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.

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.

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.

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.

In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles.

Iron oxide nanoparticles (IONPs) have been extensively used during the last two decades, either as effective bio-imaging contrast agents or as carriers of biomolecules such as drugs, nucleic acids and peptides for controlled delivery to specific organs and tissues. Most of these novel applications require elaborate tuning of the physiochemical and surface properties of the IONPs. As new IONPs designs are envisioned, synergistic consideration of the body's innate biological barriers against the administered nanoparticles and the short and long-term side effects of the IONPs become even more essential. There are several important criteria (e.g. size and size-distribution, charge, coating molecules, and plasma protein adsorption) that can be effectively tuned to control the in vivo pharmacokinetics and biodistribution of the IONPs. This paper reviews these crucial parameters, in light of biological barriers in the body, and the latest IONPs design strategies used to overcome them. A careful review of the long-term biodistribution and side effects of the IONPs in relation to nanoparticle design is also given. While the discussions presented in this review are specific to IONPs, some of the information can be readily applied to other nanoparticle systems, such as gold, silver, silica, calcium phosphates and various polymers.

Tuning surface coatings of optimized magnetite nanoparticle tracers for in vivo Magnetic Particle Imaging.

Surface coatings are important components of Magnetic Particle Imaging (MPI) tracers - they preserve their key properties responsible for optimum tracer performance in physiological environments. In vivo, surface coatings form a physical barrier between the hydrophobic SPION cores and the physiological environment, and their design dictates the blood half-life and biodistribution of MPI tracers. Here we show the effect of tuning poly(ethylene glycol) (PEG)-based surface coatings on both in vitro and in vivo (mouse model) MPI performance of SPIONs. Our results showed that varying PEG molecular weight had a profound impact on colloidal stability, characterized using Dynamic Light Scattering (DLS), and the m'(H) response of SPIONs, measured in a 25 kHz/20 mTµ0-1max Magnetic Particle Spectrometer (MPS). Increasing PEG molecular weight from 5 kDa to 20 kDa preserved colloidal stability and m'(H) response of ~25 nm SPIONs - the optimum core diameter for MPI - in serum-rich cell culture medium for up to 24 hours. Furthermore, we compared the in vivo circulation time of SPIONs as a function of hydrodynamic diameter and showed that clustered SPIONs can adversely affect blood half-life; critically, SPIONs with clusters had 5 times shorter blood half-life than individually coated SPIONs. We anticipate that the development of MPI SPION tracers with long blood half-lives have potential not only in vascular imaging applications, but also enable opportunities in molecular targeting and imaging - a critical step towards early cancer detection using the new MPI modality.

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 tracer's 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.

Self-consistent magnetic properties of magnetite tracers optimized for magnetic particle imaging measured by ac susceptometry, magnetorelaxometry and magnetic particle spectroscopy.

Sensitivity and spatial resolution in Magnetic Particle Imaging are affected by magnetic properties of the nanoparticle tracers used during imaging. Here, we have carried out a comprehensive magnetic characterization of single-core iron oxide nanoparticles that were designed for MPI. We used ac susceptometry, fluxgate magnetorelaxometry, and magnetic particle spectroscopy to evaluate the tracer's magnetic core size, hydrodynamic size, and magnetic anisotropy. Our results present a self-consistent set of magnetic and structural parameters for the tracers that is consistent with direct measurements of size using transmission electron microscopy and dynamic light scattering and that can be used to better understand their MPI performance.

Highly Stable Amine Functionalized Iron Oxide Nanoparticles Designed for Magnetic Particle Imaging (MPI).

Magnetic particle imaging (MPI) is a promising medical imaging technology that uses iron oxide nanoparticles (NPs) as clinically safe tracers. The core and hydrodynamic size of these NPs determine the signal intensity and spatial resolution in MPI, whilst their monodispersity when preserved during the biomedical applications, generates a consistently high quality MPI image. Using an effective process to coat the synthesized NPs with amine terminated PEG molecules, we show by dynamic light scattering (DLS) that they are water-soluble with long-term stability in biological media such as phosphate buffered saline (PBS) and sodium bicarbonate buffers and Dulbecco's modified Eagle medium (DMEM) enriched with 10% fetal bovine serum (FBS). Further, using magnetic particle spectroscopy (MPS), to measure the particle response function (PRF), defined as the derivative of the magnetization of the nanoparticles, we predict the MPI performance of these nanoparticles at a driving field frequency of 25 kHz. The MPS efficacy of the functionalized nanoparticles was also monitored over time, and both signal intensity and resolution remained unchanged even after seven days of incubation. This is attributed to the dominant contribution of the Néel relaxation mechanism of the monodisperse and highly stable nanoparticles, which was preserved through the incubation period.

Size-Dependent Relaxation Properties of Monodisperse Magnetite Nanoparticles Measured Over Seven Decades of Frequency by AC Susceptometry.

Magnetic relaxation is exploited in innovative biomedical applications of magnetic particles such as magnetic particle imaging (MPI), magnetic fluid hyperthermia, and bio-sensing. Relaxation behavior should be optimized to achieve high performance imaging, efficient heating, and good SNR in bio-sensing. Using two AC susceptometers with overlapping frequency ranges, we have measured the relaxation behavior of a series of monodisperse magnetic particles and demonstrated that this approach is an effective way to probe particle relaxation characteristics from a few Hz to 10 MHz, the frequencies relevant for MPI, hyperthermia, and sensing.

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.

Optimizing magnetite nanoparticles for mass sensitivity in magnetic particle imaging.

PURPOSE: Magnetic particle imaging (MPI), using magnetite nanoparticles (MNPs) as tracer material, shows great promise as a platform for fast tomographic imaging. To date, the magnetic properties of MNPs used in imaging have not been optimized. As nanoparticle magnetism shows strong size dependence, the authors explore how varying MNP size impacts imaging performance in order to determine optimal MNP characteristics for MPI at any driving field frequency f0. METHODS: Monodisperse MNPs of varying size were synthesized and their magnetic properties characterized. Their MPI response was measured experimentally using a custom-built MPI transceiver designed to detect the third harmonic of MNP magnetization. The driving field amplitude H0 = 6 mT micro0(-1) and frequency f0 = 250 kHz were chosen to be suitable for imaging small animals. Experimental results were interpreted using a model of dynamic MNP magnetization that is based on the Langevin theory of superparamagnetism and accounts for sample size distribution and size-dependent magnetic relaxation. RESULTS: The experimental results show a clear variation in the MPI signal intensity as a function of MNP diameter that is in agreement with simulated results. A maximum in the plot of MPI signal vs MNP size indicates there is a particular size that is optimal for the chosen f0. CONCLUSIONS: The authors observed that MNPs 15 nm in diameter generate maximum signal amplitude in MPI experiments at 250 kHz. The authors expect the physical basis for this result, the change in magnetic relaxation with MNP size, will impact MPI under other experimental conditions.

Electron holography study of remanence states in exchange-biased MnPd/Fe bilayers grown epitaxially on MgO(001).

We investigated magnetic remanence states of epitaxially grown, exchange-biased MnPd/Fe bilayers by electron holography emphasizing the crystallographic orientations of the layers. Thin-foil transmission electron microscopy (TEM) specimens were carefully prepared along both hard and easy axes of the Fe layer. The ex situ magnetization-reversal process was carried out using the TEM specimens, and magnetic flux densities of the ultra-thin Fe layers were evaluated at different remanence states. We show that a spin configuration in the TEM specimens is determined by the competition between an exchange coupling at the MnPd/Fe bilayer interface, shape anisotropy of TEM specimens and intrinsic magnetocrystalline anisotropy of Fe.

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.

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.

The critical role of surfactants in the growth of cobalt nanoparticles.

We report a combined experimental and computational study on the critical role of surfactants in the nucleation and growth of Co nanoparticles synthesized by chemical routes. By varying the surfactant species, Co nanoparticles of different morphologies under similar reaction conditions (e.g., temperature and Co-precursor concentration) were produced. Depending on the surfactant species, the growth of Co nanoparticles followed three different growth pathways. For example, with surfactants oleic acid (OA) and trioctylphosphine oxide (TOPO) used in combination, Co nanoparticles followed a diffusional growth pathway, leading to single crystalline nanoparticles. Multiple-grained nanoparticles, through an aggregation process, were formed with the combination of surfactants OA and dioctylamine (DOA). Further, an Ostwald ripening process was observed in the case of TOPO alone. Complementary electronic structure calculations were used to predict the optimized Co-surfactant complex structures and to quantify the binding energy between the surfactants (ligands) and the Co atoms. These calculations were further applied to predict the Co nanoparticle nucleation and growth processes based on the stability of Co-surfactant complexes.

Biomedical Nanomagnetics: A Spin Through Possibilities in Imaging, Diagnostics, and Therapy.

Biomedical nanomagnetics is a multidisciplinary area of research in science, engineering and medicine with broad applications in imaging, diagnostics and therapy. Recent developments offer exciting possibilities in personalized medicine provided a truly integrated approach, combining chemistry, materials science, physics, engineering, biology and medicine, is implemented. Emphasizing this perspective, here we address important issues for the rapid development of the field, i.e., magnetic behavior at the nanoscale with emphasis on the relaxation dynamics, synthesis and surface functionalization of nanoparticles and core-shell structures, biocompatibility and toxicity studies, biological constraints and opportunities, and in vivo and in vitro applications. Specifically, we discuss targeted drug delivery and triggered release, novel contrast agents for magnetic resonance imaging, cancer therapy using magnetic fluid hyperthermia, in vitro diagnostics and the emerging magnetic particle imaging technique, that is quantitative and sensitive enough to compete with established imaging methods. In addition, the physics of self-assembly, which is fundamental to both biology and the future development of nanoscience, is illustrated with magnetic nanoparticles. It is shown that various competing energies associated with self-assembly converge on the nanometer length scale and different assemblies can be tailored by varying particle size and size distribution. Throughout this paper, while we discuss our recent research in the broad context of the multidisciplinary literature, we hope to bridge the gap between related work in physics/chemistry/engineering and biology/medicine and, at the same time, present the essential concepts in the individual disciplines. This approach is essential as biomedical nanomagnetics moves into the next phase of innovative translational research with emphasis on development of quantitative in vivo imaging, targeted and triggered drug release, and image guided therapy including validation of delivery and therapy response.

Size-dependant heating rates of iron oxide nanoparticles for magnetic fluid hyperthermia.

Using the thermal decomposition of organometallics method we have synthesized high-quality, iron oxide nanoparticles of tailorable size up to ~15nm and transferred them to a water phase by coating with a biocompatible polymer. The magnetic behavior of these particles was measured and fit to a log-normal distribution using the Chantrell method and their polydispersity was confirmed to be very narrow. By performing calorimetry measurements with these monodisperse particles we have unambiguously demonstrated, for the first time, that at a given frequency, heating rates of superparamagnetic particles are dependent on particle size, in agreement with earlier theoretical predictions.

Optimization of nanoparticle core size for magnetic particle imaging.

Magnetic particle imaging (MPI) is a powerful new research and diagnostic imaging platform that is designed to image the amount and location of superparamagnetic nanoparticles in biological tissue. Here, we present mathematical modeling results that show how MPI sensitivity and spatial resolution both depend on the size of the nanoparticle core and its other physical properties, and how imaging performance can be effectively optimized through rational core design. Modeling is performed using the properties of magnetite cores, since these are readily produced with a controllable size that facilitates quantitative imaging. Results show that very low detection thresholds (of a few nanograms Fe(3)O(4)) and sub-millimeter spatial resolution are possible with MPI.

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.