of proteases: trypsin (digestive serine protease, involved in various cancers, promoting proliferation, invasion, and metastasis) and matrix metalloproteinase (MMP-2, observed through metastasis and tumor angiogenesis). This MPS based protease-assay is rapid, reproducible, and highly sensitive and can form the basis of a feasible, high-throughput method for detection of various other proteases.

Magnetic Nanoparticles: Material Engineering and Emerging Applications in Lithography and Biomedicine.

We present an interdisciplinary overview of material engineering and emerging applications of iron oxide nanoparticles. We discuss material engineering of nanoparticles in the broadest sense, emphasizing size and shape control, large-area self-assembly, composite/hybrid structures, and surface engineering. This is followed by a discussion of several non-traditional, emerging applications of iron oxide nanoparticles, including nanoparticle lithography, magnetic particle imaging, magnetic guided drug delivery, and positive contrast agents for magnetic resonance imaging. We conclude with a succinct discussion of the pharmacokinetics pathways of iron oxide nanoparticles in the human body -- an important and required practical consideration for any in vivo biomedical application, followed by a brief outlook of the field.