Superferromagnetic Nanoparticles Enable Order-of-Magnitude Resolution & Sensitivity Gain in Magnetic Particle Imaging.

Magnetic nanoparticles have many advantages in medicine such as their use in non-invasive imaging as a Magnetic Particle Imaging (MPI) tracer or Magnetic Resonance Imaging contrast agent, the ability to be externally shifted or actuated and externally excited to generate heat or release drugs for therapy. Existing nanoparticles have a gentle sigmoidal magnetization response that limits resolution and sensitivity. Here it is shown that superferromagnetic iron oxide nanoparticle chains (SFMIOs) achieve an ideal step-like magnetization response to improve both image resolution & SNR by more than tenfold over conventional MPI. The underlying mechanism relies on dynamic magnetization with square-like hysteresis loops in response to 20 kHz, 15 kAm-1 MPI excitation, with nanoparticles assembling into a chain under an applied magnetic field. Experimental data shows a "1D avalanche" dipole reversal of every nanoparticle in the chain when the applied field overcomes the dynamic coercive threshold of dipole-dipole fields from adjacent nanoparticles in the chain. Intense inductive signal is produced from this event resulting in a sharp signal peak. Novel MPI imaging strategies are demonstrated to harness this behavior towards order-of-magnitude medical image improvements. SFMIOs can provide a breakthrough in noninvasive imaging of cancer, pulmonary embolism, gastrointestinal bleeds, stroke, and inflammation imaging.

Using magnetic particle imaging systems to localize and guide magnetic hyperthermia treatment: tracers, hardware, and future medical applications.

Magnetic fluid hyperthermia (MFH) treatment makes use of a suspension of superparamagnetic iron oxide nanoparticles, administered systemically or locally, in combination with an externally applied alternating magnetic field, to ablate target tissue by generating heat through a process called induction. The heat generated above the mammalian euthermic temperature of 37°C induces apoptotic cell death and/or enhances the susceptibility of the target tissue to other therapies such as radiation and chemotherapy. While most hyperthermia techniques currently in development are targeted towards cancer treatment, hyperthermia is also used to treat restenosis, to remove plaques, to ablate nerves and to alleviate pain by increasing regional blood flow. While RF hyperthermia can be directed invasively towards the site of treatment, non-invasive localization of heat through induction is challenging. In this review, we discuss recent progress in the field of RF magnetic fluid hyperthermia and introduce a new diagnostic imaging modality called magnetic particle imaging that allows for a focused theranostic approach encompassing treatment planning, treatment monitoring and spatially localized inductive heating.

Combining magnetic particle imaging and magnetic fluid hyperthermia for localized and image-guided treatment.

Magnetic fluid hyperthermia (MFH) has been widely investigated as a treatment tool for cancer and other diseases. However, focusing traditional MFH to a tumor deep in the body is not feasible because the in vivo wavelength of 300 kHz very low frequency (VLF) excitation fields is longer than 100 m. Recently we demonstrated that millimeter-precision localized heating can be achieved by combining magnetic particle imaging (MPI) with MFH. In principle, real-time MPI imaging can also guide the location and dosing of MFH treatments. Hence, the combination of MPI imaging plus real time localized MPI-MFH could soon permit closed-loop high-resolution hyperthermia treatment. In this review, we will discuss the fundamentals of localized MFH (e.g. physics and biosafety limitations), hardware implementation, MPI real-time guidance, and new research directions on MPI-MFH. We will also discuss how the scale up to human-sized MPI-MFH scanners could proceed.

Optimization of Drive Parameters for Resolution, Sensitivity and Safety in Magnetic Particle Imaging.

Magnetic Particle Imaging is an emerging tracer imaging modality with zero background signal and zero ionizing radiation, high contrast and high sensitivity with quantitative images. While there is recent work showing that the low amplitude or low frequency drive parameters can improve MPI's spatial resolution by mitigating relaxation losses, the concomitant decrease of the MPI's tracer sensitivity due to the lower drive slew rates was not fully addressed. There has yet to be a wide parameter space, multi-objective optimization of MPI drive parameters for high resolution, high sensitivity and safety. In a large-scale study, we experimentally test 5 different nanoparticles ranging from multi to single-core across 18.5 nm to 32.1 nm core sizes and across an expansive drive parameter range of 0.4 - 416 kHz and 0.5 - 40 mT/ µ0 to assess spatial resolution, SNR, and safety. In addition, we analyze how drive-parameter-dependent shifts in harmonic signal energy away and towards the discarded first harmonic affect effective SNR in this optimization study. The results show that when optimizing for all four factors of resolution, SNR, discarded-harmonic-energy and safety, the overall trends are no longer monotonic and clear optimal points emerge. We present drive parameters different from conventional preclinical MPI showing ~ 2-fold improvement in spatial resolution while remaining within safety limits and addressing sensitivity by minimizing the typical SNR loss involved. Finally, validation of the optimization results with 2D images of phantoms was performed.

Pulsed Excitation in Magnetic Particle Imaging.

Magnetic particle imaging (MPI) is a promising new tracer-based imaging modality. The steady-state, nonlinear magnetization physics most fundamental to MPI typically predicts improving resolution with increasing tracer magnetic core size. For larger tracers, and given typical excitation slew rates, this steady-state prediction is compromised by dynamic processes that induce a significant secondary blur and prevent us from achieving high resolution using larger tracers. Here, we propose a new method of excitation and signal encoding in MPI we call pulsed MPI to overcome this phenomenon. Pulsed MPI allows us to directly encode the steady-state magnetic physics into the time-domain signal. This in turn gives rise to a simple reconstruction algorithm to obtain images free of secondary relaxation-induced blur. Here, we provide a detailed description of our approach in 1D, discuss how it compares with alternative approaches, and show experimental data demonstrating better than 500- [Formula: see text] resolution (at 7 T/m) with large tracers. Finally, we show experimental images from a 2D implementation.

A perspective on a rapid and radiation-free tracer imaging modality, magnetic particle imaging, with promise for clinical translation.

Magnetic particle imaging (MPI), introduced at the beginning of the twenty-first century, is emerging as a promising diagnostic tool in addition to the current repertoire of medical imaging modalities. Using superparamagnetic iron oxide nanoparticles (SPIOs), that are available for clinical use, MPI produces high contrast and highly sensitive tomographic images with absolute quantitation, no tissue attenuation at-depth, and there are no view limitations. The MPI signal is governed by the Brownian and Néel relaxation behavior of the particles. The relaxation time constants of these particles can be utilized to map information relating to the local microenvironment, such as viscosity and temperature. Proof-of-concept pre-clinical studies have shown favourable applications of MPI for better understanding the pathophysiology associated with vascular defects, tracking cell-based therapies and nanotheranostics. Functional imaging techniques using MPI will be useful for studying the pathology related to viscosity changes such as in vascular plaques and in determining cell viability of superparamagnetic iron oxide nanoparticle labeled cells. In this review article, an overview of MPI is provided with discussions mainly focusing on MPI tracers, applications of translational capabilities ranging from diagnostics to theranostics and finally outline a promising path towards clinical translation.

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.

The Relaxation Wall: Experimental Limits to Improving MPI Spatial Resolution by Increasing Nanoparticle Core size.

Magnetic Particle Imaging (MPI) is a promising new tracer modality with zero attenuation in tissue, high contrast and sensitivity, and an excellent safety profile. However, the spatial resolution of MPI is currently around 1 mm in small animal scanners. Especially considering tradeoffs when scaling up MPI scanning systems to human size, this resolution needs to be improved for clinical applications such as angiography and brain perfusion. One method to improve spatial resolution is to increase the magnetic core size of the superparamagnetic nanoparticle tracers. The Langevin model of superparamagnetism predicts a cubic improvement of spatial resolution with magnetic core diameter. However, prior work has shown that the finite temporal response, or magnetic relaxation, of the tracer increases with magnetic core diameter and eventually leads to blurring in the MPI image. Here we perform the first wide ranging study of 5 core sizes between 18-32 nm with experimental quantification of the spatial resolution of each. Our results show that increasing magnetic relaxation with core size eventually opposes the expected Langevin behavior, causing spatial resolution to stop improving after 25 nm. Different MPI excitation strategies were experimentally investigated to mitigate the effect of magnetic relaxation. The results show that magnetic relaxation could not be fully mitigated for the larger core sizes and the cubic resolution improvement predicted by the Langevin was not achieved. This suggests that magnetic relaxation is a significant and unsolved barrier to achieving the high spatial resolutions predicted by the Langevin model for large core size SPIOs.

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.

Combining magnetic particle imaging and magnetic fluid hyperthermia in a theranostic platform.

Magnetic particle imaging (MPI) is a rapidly developing molecular and cellular imaging modality. Magnetic fluid hyperthermia (MFH) is a promising therapeutic approach where magnetic nanoparticles are used as a conduit for targeted energy deposition, such as in hyperthermia induction and drug delivery. The physics germane to and exploited by MPI and MFH are similar, and the same particles can be used effectively for both. Consequently, the method of signal localization through the use of gradient fields in MPI can also be used to spatially localize MFH, allowing for spatially selective heating deep in the body and generally providing greater control and flexibility in MFH. Furthermore, MPI and MFH may be integrated together in a single device for simultaneous MPI-MFH and seamless switching between imaging and therapeutic modes. Here we show simulation and experimental work quantifying the extent of spatial localization of MFH using MPI systems: we report the first combined MPI-MFH system and demonstrate on-demand selective heating of nanoparticle samples separated by only 3 mm (up to 0.4 °C s-1 heating rates and 150 W g-1 SAR deposition). We also show experimental data for MPI performed at a typical MFH frequency and show preliminary simultaneous MPI-MFH experimental data.

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.

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.

50 years of computer simulation of the human thermoregulatory system.

This paper presents an updated and augmented version of the Wissler human thermoregulation model that has been developed continuously over the past 50 years. The existing Fortran code is translated into C with extensive embedded commentary. A graphical user interface (GUI) has been developed in Python to facilitate convenient user designation of input and output variables and formatting of data presentation. Use of the code with the GUI is described and demonstrated. New physiological elements were added to the model to represent the hands and feet, including the unique vascular structures adapted for heat transfer associated with glabrous skin. The heat transfer function and efficacy of glabrous skin is unique within the entire body based on the capacity for a very high rate of blood perfusion and the novel capability for dynamic regulation of blood flow. The model was applied to quantify the absolute and relative contributions of glabrous skin flow to thermoregulation for varying levels of blood perfusion. The model also was used to demonstrate how the unique features of glabrous skin blood flow may be recruited to implement thermal therapeutic procedures. We have developed proprietary methods to manipulate the control of glabrous skin blood flow in conjunction with therapeutic devices and simulated the effect of these methods with the model.

MR guided thermal therapy of pancreatic tumors with endoluminal, intraluminal and interstitial catheter-based ultrasound devices: Preliminary theoretical and experimental investigations.

Image-guided thermal interventions have been proposed for potential palliative and curative treatments of pancreatic tumors. Catheter-based ultrasound devices offer the potential for temporal and 3D spatial control of the energy deposition profile. The objective of this study was to apply theoretical and experimental techniques to investigate the feasibility of endogastric, intraluminal and transgastric catheter-based ultrasound for MR guided thermal therapy of pancreatic tumors. The transgastric approach involves insertion of a catheter-based ultrasound applicator (array of 1.5 mm OD x 10 mm transducers, 360° or sectored 180°, ~7 MHz frequency, 13-14G cooling catheter) directly into the pancreas, either endoscopically or via image-guided percutaneous placement. An intraluminal applicator, of a more flexible but similar construct, was considered for endoscopic insertion directly into the pancreatic or biliary duct. An endoluminal approach was devised based on an ultrasound transducer assembly (tubular, planar, curvilinear) enclosed in a cooling balloon which is endoscopically positioned within the stomach or duodenum, adjacent to pancreatic targets from within the GI tract. A 3D acoustic bio-thermal model was implemented to calculate acoustic energy distributions and used a FEM solver to determine the transient temperature and thermal dose profiles in tissue during heating. These models were used to determine transducer parameters and delivery strategies and to study the feasibility of ablating 1-3 cm diameter tumors located 2-10 mm deep in the pancreas, while thermally sparing the stomach wall. Heterogeneous acoustic and thermal properties were incorporated, including approximations for tumor desmoplasia and dynamic changes during heating. A series of anatomic models based on imaging scans of representative patients were used to investigate the three approaches. Proof of concept (POC) endogastric and transgastric applicators were fabricated and experimentally evaluated in tissue mimicking phantoms, ex vivo tissue and in vivo canine model under multi-slice MR thermometry. RF micro-coils were evaluated to enable active catheter-tracking and prescription of thermometry slice positions. Interstitial and intraluminal ultrasound applicators could be used to ablate (t43>240 min) tumors measuring 2.3-3.4 cm in diameter when powered with 20-30 W/cm2 at 7 MHz for 5-10 min. Endoluminal applicators with planar and curvilinear transducers operating at 3-4 MHz could be used to treat tumors up to 20-25 mm deep from the stomach wall within 5 min. POC devices were fabricated and successfully integrated into the MRI environment with catheter tracking, real-time thermometry and closed-loop feedback control.