[Magnetic particle imaging : From research to the prospect of clinical use]. / "Magnetic particle imaging" : Von der Forschung zur klinischen Perspektive.

BACKGROUND: Magnetic particle imaging offers far-reaching potential with a unique range of applications. OBJECTIVES: Identification of application scenarios with added value for clinical use. METHODS: Overview of previous application scenarios in phantom and small animal models, evaluation of dual-use potential. RESULTS: With its unique application profile, magnetic particle imaging offers a solution for clinical use where common, established imaging techniques reach their limits. As a tracer imaging technique, it is particularly characterized by its high speed, sensitivity and contrast-to-noise ratio. The low magnetic fields and low power consumption allow imaging to be mobile and taken to locations that were previously inaccessible. CONCLUSION: Magnetic particle imaging has seen rapid development in recent years. The applications demonstrated in the small animal model and phantom were able to support the versatility and added value of the method. With the availability of human imaging systems, the technology must face clinical verification studies.

Bimodal Interventional Instrument Markers for Magnetic Particle Imaging and Magnetic Resonance Imaging-A Proof-of-Concept Study.

The purpose of this work was to develop instrument markers that are visible in both magnetic particle imaging (MPI) and magnetic resonance imaging (MRI). The instrument markers were based on two different magnetic nanoparticle types (synthesized in-house KLB and commercial Bayoxide E8706). Coatings containing one of both particle types were fabricated and measured with a magnetic particle spectrometer (MPS) to estimate their MPI performance. Coatings based on both particle types were then applied on a segment of a nonmetallic guidewire. Imaging experiments were conducted using a commercial, preclinical MPI scanner and a preclinical 1 tesla MRI system. MPI image reconstruction was performed based on system matrices measured with dried KLB and Bayoxide E8706 coatings. The bimodal markers were clearly visible in both methods. They caused circular signal voids in MRI and areas of high signal intensity in MPI. Both the signal voids as well as the areas of high signal intensity were larger than the real marker size. Images that were reconstructed with a Bayoxide E8706 system matrix did not show sufficient MPI signal. Instrument markers with bimodal visibility are essential for the perspective of monitoring cardiovascular interventions with MPI/MRI hybrid systems.

Impact of Superparamagnetic Iron Oxide Nanoparticles on THP-1 Monocytes and Monocyte-Derived Macrophages.

Superparamagnetic iron oxide nanoparticles (SPIONs) are currently under examination for magnetic particle imaging, which represents a radiation free technology for three-dimensional imaging with high sensitivity, resolution and imaging speed. SPIONs are rapidly taken up by monocytes and other phagocytes which carry them to the site of inflammation. Therefore, the SPION biocompatibility is an essential parameter for a widespread MPI usage. Many improvements are expected from SPION development and its applications for cell visualization, but the impact of MPI optimized dextran coated SPIONs on the cellular characteristics of monocytic cells has been poorly studied up to now. THP-1 monocytes, monocyte-derived macrophages (MDM) as well as peripheral blood monocytes were incubated with MPI-optimized dextran-coated SPIONs of a size between 83.5 and 86 nm. SPION uptake was measured by FITC fluorescence of labeled SPIONs and Prussian blue staining. The activation of monocytes and MDMs was evaluated by CD14, CD11b and CD86 in flow cytometry. The secretion of IL-1ß, and IL-10 was analyzed in supernatants. SPIONs were rapidly taken up by monocytes and monocyte-derived macrophages while no decrease in cell viability was observed. Expression patterns of CD11b, CD14, and CD86 were not affected in THP-1 monocytes and MDMs. Monocyte differentiation in macrophages was hindered during SPION uptake. THP-1 monocytes as well as monocyte-derived macrophages showed significantly increased IL-1ß and decreased IL-10 secretion by tendency after SPION treatment. Dextran-coated SPIONs showed a low cytotoxicity on monocytes but exert undesirable inflammatory side effects that have to be considered for imaging applications.

Multimodal Targeted Nanoparticle-Based Delivery System for Pancreatic Tumor Imaging in Cellular and Animal Models.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), which ranks forth on the cancer-related death statistics still is both a diagnostic and a therapeutic challenge. Adenocarcinoma of the exocrine human pancreas originates in most instances from malignant transformation of ductal epithelial cells, alternatively by Acinar-Ductal Metaplasia (ADM). RA-96 antibody targets to a mucin M1, according to the more recent nomenclature MUC5AC, an extracellular matrix component excreted by PDAC cells. In this study, we tested the usability of multimodal nanoparticle carrying covalently coupled RA-96 Fab fragments for pancreatic tumor imaging. METHODS: In order to make and evaluate a novel, better targeting, theranostic nanoparticle, iron nanoparticles and the optical dye indocyanin green (ICG) were encapsulated into the cationic sphingomyelin (SM) consisting liposomes. RA-96 Fab fragment was conjugated to the liposomal surface of the nanoparticle to increase tumor homing ability. ICG and iron nanoparticle-encapsulated liposomes were studied in vitro with cells and (i) their visibility in magnetic resonance imaging (MRI), (ii) optical, (iii) Magnetic particle spectroscopy (MPS) and (iv) photoacoustic settings was tested in vitro and also in in vivo models. The targeting ability and MRI and photoacoustic visibility of the RA-96-nanoparticles were first tested in vitro cell models where cell binding and internalization were studied. In in vivo experiments liposomal nanoparticles were injected into the tail vain using an orthotopic pancreatic tumor xenograft model and subcutaneous pancreatic cancer cell xenografts bearing mice to determine in vivo targeting abilities of RA-96-conjugated liposomes Results: Multimodal liposomes could be detected by MRI, MPS and by photoacoustic imaging in addition to optical imaging showing a wide range of imaging utility. The fluorescent imaging of ICG in pancreatic tumor cells Panc89 and Capan-2 revealed an increased association of ICG-encapsulated liposomes carrying RA-96 Fab fragments in vitro compared to the control liposomes without covalently linked RA-96. Fluorescent molecular tomography (FMT) studies showed increased accumulation of the RA96-targeted nanoparticles in the tumor area compared to non-targeted controls in vivo. Similar accumulation in the tumor sites could be seen with liposomal ferric particles in MRI. Fluorescent tumor signal was confirmed by using an intraoperative fluorescent imaging system, which showed fluorescent labeling of pancreatic tumors. CONCLUSION: These results suggest that RA-96-targeted liposomes encapsulating ICG and iron nanoparticles can be used to image pancreatic tumors with a variety of optical and magnetic imaging techniques. Additionally, they might be a suitable drug delivery tool to improve treatment of PDAC patients.

Navigation of a magnetic micro-robot through a cerebral aneurysm phantom with magnetic particle imaging.

Cerebral aneurysms are potentially life threatening and nowadays treated by a catheter-guided coiling or by a neurosurgical clipping intervention. Here, we propose a helically shaped magnetic micro-robot, which can be steered by magnetic fields in an untethered manner and could be applied for a novel coiling procedure. This is shown by navigating the micro-robot through an additively manufactured phantom of a human cerebral aneurysm. The magnetic fields are applied with a magnetic particle imaging (MPI) scanner, which allows for the navigation and tomographic visualization by the same machine. With MPI the actuation process can be visualized with a localization accuracy of 0.68 mm and an angiogram can be acquired both without any radiation exposure. First in-vitro phantom experiments are presented, showing an idea of a robot conducted treatment of cerebral aneurysms.

Magnetic Particle Imaging: In vitro Signal Analysis and Lumen Quantification of 21 Endovascular Stents.

PURPOSE: Endovascular stents are medical devices, which are implanted in stenosed blood vessels to ensure sufficient blood flow. Due to a high rate of in-stent re-stenoses, there is the need of a noninvasive imaging method for the early detection of stent occlusion. The evaluation of the stent lumen with computed tomography (CT) and magnetic resonance imaging (MRI) is limited by material-induced artifacts. The purpose of this work is to investigate the potential of the tracer-based modality magnetic particle imaging (MPI) for stent lumen visualization and quantification. METHODS: In this in vitro study, 21 endovascular stents were investigated in a preclinical MPI scanner. Therefore, the stents were implanted in vessel phantoms. For the signal analysis, the phantoms were scanned without tracer material, and the signal-to-noise-ratio was analyzed. For the evaluation of potential artifacts and the lumen quantification, the phantoms were filled with diluted tracer agent. To calculate the stent lumen diameter a calibrated threshold value was applied. RESULTS: We can show that it is possible to visualize the lumen of a variety of endovascular stents without material induced artifacts, as the stents do not generate sufficient signals in MPI. The stent lumen quantification showed a direct correlation between the calculated and nominal diameter (r = 0.98). CONCLUSION: In contrast to MRI and CT, MPI is able to visualize and quantify stent lumina very accurately.

Magnetic Particle Imaging: Artifact-Free Metallic Stent Lumen Imaging in a Phantom Study.

PURPOSE: To illustrate the potential of magnetic particle imaging (MPI) for stent lumen imaging in comparison with clinical computed tomography (CT) and magnetic resonance imaging (MRI). MATERIALS AND METHODS: Imaging of eight tracer-filled, stented vessel phantoms and a tracer-filled, non-stented reference phantom for each diameter was performed on a preclinical MPI scanner: eight commercially available coronary stents of different dimensions (diameter: 3-4 mm; length: 11-38 mm) and materials (stainless steel, platinum-chromium) were implanted into silicone vessel phantoms. For comparison, all vessel phantoms were also visualized by MRI and CT. Two radiologists assessed the images regarding stent-induced artifacts using a 5-point grading scale. RESULTS: The visualization of all stented vessel phantoms was achieved without stent-induced artifacts with MPI. In contrast, MRI and CT images revealed multiform stent-induced artifacts. CONCLUSION: Given its clinical introduction, MPI has the potential to overcome the disadvantages of MRI and CT concerning the visualization of the stent lumen.

Tracking the Growth of Superparamagnetic Nanoparticles with an In-Situ Magnetic Particle Spectrometer (INSPECT).

Magnetic Particle Spectroscopy (MPS) is a measurement technique to determine the magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) in an oscillating magnetic field as applied in Magnetic Particle Imaging (MPI). State of the art MPS devices are solely capable of measuring the magnetization response of the SPIONs to an oscillatory magnetic excitation retrospectively, i.e. after the synthesis process. In this contribution, a novel in-situ magnetic particle spectrometer (INSPECT) is presented, which can be used to monitor the entire synthesis process from particle genesis via growth to the stable colloidal suspension of the nanoparticles in real time. The device is suitable for the use in a biochemistry environment. It has a chamber size of 72 mm such that a 100 ml reaction flask can be used for synthesis. For an alkaline-based precipitation, the change of magnetic properties of SPIONs during the nucleation and growth phase of the synthesis is demonstrated. The device is able to record the changes in the amplitude and phase spectra, and, in turn, the hysteresis. Hence, it is a powerful tool for an in-depth understanding of the nanoparticle formation dynamics during the synthesis process.

Magnetic particle imaging in vascular medicine.

Magnetic particle imaging (MPI) is a new medical imaging technique that enables three-dimensional real-time imaging of a magnetic tracer material. Although it is not yet in clinical use, it is highly promising, especially for vascular and interventional imaging. The advantages of MPI are that no ionizing radiation is necessary, its high sensitivity enables the detection of very small amounts of the tracer material, and its high temporal resolution enables real-time imaging, which makes MPI suitable as an interventional imaging technique. As MPI is a tracer-based imaging technique, functional imaging is possible by attaching specific molecules to the tracer material. In the first part of this article, the basic principle of MPI will be explained and a short overview of the principles of the generation and spatial encoding of the tracer signal will be given. After this, the used tracer materials as well as their behavior in MPI will be introduced. A subsequent presentation of selected scanner topologies will show the current state of research and the limitations researchers are facing on the way from preclinical toward human-sized scanners. Furthermore, it will be briefly shown how to reconstruct an image from the tracer materials' signal. In the last part, a variety of possible future clinical applications will be presented with an emphasis on vascular imaging, such as the use of MPI during cardiovascular interventions by visualizing the instruments. Investigations will be discussed, which show the feasibility to quantify the degree of stenosis and diagnose strokes and traumatic brain injuries as well as cerebral or gastrointestinal bleeding with MPI. As MPI is not only suitable for vascular medicine but also offers a broad range of other possible applications, a selection of those will be briefly presented at the end of the article.

Magnetic particle imaging: current developments and future directions.

Magnetic particle imaging (MPI) is a novel imaging method that was first proposed by Gleich and Weizenecker in 2005. Applying static and dynamic magnetic fields, MPI exploits the unique characteristics of superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs' response allows a three-dimensional visualization of their distribution in space with a superb contrast, a very high temporal and good spatial resolution. Essentially, it is the SPIONs' superparamagnetic characteristics, the fact that they are magnetically saturable, and the harmonic composition of the SPIONs' response that make MPI possible at all. As SPIONs are the essential element of MPI, the development of customized nanoparticles is pursued with the greatest effort by many groups. Their objective is the creation of a SPION or a conglomerate of particles that will feature a much higher MPI performance than nanoparticles currently available commercially. A particle's MPI performance and suitability is characterized by parameters such as the strength of its MPI signal, its biocompatibility, or its pharmacokinetics. Some of the most important adjuster bolts to tune them are the particles' iron core and hydrodynamic diameter, their anisotropy, the composition of the particles' suspension, and their coating. As a three-dimensional, real-time imaging modality that is free of ionizing radiation, MPI appears ideally suited for applications such as vascular imaging and interventions as well as cellular and targeted imaging. A number of different theories and technical approaches on the way to the actual implementation of the basic concept of MPI have been seen in the last few years. Research groups around the world are working on different scanner geometries, from closed bore systems to single-sided scanners, and use reconstruction methods that are either based on actual calibration measurements or on theoretical models. This review aims at giving an overview of current developments and future directions in MPI about a decade after its first appearance.

Biological impact of superparamagnetic iron oxide nanoparticles for magnetic particle imaging of head and neck cancer cells.

BACKGROUND: As a tomographic imaging technology, magnetic particle imaging (MPI) allows high spatial resolution and sensitivity, and the possibility to create real-time images by determining the spatial distribution of magnetic particles. To ensure a prospective biosafe application of UL-D (University of Luebeck-Dextran coated superparamagnetic nanoparticles), we evaluated the biocompatibility of superparamagnetic iron oxide nanoparticles (SPIONs), their impact on biological properties, and their cellular uptake using head and neck squamous cancer cells (HNSCCs). METHODS: SPIONs that met specific MPI requirements were synthesized as tracers. Labeling and uptake efficiency were analyzed by hematoxylin and eosin staining and magnetic particle spectrometry. Flow cytometry, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays, and real-time cell analyzer assays were used to investigate apoptosis, proliferation, and the cytokine response of SPION-labeled cells. The production of reactive oxygen species (ROS) was determined using a fluorescent dye. Experimental results were compared to the contrast agent Resovist(®), a standard agent used in MPI. RESULTS: UL-D nanoparticles and Resovist particles were taken up in vitro by HNSCCs via unspecific phagocytosis followed by cytosolic accumulation. To evaluate toxicity, flow cytometry analysis was performed; results showed that dose- and time-dependent administration of Resovist induced apoptosis whereas cell viability of UL-D-labeled cells was not altered. We observed decreased cell proliferation in response to increased SPION concentrations. An intracellular production of ROS could not be detected, suggesting that the particles did not cause oxidative stress. Tumor necrosis factor alpha (TNF-α) and interleukins IL-6, IL-8, and IL-1ß were measured to distinguish inflammatory responses. Only the primary tumor cell line labeled with >0.5 mM Resovist showed a significant increase in IL-1ß secretion. CONCLUSION: Our data suggest that UL-D SPIONs are a promising tracer material for use in innovative tumor cell analysis in MPI.

Magnetic particle imaging: kinetics of the intravascular signal in vivo.

BACKGROUND: Magnetic particle imaging (MPI) uses magnetic fields to visualize superparamagnetic iron oxide nanoparticles (SPIO). Today, Resovist(®) is still the reference SPIO for MPI. The objective of this study was to evaluate the in vivo blood half-life of two different types of Resovist (one from Bayer Pharma AG, and one from I'rom Pharmaceutical Co Ltd) in MPI. METHODS: A Resovist concentration of 50 µmol/kg was injected into the ear artery of ten New Zealand White rabbits. Five animals received Resovist distributed by I'rom Pharmaceutical Co Ltd and five received Resovist by Bayer Pharma AG. Blood samples were drawn before and directly after injection of Resovist, at 5, 10, and 15 minutes, and then every 15 minutes until 120 minutes after the injection. The MPI signal of the blood samples was evaluated using magnetic particle spectroscopy. RESULTS: The average decline of the blood MPI signal from the two distributions differed significantly (P=0.0056). Resovist distributed by Bayer Pharma AG showed a slower decline of the MPI signal (39.7% after 5 minutes, 20.5% after 10 minutes, and 12.1% after 15 minutes) compared with Resovist produced by I'rom Pharmaceutical Co Ltd (20.4% after 5 minutes, 7.8% after 10 minutes, no signal above noise level after 15 minutes). CONCLUSION: In MPI, the blood half-life of an SPIO tracer cannot be equalized to the blood half-life of its MPI signal. Resovist shows a very rapid decline of blood MPI signal and is thus not suitable as a long circulating tracer. For cardiovascular applications in MPI, it may be used as a bolus tracer.

Simulation of the magnetization dynamics of diluted ferrofluids in medical applications.

Ferrofluids, which are stable, colloidal suspensions of single-domain magnetic nanoparticles, have a large impact on medical technologies like magnetic particle imaging (MPI), magnetic resonance imaging (MRI) and hyperthermia. Here, computer simulations promise to improve our understanding of the versatile magnetization dynamics of diluted ferrofluids. A detailed algorithmic introduction into the simulation of diluted ferrofluids will be presented. The algorithm is based on Langevin equations and resolves the internal and the external rotation of the magnetic moment of the nanoparticles, i.e., the Néel and Brown diffusion. The derived set of stochastic differential equations are solved by a combination of an Euler and a Heun integrator and tested with respect to Boltzmann statistics.

Comparison of commercial iron oxide-based MRI contrast agents with synthesized high-performance MPI tracers.

Magnetic particle imaging (MPI) recently emerged as a new tomographic imaging method directly visualizing the amount and location of superparamagnetic iron oxide particles (SPIOs) with high spatial resolution. To fully exploit the imaging performance of MPI, specific requirements are demanded on the SPIOs. Most important, a sufficiently high number of detectable harmonics of the receive signal spectrum is required. In this study, an assessment of commercial iron oxide-based MRI contrast agents is carried out, and the result is compared with that of a new self-synthesized high-performance MPI tracer. The decay of the harmonics is measured with a magnetic particle spectrometer (MPS). For the self-synthesized carboxymethyldextran-coated SPIO, it can be demonstrated that despite a small iron core diameter, the particle performance is as good as in Resovist, the best-performing commercial SPIO today. However, the self-synthesized particles show the lowest iron concentration compared with Resovist, Sinerem, and Endorem. As the iron dose will be an important issue in human MPI, the synthesis technique and the separation chain for self-synthesis will be pursued for further improvements. In evaluations carried out with MPS, it can be shown in this work that the quality of the self-synthesized nanoparticles outperforms the three commercial tracer materials when the decay of harmonics is normalized by the iron concentration. The results of this work emphasize the importance of producing highly uniform and monodisperse superparamagnetic particles contributing to lower application of tracer concentration, better sensitivity, or a higher spatial resolution.

Magnetic particle imaging: introduction to imaging and hardware realization.

Magnetic Particle Imaging (MPI) is a recently invented tomographic imaging method that quantitatively measures the spatial distribution of a tracer based on magnetic nanoparticles. The new modality promises a high sensitivity and high spatial as well as temporal resolution. There is a high potential of MPI to improve interventional and image-guided surgical procedures because, today, established medical imaging modalities typically excel in only one or two of these important imaging properties. MPI makes use of the non-linear magnetization characteristics of the magnetic nanoparticles. For this purpose, two magnetic fields are created and superimposed, a static selection field and an oscillatory drive field. If superparamagnetic iron-oxide nanoparticles (SPIOs) are subjected to the oscillatory magnetic field, the particles will react with a non-linear magnetization response, which can be measured with an appropriate pick-up coil arrangement. Due to the non-linearity of the particle magnetization, the received signal consists of the fundamental excitation frequency as well as of harmonics. After separation of the fundamental signal, the nanoparticle concentration can be reconstructed quantitatively based on the harmonics. The spatial coding is realized with the static selection field that produces a field-free point, which is moved through the field of view by the drive fields. This article focuses on the frequency-based image reconstruction approach and the corresponding imaging devices while alternative concepts like x-space MPI and field-free line imaging are described as well. The status quo in hardware realization is summarized in an overview of MPI scanners.