Clinical magnetic hyperthermia requires integrated magnetic particle imaging.

Magnetic nanomaterials that respond to clinical magnetic devices have significant potential as cancer nanotheranostics. The complexities of their physics, however, introduce challenges for these applications. Hyperthermia is a heat-based cancer therapy that improves treatment outcomes and patient survival when controlled energy delivery is combined with accurate thermometry. To date, few technologies have achieved the needed evolution for the demands of the clinic. Magnetic fluid hyperthermia (MFH) offers this potential, but to be successful it requires particle-imaging technology that provides real-time thermometry. Presently, the only technology having the potential to meet these requirements is magnetic particle imaging (MPI), for which a proof-of-principle demonstration with MFH has been achieved. Successful clinical translation and adoption of integrated MPI/MFH technology will depend on successful resolution of the technological challenges discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Magnetic particle imaging for radiation-free, sensitive and high-contrast vascular imaging and cell tracking.

Magnetic particle imaging (MPI) is an emerging ionizing radiation-free biomedical tracer imaging technique that directly images the intense magnetization of superparamagnetic iron oxide nanoparticles (SPIOs). MPI offers ideal image contrast because MPI shows zero signal from background tissues. Moreover, there is zero attenuation of the signal with depth in tissue, allowing for imaging deep inside the body quantitatively at any location. Recent work has demonstrated the potential of MPI for robust, sensitive vascular imaging and cell tracking with high contrast and dose-limited sensitivity comparable to nuclear medicine. To foster future applications in MPI, this new biomedical imaging field is welcoming researchers with expertise in imaging physics, magnetic nanoparticle synthesis and functionalization, nanoscale physics, and small animal imaging applications.

Magnetic particle imaging of islet transplantation in the liver and under the kidney capsule in mouse models.

BACKGROUND: Islet transplantation (Tx) represents the most promising therapy to restore normoglycemia in type 1 diabetes (T1D) patients to date. As significant islet loss has been observed after the procedure, there is an urgent need for developing strategies for monitoring transplanted islet grafts. In this report we describe for the first time the application of magnetic particle imaging (MPI) for monitoring transplanted islets in the liver and under the kidney capsule in experimental animals. METHODS: Pancreatic islets isolated from Papio hamadryas were labeled with superparamagnetic iron oxides (SPIOs) and used for either islet phantoms or Tx in the liver or under the kidney capsule of NOD scid mice. MPI was used to image and quantify islet phantoms and islet transplanted experimental animals post-mortem at 1 and 14 days after Tx. Magnetic resonance imaging (MRI) was used to confirm the presence of labeled islets in the liver and under the kidney capsule 1 day after Tx. RESULTS: MPI of labeled islet phantoms confirmed linear correlation between the number of islets and the MPI signal (R2=0.988). Post-mortem MPI performed on day 1 after Tx showed high signal contrast in the liver and under the kidney capsule. Quantitation of the signal supports islet loss over time, which is normally observed 2 weeks after Tx. No MPI signal was observed in control animals. In vivo MRI confirmed the presence of labeled islets/islet clusters in liver parenchyma and under the kidney capsule one day after Tx. CONCLUSIONS: Here we demonstrate that MPI can be used for quantitative detection of labeled pancreatic islets in the liver and under the kidney capsule of experimental animals. We believe that MPI, a modality with no depth attenuation and zero background tissue signal could be a suitable method for imaging transplanted islet grafts.

Magnetic Particle Imaging-Guided Heating in Vivo Using Gradient Fields for Arbitrary Localization of Magnetic Hyperthermia Therapy.

Image-guided treatment of cancer enables physicians to localize and treat tumors with great precision. Here, we present in vivo results showing that an emerging imaging modality, magnetic particle imaging (MPI), can be combined with magnetic hyperthermia into an image-guided theranostic platform. MPI is a noninvasive 3D tomographic imaging method with high sensitivity and contrast, zero ionizing radiation, and is linearly quantitative at any depth with no view limitations. The same superparamagnetic iron oxide nanoparticle (SPIONs) tracers imaged in MPI can also be excited to generate heat for magnetic hyperthermia. In this study, we demonstrate a theranostic platform, with quantitative MPI image guidance for treatment planning and use of the MPI gradients for spatial localization of magnetic hyperthermia to arbitrarily selected regions. This addresses a key challenge of conventional magnetic hyperthermia-SPIONs delivered systemically accumulate in off-target organs ( e.g., liver and spleen), and difficulty in localizing hyperthermia results in collateral heat damage to these organs. Using a MPI magnetic hyperthermia workflow, we demonstrate image-guided spatial localization of hyperthermia to the tumor while minimizing collateral damage to the nearby liver (1-2 cm distance). Localization of thermal damage and therapy was validated with luciferase activity and histological assessment. Apart from localizing thermal therapy, the technique presented here can also be extended to localize actuation of drug release and other biomechanical-based therapies. With high contrast and high sensitivity imaging combined with precise control and localization of the actuated therapy, MPI is a powerful platform for magnetic-based theranostics.

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.

Optimal Broadband Noise Matching to Inductive Sensors: Application to Magnetic Particle Imaging.

Inductive sensor-based measurement techniques are useful for a wide range of biomedical applications. However, optimizing the noise performance of these sensors is challenging at broadband frequencies, owing to the frequency-dependent reactance of the sensor. In this work, we describe the fundamental limits of noise performance and bandwidth for these sensors in combination with a low-noise amplifier. We also present three equivalent methods of noise matching to inductive sensors using transformer-like network topologies. Finally, we apply these techniques to improve the noise performance in magnetic particle imaging, a new molecular imaging modality with excellent detection sensitivity. Using a custom noise-matched amplifier, we experimentally demonstrate an 11-fold improvement in noise performance in a small animal magnetic particle imaging scanner.

Seeing SPIOs Directly In Vivo with Magnetic Particle Imaging.

Magnetic particle imaging (MPI) is a new molecular imaging technique that directly images superparamagnetic tracers with high image contrast and sensitivity approaching nuclear medicine techniques-but without ionizing radiation. Since its inception, the MPI research field has quickly progressed in imaging theory, hardware, tracer design, and biomedical applications. Here, we describe the history and field of MPI, outline pressing challenges to MPI technology and clinical translation, highlight unique applications in MPI, and describe the role of the WMIS MPI Interest Group in collaboratively advancing MPI as a molecular imaging technique. We invite interested investigators to join the MPI Interest Group and contribute new insights and innovations to the MPI field.

First in vivo magnetic particle imaging of lung perfusion in rats.

Pulmonary embolism (PE), along with the closely related condition of deep vein thrombosis, affect an estimated 600 000 patients in the US per year. Untreated, PE carries a mortality rate of 30%. Because many patients experience mild or non-specific symptoms, imaging studies are necessary for definitive diagnosis of PE. Iodinated CT pulmonary angiography is recommended for most patients, while nuclear medicine-based ventilation/perfusion (V/Q) scans are reserved for patients in whom the use of iodine is contraindicated. Magnetic particle imaging (MPI) is an emerging tracer imaging modality with high image contrast (no tissue background signal) and sensitivity to superparamagnetic iron oxide (SPIO) tracer. Importantly, unlike CT or nuclear medicine, MPI uses no ionizing radiation. Further, MPI is not derived from magnetic resonance imaging (MRI); MPI directly images SPIO tracers via their strong electronic magnetization, enabling deep imaging of anatomy including within the lungs, which is very challenging with MRI. Here, the first high-contrast in vivo MPI lung perfusion images of rats are shown using a novel lung perfusion agent, MAA-SPIOs.

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.

A High-Throughput, Arbitrary-Waveform, MPI Spectrometer and Relaxometer for Comprehensive Magnetic Particle Optimization and Characterization.

Magnetic Particle Imaging (MPI) is a promising new tracer modality with zero attenuation deep in tissue, high contrast and sensitivity, and an excellent safety profile. However, the spatial resolution of MPI is limited to around 1 mm currently and urgently needs to be improved for clinical applications such as angiography and brain perfusion. Although MPI resolution is highly dependent on tracer characteristics and the drive waveforms, optimization is limited to a small subset of possible excitation strategies by current MPI hardware that only does sinusoidal drive waveforms at very few frequencies. To enable a more comprehensive and rapid optimization of drive waveforms for multiple metrics like resolution and signal strength simultaneously, we demonstrate the first untuned MPI spectrometer/relaxometer with unprecedented 400 kHz excitation bandwidth and capable of high-throughput acquisition of harmonic spectra (100 different drive-field frequencies in only 500 ms). It is also capable of arbitrary drive-field waveforms which have not been experimentally evaluated in MPI to date. Its high-throughput capability, frequency-agility and tabletop size makes this Arbitrary Waveform Relaxometer/Spectrometer (AWR) a convenient yet powerfully flexible tool for nanoparticle experts seeking to characterize magnetic particles and optimize MPI drive waveforms for in vitro biosensing and in vivo imaging with MPI.

Quantitative Magnetic Particle Imaging Monitors the Transplantation, Biodistribution, and Clearance of Stem Cells In Vivo.

Stem cell therapies have enormous potential for treating many debilitating diseases, including heart failure, stroke and traumatic brain injury. For maximal efficacy, these therapies require targeted cell delivery to specific tissues followed by successful cell engraftment. However, targeted delivery remains an open challenge. As one example, it is common for intravenous deliveries of mesenchymal stem cells (MSCs) to become entrapped in lung microvasculature instead of the target tissue. Hence, a robust, quantitative imaging method would be essential for developing efficacious cell therapies. Here we show that Magnetic Particle Imaging (MPI), a novel technique that directly images iron-oxide nanoparticle-tagged cells, can longitudinally monitor and quantify MSC administration in vivo. MPI offers near-ideal image contrast, depth penetration, and robustness; these properties make MPI both ultra-sensitive and linearly quantitative. Here, we imaged, for the first time, the dynamic trafficking of intravenous MSC administrations using MPI. Our results indicate that labeled MSC injections are immediately entrapped in lung tissue and then clear to the liver within one day, whereas standard iron oxide particle (Resovist) injections are immediately taken up by liver and spleen. Longitudinal MPI-CT imaging also indicated a clearance half-life of MSC iron oxide labels in the liver at 4.6 days. Finally, our ex vivo MPI biodistribution measurements of iron in liver, spleen, heart, and lungs after injection showed excellent agreement (R(2) = 0.943) with measurements from induction coupled plasma spectrometry. These results demonstrate that MPI offers strong utility for noninvasively imaging and quantifying the systemic distribution of cell therapies and other therapeutic agents.

Low drive field amplitude for improved image resolution in magnetic particle imaging.

PURPOSE: Magnetic particle imaging (MPI) is a new imaging technology that directly detects superparamagnetic iron oxide nanoparticles. The technique has potential medical applications in angiography, cell tracking, and cancer detection. In this paper, the authors explore how nanoparticle relaxation affects image resolution. Historically, researchers have analyzed nanoparticle behavior by studying the time constant of the nanoparticle physical rotation. In contrast, in this paper, the authors focus instead on how the time constant of nanoparticle rotation affects the final image resolution, and this reveals nonobvious conclusions for tailoring MPI imaging parameters for optimal spatial resolution. METHODS: The authors first extend x-space systems theory to include nanoparticle relaxation. The authors then measure the spatial resolution and relative signal levels in an MPI relaxometer and a 3D MPI imager at multiple drive field amplitudes and frequencies. Finally, these image measurements are used to estimate relaxation times and nanoparticle phase lags. RESULTS: The authors demonstrate that spatial resolution, as measured by full-width at half-maximum, improves at lower drive field amplitudes. The authors further determine that relaxation in MPI can be approximated as a frequency-independent phase lag. These results enable the authors to accurately predict MPI resolution and sensitivity across a wide range of drive field amplitudes and frequencies. CONCLUSIONS: To balance resolution, signal-to-noise ratio, specific absorption rate, and magnetostimulation requirements, the drive field can be a low amplitude and high frequency. Continued research into how the MPI drive field affects relaxation and its adverse effects will be crucial for developing new nanoparticles tailored to the unique physics of MPI. Moreover, this theory informs researchers how to design scanning sequences to minimize relaxation-induced blurring for better spatial resolution or to exploit relaxation-induced blurring for MPI with molecular contrast.

A Convex Formulation for Magnetic Particle Imaging X-Space Reconstruction.

Magnetic Particle Imaging (mpi) is an emerging imaging modality with exceptional promise for clinical applications in rapid angiography, cell therapy tracking, cancer imaging, and inflammation imaging. Recent publications have demonstrated quantitative mpi across rat sized fields of view with x-space reconstruction methods. Critical to any medical imaging technology is the reliability and accuracy of image reconstruction. Because the average value of the mpi signal is lost during direct-feedthrough signal filtering, mpi reconstruction algorithms must recover this zero-frequency value. Prior x-space mpi recovery techniques were limited to 1d approaches which could introduce artifacts when reconstructing a 3d image. In this paper, we formulate x-space reconstruction as a 3d convex optimization problem and apply robust a priori knowledge of image smoothness and non-negativity to reduce non-physical banding and haze artifacts. We conclude with a discussion of the powerful extensibility of the presented formulation for future applications.

Magnetic Particle Imaging tracks the long-term fate of in vivo neural cell implants with high image contrast.

We demonstrate that Magnetic Particle Imaging (MPI) enables monitoring of cellular grafts with high contrast, sensitivity, and quantitativeness. MPI directly detects the intense magnetization of iron-oxide tracers using low-frequency magnetic fields. MPI is safe, noninvasive and offers superb sensitivity, with great promise for clinical translation and quantitative single-cell tracking. Here we report the first MPI cell tracking study, showing 200-cell detection in vitro and in vivo monitoring of human neural graft clearance over 87 days in rat brain.

Effects of pulse duration on magnetostimulation thresholds.

PURPOSE: Medical imaging techniques such as magnetic resonance imaging and magnetic particle imaging (MPI) utilize time-varying magnetic fields that are subject to magnetostimulation limits, which often limit the speed of the imaging process. Various human-subject experiments have studied the amplitude and frequency dependence of these thresholds for gradient or homogeneous magnetic fields. Another contributing factor was shown to be number of cycles in a magnetic pulse, where the thresholds decreased with longer pulses. The latter result was demonstrated on two subjects only, at a single frequency of 1.27 kHz. Hence, whether the observed effect was due to the number of cycles or due to the pulse duration was not specified. In addition, a gradient-type field was utilized; hence, whether the same phenomenon applies to homogeneous magnetic fields remained unknown. Here, the authors investigate the pulse duration dependence of magnetostimulation limits for a 20-fold range of frequencies using homogeneous magnetic fields, such as the ones used for the drive field in MPI. METHODS: Magnetostimulation thresholds were measured in the arms of six healthy subjects (age: 27 ± 5 yr). Each experiment comprised testing the thresholds at eight different pulse durations between 2 and 125 ms at a single frequency, which took approximately 30-40 min/subject. A total of 34 experiments were performed at three different frequencies: 1.2, 5.7, and 25.5 kHz. A solenoid coil providing homogeneous magnetic field was used to induce stimulation, and the field amplitude was measured in real time. A pre-emphasis based pulse shaping method was employed to accurately control the pulse durations. Subjects reported stimulation via a mouse click whenever they felt a twitching/tingling sensation. A sigmoid function was fitted to the subject responses to find the threshold at a specific frequency and duration, and the whole procedure was repeated at all relevant frequencies and pulse durations. RESULTS: The magnetostimulation limits decreased with increasing pulse duration (T(pulse)). For T(pulse) < 18 ms, the thresholds were significantly higher than at the longest pulse durations (p < 0.01, paired Wilcoxon signed-rank test). The normalized magnetostimulation threshold (B(Norm)) vs duration curve at all three frequencies agreed almost identically, indicating that the observed effect is independent of the operating frequency. At the shortest pulse duration (T(pulse) ≈ 2 ms), the thresholds were approximately 24% higher than at the asymptotes. The thresholds decreased to within 4% of their asymptotic values for T(pulse) > 20 ms. These trends were well characterized (R(2) = 0.78) by a stretched exponential function given by B(Norm)=1+αe(-T(pulse)/ß(γ)) , where the fitted parameters were α = 0.44, ß = 4.32, and γ = 0.60. CONCLUSIONS: This work shows for the first time that the magnetostimulation thresholds decrease with increasing pulse duration, and that this effect is independent of the operating frequency. Normalized threshold vs duration trends are almost identical for a 20-fold range of frequencies: the thresholds are significantly higher at short pulse durations and settle to within 4% of their asymptotic values for durations longer than 20 ms. These results emphasize the importance of matching the human-subject experiments to the imaging conditions of a particular setup. Knowing the dependence of the safety limits to all contributing factors is critical for increasing the time-efficiency of imaging systems that utilize time-varying magnetic fields.

In vivo multimodal magnetic particle imaging (MPI) with tailored magneto/optical contrast agents.

Magnetic Particle Imaging (MPI) is a novel non-invasive biomedical imaging modality that uses safe magnetite nanoparticles as tracers. Controlled synthesis of iron oxide nanoparticles (NPs) with tuned size-dependent magnetic relaxation properties is critical for the development of MPI. Additional functionalization of these NPs for other imaging modalities (e.g. MRI and fluorescent imaging) would accelerate screening of the MPI tracers based on their in vitro and in vivo performance in pre-clinical trials. Here, we conjugated two different types of poly-ethylene-glycols (NH2-PEG-NH2 and NH2-PEG-FMOC) to monodisperse carboxylated 19.7 nm NPs by amide bonding. Further, we labeled these NPs with Cy5.5 near infra-red fluorescent (NIRF) molecules. Bi-functional PEG (NH2-PEG-NH2) resulted in larger hydrodynamic size (∼98 nm vs. ∼43 nm) of the tracers, due to inter-particle crosslinking. Formation of such clusters impacted the multimodal imaging performance and pharmacokinetics of these tracers. We found that MPI signal intensity of the tracers in blood depends on their plasmatic clearance pharmacokinetics. Whole body mice MPI/MRI/NIRF, used to study the biodistribution of the injected NPs, showed primary distribution in liver and spleen. Biodistribution of tracers and their clearance pathway was further confirmed by MPI and NIRF signals from the excised organs where the Cy5.5 labeling enabled detailed anatomical mapping of the tracers.in tissue sections. These multimodal MPI tracers, combining the strengths of each imaging modality (e.g. resolution, tracer sensitivity and clinical use feasibility) pave the way for various in vitro and in vivo MPI applications.

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 MPI's unique physics, synthesized using an organic-phase process and functionalized to ensure biocompatibility and adequate in vivo circulation time. Tailored tracers showed up to 3 × greater signal-to-noise ratio and better spatial resolution than existing commercial tracers in MPI images of phantoms.

Biogenic gas nanostructures as ultrasonic molecular reporters.

Ultrasound is among the most widely used non-invasive imaging modalities in biomedicine, but plays a surprisingly small role in molecular imaging due to a lack of suitable molecular reporters on the nanoscale. Here, we introduce a new class of reporters for ultrasound based on genetically encoded gas nanostructures from microorganisms, including bacteria and archaea. Gas vesicles are gas-filled protein-shelled compartments with typical widths of 45-250 nm and lengths of 100-600 nm that exclude water and are permeable to gas. We show that gas vesicles produce stable ultrasound contrast that is readily detected in vitro and in vivo, that their genetically encoded physical properties enable multiple modes of imaging, and that contrast enhancement through aggregation permits their use as molecular biosensors.

Twenty-fold acceleration of 3D projection reconstruction MPI.

We experimentally demonstrate a 20-fold improvement in acquisition time in projection reconstruction (PR) magnetic particle imaging (MPI) relative to the state-of-the-art PR MPI imaging results. We achieve this acceleration in our imaging system by introducing an additional Helmholtz electromagnet pair, which creates a slow shift (focus) field. Because of magnetostimulation limits in humans, we show that scan time with three-dimensional (3D) PR MPI is theoretically within the same order of magnitude as 3D MPI with a field free point; however, PR MPI has an order of magnitude signal-to-noise ratio gain.