Human-sized quantitative imaging of magnetic nanoparticles with nonlinear magnetorelaxometry.

Objective.Magnetorelaxomety imaging (MRXI) is a noninvasive imaging technique for quantitative detection of magnetic nanoparticles (MNPs). The qualitative and quantitative knowledge of the MNP distribution inside the body is a prerequisite for a number of arising biomedical applications, such as magnetic drug targeting and magnetic hyperthermia therapy. It was shown throughout numerous studies that MRXI is able to successfully localize and quantify MNP ensembles in volumes up to the size of a human head. However, deeper regions that lie far from the excitation coils and the magnetic sensors are harder to reconstruct due to the weaker signals from the MNPs in these areas. On the one hand, stronger magnetic fields need to be applied to produce measurable signals from such MNP distributions to further upscale MRXI, on the other hand, this invalidates the assumption of a linear relation between applied magnetic field and particle magnetization in the current MRXI forward model which is required for the imaging procedure.Approach.We tackle this problem by introducing a nonlinear MRXI forward model that is also valid for strong magnetic excitation fields.Main results.We demonstrate in our experimental feasibility study that scaling up the imaging region to the size of a human torso using nonlinear MRXI is possible. Despite the extreme simplicity of the imaging setup applied in this study, an immobilized MNP sample with 6.3 cm3and 12 mg Fe could be localized and quantified with an acceptable quality.Significance.A well-engineered MRXI setup could provide much better imaging qualities in shorter data acquisition times, making nonlinear MRXI a viable option for the supervision of MNP related therapies in all regions of the human body, specifically magnetic hyperthermia.

Developing magnetorelaxometry imaging for human applications.

Objective.Magnetic nanoparticles (MNPs) are a promising tool in biomedical applications such as cancer therapy and diagnosis, where localization and quantification of MNP distributions are often mandatory. This can be obtained by magnetorelaxometry imaging (MRXI).Approach.In this work, the capability of MRXI for quantitative imaging of MNP inside larger volumes such as a human head is investigated. We developed a human head phantom simulating a glioblastoma multiforme (GBM) tumor containing MNP for magnetic hyperthermia treatment. The sensitivity of our MRXI setup for detection of MNP concentrations in the range of 3-19 mg cm-3was studied.Main result.The results show the high capability of MRXI to detect MNPs in a human head sized volume. Superficial sources with a concentration larger than 12 mg cm-3could be reconstructed with a resulotion of about 1 cm-3.Significance.The reconstruction of the MNP distribution, mimicking a GBM tumor of 7 cm3volume with clinically relevant iron concentration, demonstrates thein vivofeasibility of MRXI in humans.

Experimental demonstration of improved magnetorelaxometry imaging performance using optimized coil configurations.

BACKGROUND: Magnetorelaxometry imaging is an experimental imaging technique capable of reconstructing magnetic nanoparticle distributions inside a volume noninvasively and with high specificity. Thus, magnetorelaxometry imaging is a promising candidate for monitoring a number of therapeutical approaches that employ magnetic nanoparticles, such as magnetic drug targeting and magnetic hyperthermia, to guarantee their safety and efficacy. Prior to a potential clinical application of this imaging modality, it is necessary to optimize magnetorelaxometry imaging systems to produce reliable imaging results and to maximize the reconstruction accuracy of the magnetic nanoparticle distributions. Multiple optimization approaches were already applied throughout a number of simulation studies, all of which yielded increased imaging qualities compared to intuitively designed measurement setups. PURPOSE: None of these simulative approaches was conducted in practice such that it still remains unclear if the theoretical results are achievable in an experimental setting. In this study, we demonstrate the technical feasibility and the increased reconstruction accuracy of optimized coil configurations in two distinct magnetorelaxometry setups. METHODS: The electromagnetic coil positions and radii of a cuboidal as well as a cylindrical magnetorelaxometry imaging setup are optimized by minimizing the system matrix condition numbers of their corresponding linear forward models. The optimized coil configurations are manufactured alongside with two regular coil grids. Magnetorelaxometry measurements of three cuboidal and four cylindrical magnetic nanoparticle phantoms are conducted, and the resulting reconstruction qualities of the optimized and the regular coil configurations are compared. RESULTS: The computed condition numbers of the optimized coil configurations are approximately one order of magnitude lower compared to the regular coil grids. The reconstruction results show that for both setups, every phantom is recovered more accurately by the optimized coil configurations compared to the regular coil grids. Additionally, the optimized coil configurations yield better signal qualities. CONCLUSIONS: The presented experimental study provides a proof of the practicality and the efficacy of optimizing magnetorelaxometry imaging systems with respect to the condition numbers of their system matrices, previously only demonstrated in simulations. From the promising results of our study, we infer that the minimization of the system matrix condition number will also enable the practical optimization of other design parameters of magnetorelaxometry imaging setups (e.g., sensor configuration, coil currents, etc.) in order to improve the achievable reconstruction qualities even further, eventually paving the way towards clinical application of this imaging modality.

Quantitative 2D Magnetorelaxometry Imaging of Magnetic Nanoparticles using Optically Pumped Magnetometers.

For biomagnetical applications exploiting physical properties of magnetic nanoparticles (MNP), e.g., magnetic hyperthermia, knowledge about the quantitative spatial MNP distribution is crucial, which can be extracted by magnetorelaxometry (MRX) imaging. In this paper, we present quantification, quantitative 1D reconstruction, and quantitative 2D imaging of MNP by exploiting optically pumped magnetometers for MRX. While highlighting the potential of commercially available optically pumped magnetometers (OPM) for MRXI, we discuss current limitations of the used OPM. We show, that with our OPM setup, MNP can be precisely quantified with iron amounts down to ≈ 6 g , which can be improved easily. With a 1D-reconstruction setup, point-like and complex MNP phantoms can be reconstructed quantitatively with high precision and accuracy. We show that with our developed 2D MRX imaging setup, which measures 12 c m by 8 c m , point-like MNP distributions with clinically relevant iron concentrations can be reconstructed precisely and accurately. Our 2D setup has the potential to be easily extended to a tomography styled (and thus slice-selective) 3D scanner, by adding a mechanical axis to the phantom.

Model-Based Vestibular Afferent Stimulation: Evaluating Selective Electrode Locations and Stimulation Waveform Shapes.

A dysfunctional vestibular system can be a severe detriment to the quality of life of a patient. Recent studies have shown the feasibility for a vestibular implant to restore rotational sensation via electrical stimulation of vestibular ampullary nerves. However, the optimal stimulation site for selective elicitation of the desired nerve is still unknown. We realized a finite element model on the basis of µCT scans of a human inner ear and incorporated naturally distributed, artificial neural trajectories. A well-validated neuron model of myelinated fibers was incorporated to predict nerve responses to electrical stimulation. Several virtual electrodes were placed in locations of interest inside the bony labyrinth (intra-labyrinthine) and inside the temporal bone, near the target nerves (extra-labyrinthine), to determine preferred stimulation sites and electrode insertion depths. We investigated various monopolar and bipolar electrode configurations as well as different pulse waveform shapes for their ability to selectively stimulate the target nerve and for their energy consumption. The selectivity was evaluated with an objective measure of the fiber recruitment. Considerable differences of required energy and achievable selectivity between the configurations were observed. Bipolar, intra-labyrinthine electrodes provided the best selectivities but also consumed the highest amount of energy. Bipolar, extra-labyrinthine configurations did not offer any advantages compared to the monopolar approach. No selective stimulation could be performed with the monopolar, intra-labyrinthine approach. The monopolar, extra-labyrinthine electrodes required the least energy for satisfactory selectivities, making it the most promising approach for functional vestibular implants. Different pulse waveform shapes did not affect the achieved selectivity considerably but shorter pulse durations showed consistently a more selective activation of the target nerves. A cathodic, centered triangular waveform shape was identified as the most energy-efficient of the tested shapes. Based on these simulations we are able to recommend the monopolar, extra-labyrinthine stimulation approach with cathodic, centered triangular pulses as good trade-off between selectivity and energy consumption. Future implant designs could benefit from the findings presented here.

Analysis of Vestibular Labyrinthine Geometry and Variation in the Human Temporal Bone.

Stable posture and body movement in humans is dictated by the precise functioning of the ampulla organs in the semi-circular canals. Statistical analysis of the interrelationship between bony and membranous compartments within the semi-circular canals is dependent on the visualization of soft tissue structures. Thirty-one human inner ears were prepared, post-fixed with osmium tetroxide and decalcified for soft tissue contrast enhancement. High resolution X-ray microtomography images at 15 µm voxel-size were manually segmented. This data served as templates for centerline generation and cross-sectional area extraction. Our estimates demonstrate the variability of individual specimens from averaged centerlines of both bony and membranous labyrinth. Centerline lengths and cross-sectional areas along these lines were identified from segmented data. Using centerlines weighted by the inverse squares of the cross-sectional areas, plane angles could be quantified. The fit planes indicate that the bony labyrinth resembles a Cartesian coordinate system more closely than the membranous labyrinth. A widening in the membranous labyrinth of the lateral semi-circular canal was observed in some of the specimens. Likewise, the cross-sectional areas in the perilymphatic spaces of the lateral canal differed from the other canals. For the first time we could precisely describe the geometry of the human membranous labyrinth based on a large sample size. Awareness of the variations in the canal geometry of the membranous and bony labyrinth would be a helpful reference in designing electrodes for future vestibular prosthesis and simulating fluid dynamics more precisely.

Model-based Vestibular Afferent Stimulation: Modular Workflow for Analyzing Stimulation Scenarios in Patient Specific and Statistical Vestibular Anatomy.

Our sense of balance and spatial orientation strongly depends on the correct functionality of our vestibular system. Vestibular dysfunction can lead to blurred vision and impaired balance and spatial orientation, causing a significant decrease in quality of life. Recent studies have shown that vestibular implants offer a possible treatment for patients with vestibular dysfunction. The close proximity of the vestibular nerve bundles, the facial nerve and the cochlear nerve poses a major challenge to targeted stimulation of the vestibular system. Modeling the electrical stimulation of the vestibular system allows for an efficient analysis of stimulation scenarios previous to time and cost intensive in vivo experiments. Current models are based on animal data or CAD models of human anatomy. In this work, a (semi-)automatic modular workflow is presented for the stepwise transformation of segmented vestibular anatomy data of human vestibular specimens to an electrical model and subsequently analyzed. The steps of this workflow include (i) the transformation of labeled datasets to a tetrahedra mesh, (ii) nerve fiber anisotropy and fiber computation as a basis for neuron models, (iii) inclusion of arbitrary electrode designs, (iv) simulation of quasistationary potential distributions, and (v) analysis of stimulus waveforms on the stimulation outcome. Results obtained by the workflow based on human datasets and the average shape of a statistical model revealed a high qualitative agreement and a quantitatively comparable range compared to data from literature, respectively. Based on our workflow, a detailed analysis of intra- and extra-labyrinthine electrode configurations with various stimulation waveforms and electrode designs can be performed on patient specific anatomy, making this framework a valuable tool for current optimization questions concerning vestibular implants in humans.