Feasibility of Dark-Field Radiography to Enhance Detection of Nondisplaced Fractures.

Background Many clinically relevant fractures are occult on conventional radiographs and therefore challenging to diagnose reliably. X-ray dark-field radiography is a developing method that uses x-ray scattering as an additional signal source. Purpose To investigate whether x-ray dark-field radiography enhances the depiction of radiographically occult fractures in an experimental model compared with attenuation-based radiography alone and whether the directional dependence of dark-field signal impacts observer ratings. Materials and Methods Four porcine loin ribs had nondisplaced fractures experimentally introduced. Microstructural changes were visually verified using high-spatial-resolution three-dimensional micro-CT. X-ray dark-field radiographs were obtained before and after fracture, with the before-fracture scans serving as control images. The presence of a fracture was scored by three observers using a six-point scale (6, surely; 5, very likely; 4, likely; 3, unlikely; 2, very unlikely; and 1, certainly not). Differences between scores based on attenuation radiographs alone (n = 96) and based on combined attenuation and dark-field radiographs (n = 96) were evaluated by using the DeLong method to compare areas under the receiver operating characteristic curve. The impact of the dark-field signal directional sensitivity on observer ratings was evaluated using the Wilcoxon test. The dark-field data were split into four groups (24 images per group) according to their sensitivity orientation and tested against each other. Musculoskeletal dark-field radiography was further demonstrated on human finger and foot specimens. Results The addition of dark-field radiographs was found to increase the area under the receiver operating characteristic curve to 1 compared with an area under the receiver operating characteristic curve of 0.87 (95% CI: 0.80, 0.94) using attenuation-based radiographs alone (P < .001). There were similar observer ratings for the four different dark-field sensitivity orientations (P = .16-.65 between the groups). Conclusion These results suggested that the inclusion of dark-field radiography has the potential to help enhance the detection of nondisplaced fractures compared with attenuation-based radiography alone. © RSNA, 2024 See also the editorial by Rubin in this issue.

The versatile X-ray beamline of the Munich Compact Light Source: design, instrumentation and applications.

Inverse Compton scattering provides means to generate low-divergence partially coherent quasi-monochromatic, i.e. synchrotron-like, X-ray radiation on a laboratory scale. This enables the transfer of synchrotron techniques into university or industrial environments. Here, the Munich Compact Light Source is presented, which is such a compact synchrotron radiation facility based on an inverse Compton X-ray source (ICS). The recent improvements of the ICS are reported first and then the various experimental techniques which are most suited to the ICS installed at the Technical University of Munich are reviewed. For the latter, a multipurpose X-ray application beamline with two end-stations was designed. The beamline's design and geometry are presented in detail including the different set-ups as well as the available detector options. Application examples of the classes of experiments that can be performed are summarized afterwards. Among them are dynamic in vivo respiratory imaging, propagation-based phase-contrast imaging, grating-based phase-contrast imaging, X-ray microtomography, K-edge subtraction imaging and X-ray spectroscopy. Finally, plans to upgrade the beamline in order to enhance its capabilities are discussed.

Myoanatomy of the velvet worm leg revealed by laboratory-based nanofocus X-ray source tomography.

X-ray computed tomography (CT) is a powerful noninvasive technique for investigating the inner structure of objects and organisms. However, the resolution of laboratory CT systems is typically limited to the micrometer range. In this paper, we present a table-top nanoCT system in conjunction with standard processing tools that is able to routinely reach resolutions down to 100 nm without using X-ray optics. We demonstrate its potential for biological investigations by imaging a walking appendage of Euperipatoides rowelli, a representative of Onychophora-an invertebrate group pivotal for understanding animal evolution. Comparative analyses proved that the nanoCT can depict the external morphology of the limb with an image quality similar to scanning electron microscopy, while simultaneously visualizing internal muscular structures at higher resolutions than confocal laser scanning microscopy. The obtained nanoCT data revealed hitherto unknown aspects of the onychophoran limb musculature, enabling the 3D reconstruction of individual muscle fibers, which was previously impossible using any laboratory-based imaging technique.

A proof of principle experiment for microbeam radiation therapy at the Munich compact light source.

Microbeam radiation therapy (MRT), a preclinical form of spatially fractionated radiotherapy, uses an array of microbeams of hard synchrotron X-ray radiation. Recently, compact synchrotron X-ray sources got more attention as they provide essential prerequisites for the translation of MRT into clinics while overcoming the limited access to synchrotron facilities. At the Munich compact light source (MuCLS), one of these novel compact X-ray facilities, a proof of principle experiment was conducted applying MRT to a xenograft tumor mouse model. First, subcutaneous tumors derived from the established squamous carcinoma cell line FaDu were irradiated at a conventional X-ray tube using broadbeam geometry to determine a suitable dose range for the tumor growth delay. For irradiations at the MuCLS, FaDu tumors were irradiated with broadbeam and microbeam irradiation at integral doses of either 3 Gy or 5 Gy and tumor growth delay was measured. Microbeams had a width of 50 µm and a center-to-center distance of 350 µm with peak doses of either 21 Gy or 35 Gy. A dose rate of up to 5 Gy/min was delivered to the tumor. Both doses and modalities delayed the tumor growth compared to a sham-irradiated tumor. The irradiated area and microbeam pattern were verified by staining of the DNA double-strand break marker γH2AX. This study demonstrates for the first time that MRT can be successfully performed in vivo at compact inverse Compton sources.

Microfluidic-Based Synthesis of Magnetic Nanoparticles Coupled with Miniaturized NMR for Online Relaxation Studies.

Using compact desktop NMR systems for rapid characterization of relaxation properties directly after synthesis can expedite the development of functional magnetic nanoparticles. Therefore, an automated system that combines a miniaturized NMR relaxometer and a flow-based microreactor for online synthesis and characterization of magnetic iron oxide nanoparticles is constructed and tested. NMR relaxation properties are quantified online with a 0.5 T permanent magnet for measurement of transverse ( T2) and longitudinal ( T1) relaxation times. Nanoparticles with a primary particle size of about 25 nm are prepared by coprecipitation in a tape-based microreactor that utilizes 3D hydrodynamic flow focusing to avoid channel clogging. Cluster sizes are expeditiously optimized for maximum transverse relaxivity of 115.5 mM s-1. The compact process control system is an efficient tool that speeds up synthesis optimization and product characterization of magnetic nanoparticles for nanomedical, theranostic, and NMR-based biosensing applications.

The Munich Compact Light Source: initial performance measures.

While large-scale synchrotron sources provide a highly brilliant monochromatic X-ray beam, these X-ray sources are expensive in terms of installation and maintenance, and require large amounts of space due to the size of storage rings for GeV electrons. On the other hand, laboratory X-ray tube sources can easily be implemented in laboratories or hospitals with comparatively little cost, but their performance features a lower brilliance and a polychromatic spectrum creates problems with beam hardening artifacts for imaging experiments. Over the last decade, compact synchrotron sources based on inverse Compton scattering have evolved as one of the most promising types of laboratory-scale X-ray sources: they provide a performance and brilliance that lie in between those of large-scale synchrotron sources and X-ray tube sources, with significantly reduced financial and spatial requirements. These sources produce X-rays through the collision of relativistic electrons with infrared laser photons. In this study, an analysis of the performance, such as X-ray flux, source size and spectra, of the first commercially sold compact light source, the Munich Compact Light Source, is presented.

Correction for Mechanical Inaccuracies in a Scanning Talbot-Lau Interferometer.

Grating-based X-ray phase-contrast and in particular dark-field radiography are promising new imaging modalities for medical applications. Currently, the potential advantage of dark-field imaging in early-stage diagnosis of pulmonary diseases in humans is being investigated. These studies make use of a comparatively large scanning interferometer at short acquisition times, which comes at the expense of a significantly reduced mechanical stability as compared to tabletop laboratory setups. Vibrations create random fluctuations of the grating alignment, causing artifacts in the resulting images. Here, we describe a novel maximum likelihood method for estimating this motion, thereby preventing these artifacts. It is tailored to scanning setups and does not require any sample-free areas. Unlike any previously described method, it accounts for motion in between as well as during exposures.

PLUSPULS: A transcranial magnetic stimulator with extended pulse protocols.

Transcranial magnetic stimulation (TMS) is increasingly applied in basic neuroscience while its field of usage for diagnosing and treating various neurological diseases broadens steadily. A TMS device generates a current pulse in the reach of several thousand ampére to produce a magnetic pulse which induces an electric field around neurons. This electric field, if high enough to depolarize the neuron membrane, generates an action potential at the neuron which travels down the neurons connected to it. The PLUSPULS TMS generates this magnetic pulse by pre-charging a pulse capacitor C with the voltage V C 0 and connecting it with a stimulation coil L . The oscillation of the resonance circuit is cut off after one period and is called a biphasic pulse. PLUSPULS is a high frequency stimulator with inter stimulus intervals (ISI) down to 1ms which enables different pulse protocols as paired pulse or quadri theta burst stimulation. A GUI on PC allows a flexible control of PLUSPULS with varying amplitudes and ISI in one burst. The modular hardware and the control via GUI on PC allows for an easier adjustment on requirements to come. The article provides design considerations, hardware, firmware and software to reconstruct a modular biphasic TMS with enhanced charging network to enable extended pulse protocols.

Miniature magneto-mechanical resonators for wireless tracking and sensing.

Sensor miniaturization enables applications such as minimally invasive medical procedures or patient monitoring by providing process feedback in situ. Ideally, miniature sensors should be wireless, inexpensive, and allow for remote detection over sufficient distance by an affordable detection system. We analyze the signal strength of wireless sensors theoretically and derive a simple design of high-signal resonant magneto-mechanical sensors featuring volumes below 1 cubic millimeter. As examples, we demonstrate real-time tracking of position and attitude of a flying bee, navigation of a biopsy needle, tracking of a free-flowing marker, and sensing of pressure and temperature, all in unshielded environments. The achieved sensor size, measurement accuracy, and workspace of ~25 centimeters show the potential for a low-cost wireless tracking and sensing platform for medical and nonmedical applications.

Initial Characterization of Dark-Field CT on a Clinical Gantry.

X-ray computed tomography (CT) is an important non-destructive imaging technique, particularly in clinical diagnostics. Even with the latest innovations like dual-energy and photon-counting CT, the image contrast is solely generated from attenuation in the tissue. An extension - fully compatible with these novelties - is dark-field CT, which retrieves an additional, so-called dark-field contrast. Unlike the attenuation channel, the dark-field channel is sensitive to tissue microstructure and porosity below the resolution of the imaging system, which allows additional insights into the health of the lung tissue or the structure of calcifications. The potential clinical value has been demonstrated in several preclinical studies and recently also in radiography patient studies. Just recently the first dark-field CT for the human body was established at the Technical University of Munich and in this paper, we discuss the performance of this prototype. We evaluate the interferometer components and the imposed challenges that the integration into the CT gantry brings by comparing the results to simulations and measurements at a laboratory setup. The influence of the clinical X-ray source on the Talbot-Lau interferometer and the impact of vibrations, which are immanent on the clinical CT gantry, are analyzed in detail to reveal their characteristic frequencies and origin. A beam hardening correction is introduced as an important step to adapt to the poly-chromatic spectrum and make quantitative dark-field imaging possible. We close with an analysis of the image resolution and the applied patient dose, and conclude that the performance is sufficient to suggest initial patient studies using the presented dark-field CT system.

Dark-Field Chest Radiography Outperforms Conventional Chest Radiography for the Diagnosis and Staging of Pulmonary Emphysema.

OBJECTIVES: Dark-field chest radiography (dfCXR) has recently reached clinical trials. Here we compare dfCXR to conventional radiography for the detection and staging of pulmonary emphysema. MATERIALS AND METHODS: Subjects were included after a medically indicated computed tomography (CT) scan, showing either no lung impairments or different stages of emphysema. To establish a ground truth, all CT scans were assessed by 3 radiologists assigning emphysema severity scores based on the Fleischner Society classification scheme.Participants were imaged at a commercial chest radiography device and at a prototype for dfCXR, yielding both attenuation-based and dark-field images. Three radiologists blinded to CT score independently assessed images from both devices for presence and severity of emphysema (no, mild, moderate, severe).Statistical analysis included evaluation of receiver operating characteristic curves and pairwise comparison of adjacent Fleischner groups using an area under the curve (AUC)-based z test with a significance level of 0.05. RESULTS: A total of 88 participants (54 men) with a mean age of 64 ± 12 years were included. Compared with conventional images (AUC = 0.73), readers were better able to identify emphysema with images from the dark-field prototype (AUC = 0.85, P = 0.005). Although ratings of adjacent emphysema severity groups with conventional radiographs differed only for trace and mild emphysema, ratings based on images from the dark-field prototype were different for trace and mild, mild and moderate, and moderate and confluent emphysema. CONCLUSIONS: Dark-field chest radiography is superior to conventional chest radiography for emphysema diagnosis and staging, indicating the technique's potential as a low-dose diagnostic tool for emphysema assessment.

Magnetic particle imaging: visualization of instruments for cardiovascular intervention.

PURPOSE: To evaluate the feasibility of different approaches of instrument visualization for cardiovascular interventions guided by using magnetic particle imaging (MPI). MATERIALS AND METHODS: Two balloon (percutaneous transluminal angioplasty) catheters were used. The balloon was filled either with diluted superparamagnetic iron oxide (SPIO) ferucarbotran (25 mmol of iron per liter) or with sodium chloride. Both catheters were inserted into a vessel phantom that was filled oppositional to the balloon content with sodium chloride or diluted SPIO (25 mmol of iron per liter). In addition, the administration of a 1.4-mL bolus of pure SPIO (500 mmol of iron per liter) followed by 5 mL of sodium chloride through a SPIO-labeled balloon catheter into the sodium chloride-filled vessel phantom was recorded. Images were recorded by using a preclinical MPI demonstrator. All images were acquired by using a field of view of 3.6 × 3.6 × 2.0 cm. RESULTS: By using MPI, both balloon catheters could be visualized with high temporal (21.54 msec per image) and sufficient spatial (≤ 3 mm) resolution without any motion artifacts. The movement through the field of view, the inflation and deflation of the balloon, and the application of the SPIO bolus were visualized at a rate of 46 three-dimensional data sets per second. CONCLUSION: Visualization of SPIO-labeled instruments for cardiovascular intervention at high temporal resolution as well as monitoring the application of a SPIO-based tracer by using labeled instruments is feasible. Further work is necessary to evaluate different labeling approaches for diagnostic catheters and guidewires and to demonstrate their navigation in the vascular system after administration of contrast material. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120424/-/DC1.

Transcranial magnetic stimulation with a half-sine wave pulse elicits direction-specific effects in human motor cortex.

BACKGROUND: Transcranial magnetic stimulation (TMS) commonly uses so-called monophasic pulses where the initial rapidly changing current flow is followed by a critically dampened return current. It has been shown that a monophasic TMS pulse preferentially excites different cortical circuits in the human motor hand area (M1-HAND), if the induced tissue current has a posterior-to-anterior (PA) or anterior-to-posterior (AP) direction. Here we tested whether similar direction-specific effects could be elicited in M1-HAND using TMS pulses with a half-sine wave configuration. RESULTS: In 10 young participants, we applied half-sine pulses to the right M1-HAND which elicited PA or AP currents with respect to the orientation of the central sulcus.Measurements of the motor evoked potential (MEP) revealed that PA half-sine stimulation resulted in lower resting motor threshold (RMT) than AP stimulation. When stimulus intensity (SI) was gradually increased as percentage of maximal stimulator output, the stimulus-response curve (SRC) of MEP amplitude showed a leftward shift for PA as opposed to AP half-sine stimulation. Further, MEP latencies were approximately 1 ms shorter for PA relative to AP half-sine stimulation across the entire SI range tested. When adjusting SI to the respective RMT of PA and AP stimulation, the direction-specific differences in MEP latencies persisted, while the gain function of MEP amplitudes was comparable for PA and AP stimulation. CONCLUSIONS: Using half-sine pulse configuration, single-pulse TMS elicits consistent direction-specific effects in M1-HAND that are similar to TMS with monophasic pulses. The longer MEP latency for AP half-sine stimulation suggests that PA and AP half-sine stimulation preferentially activates different sets of cortical neurons that are involved in the generation of different corticospinal descending volleys.

Analysis of trajectories for targeting of magnetic nanoparticles in blood vessels.

The technique of magnetic drug targeting deals with binding drugs or genetic material to superparamagnetic nanoparticles and accumulating these complexes via an external magnetic field in a target region. For a successful approach, it is necessary to know the required magnetic setup as well as the physical properties of the complexes. With the help of computational methods, the complex accumulation and behavior can be predicted. We present a model for vascular targeting with a full three-dimensional analysis of the magnetic and fluidic forces and a subsequent evaluation of the resulting trajectories of the complexes. These trajectories were calculated with respect to the physiological boundary conditions, the magnetic properties of both the external field and the particles as well as the hydrodynamics of the fluid. We paid special regard to modeling input parameters like flow velocity as well as the distribution functions of the hydrodynamic size and magnetic moment of the nanoparticle complexes. We are able to estimate the amount of complexes, as well as the spatial distribution of those complexes. Additionally, we examine the development of the trapping rate for multiple passages of the complexes and compare the influence of several input parameters. Finally, we provide experimental data of an ex vivo flow-loop system which serves as a model for large vessel targeting. In this model, we achieve a deposition of lentivirus/magnetic nanoparticle complexes in a murine aorta and compare our simulation with the experimental results gained by a non-heme-iron assay.

Magnetic nanoparticles in magnetic resonance imaging and diagnostics.

Magnetic nanoparticles are useful as contrast agents for magnetic resonance imaging (MRI). Paramagnetic contrast agents have been used for a long time, but more recently superparamagnetic iron oxide nanoparticles (SPIOs) have been discovered to influence MRI contrast as well. In contrast to paramagnetic contrast agents, SPIOs can be functionalized and size-tailored in order to adapt to various kinds of soft tissues. Although both types of contrast agents have a inducible magnetization, their mechanisms of influence on spin-spin and spin-lattice relaxation of protons are different. A special emphasis on the basic magnetism of nanoparticles and their structures as well as on the principle of nuclear magnetic resonance is made. Examples of different contrast-enhanced magnetic resonance images are given. The potential use of magnetic nanoparticles as diagnostic tracers is explored. Additionally, SPIOs can be used in diagnostic magnetic resonance, since the spin relaxation time of water protons differs, whether magnetic nanoparticles are bound to a target or not.

Targeted endothelial gene delivery by ultrasonic destruction of magnetic microbubbles carrying lentiviral vectors.

PURPOSE: Site specific vascular gene delivery is a promising tool for treatment of cardiovascular diseases. By combining ultrasound mediated microbubble destruction with site specific magnetic targeting of lentiviruses, we aimed to develop a technique suitable for systemic application. METHODS: The magnetic nanoparticle coupling to lipid microbubbles was confirmed by absorbance measurements. Association of fluorescent lentivirus to magnetic microbubbles (MMB) was determined by microscopy and flow cytometry. Functionality and efficiency of GFP-encoding lentiviral MMB transduction was evaluated by endothelial (HMEC) GFP expression and cytotoxicity was measured by MTT reduction. RESULTS: Microbubbles with a mean diameter of 4.3 ± 0.04 µm were stable for 2 days, readily magnetizable and magnetically steerable in vitro and efficiently associated with lentivirus. Exposure of eGFP-encoding lentiviral MMB to human endothelial cells followed by application of an external static magnetic field (30 min) and ultrasonic destruction of the microbubbles did not markedly affect cellular viability. Finally, this combination led to a 30-fold increase in transduction efficiency compared to application of naked virus alone. CONCLUSIONS: By associating microbubbles with magnetic iron nanoparticles, these function as carriers for lentiviruses achieving tissue specific deposition at the site of interest.

Magnetized aerosols comprising superparamagnetic iron oxide nanoparticles improve targeted drug and gene delivery to the lung.

PURPOSE: Targeted delivery of aerosols could not only improve efficacy of inhaled drugs but also reduce side effects resulting from their accumulation in healthy tissue. Here we investigated the impact of magnetized aerosols on model drug accumulation and transgene expression in magnetically targeted lung regions of unanesthetized mice. METHODS: Solutions containing superparamagnetic iron oxide nanoparticles (SPIONs) and model drugs (fluorescein or complexed plasmid DNA) were nebulized to unanesthetized mice under the influence of an external magnetic gradient directed to the lungs. Drug accumulation and transgene expression was subsequently measured at different time points. RESULTS: We could demonstrate 2-3 fold higher accumulation of the model drug fluorescein and specific transgene expression in lung regions of mice which had been exposed to an external magnetic gradient during nebulization compared to the control mice without any exposure to magnetic gradient. CONCLUSIONS: Magnetized aerosols present themselves as an efficient approach for targeted pulmonary delivery of drugs and gene therapeutic agents in order to treat localized diseases of the deeper airways.

Local gene targeting and cell positioning using magnetic nanoparticles and magnetic tips: comparison of mathematical simulations with experiments.

PURPOSE: Magnetic nanoparticles (MNPs) and magnets can be used to enhance gene transfer or cell attachment but gene or cell delivery to confined areas has not been addressed. We therefore searched for an optimal method to simulate and perform local gene targeting and cell delivery in vitro. METHODS: Localized gene transfer or cell positioning was achieved using permanent magnets with newly designed soft iron tips and MNP/lentivirus complexes or MNP-loaded cells, respectively. Their distribution was simulated with a mathematical model calculating magnetic flux density gradients and particle trajectories. RESULTS: Soft iron tips generated strong confined magnetic fields and could be reliably used for local (~500 µm diameter) gene targeting and positioning of bone marrow cells or cardiomyocytes. The calculated distribution of MNP/lentivirus complexes and MNP-loaded cells concurred very well with the experimental results of local gene expression and cell attachment, respectively. CONCLUSION: MNP-based gene targeting and cell positioning can be reliably performed in vitro using magnetic soft iron tips, and computer simulations are effective methods to predict and optimize experimental results.

Site directed vascular gene delivery in vivo by ultrasonic destruction of magnetic nanoparticle coated microbubbles.

Site specific vascular gene delivery for therapeutic implications is favorable because of reduction of possible side effects. Yet this technology faces numerous hurdles that result in low transfection rates because of suboptimal delivery. Combining ultrasonic microbubble technology with magnetic nanoparticle enhanced gene transfer could make it possible to use the systemic vasculature as the route of application and to magnetically trap these compounds at the target of interest. In this study we show that magnetic nanoparticle-coated microbubbles bind plasmid DNA and successfully deliver it to endothelial cells in vitro and more importantly transport their cargo through the vascular system and specifically deliver it to the vascular wall in vivo at sites where microbubbles are retained by magnetic force and burst by local ultrasound application. This resulted in a significant enhancement in site specific gene delivery compared with the conventional microbubble technique. Thus, this technology may have promising therapeutic potential. FROM THE CLINICAL EDITOR: This work focuses on combining ultrasonic microbubble technology with magnetic nanoparticle enhanced gene transfer to enable targeted gene delivery via the systemic vasculature and magnetic trapping of these compounds at the target of interest.

Combined targeting of lentiviral vectors and positioning of transduced cells by magnetic nanoparticles.

Targeting of viral vectors is a major challenge for in vivo gene delivery, especially after intravascular application. In addition, targeting of the endothelium itself would be of importance for gene-based therapies of vascular disease. Here, we used magnetic nanoparticles (MNPs) to combine cell transduction and positioning in the vascular system under clinically relevant, nonpermissive conditions, including hydrodynamic forces and hypothermia. The use of MNPs enhanced transduction efficiency of endothelial cells and enabled direct endothelial targeting of lentiviral vectors (LVs) by magnetic force, even in perfused vessels. In addition, application of external magnetic fields to mice significantly changed LV/MNP biodistribution in vivo. LV/MNP-transduced cells exhibited superparamagnetic behavior as measured by magnetorelaxometry, and they were efficiently retained by magnetic fields. The magnetic interactions were strong enough to position MNP-containing endothelial cells at the intima of vessels under physiological flow conditions. Importantly, magnetic positioning of MNP-labeled cells was also achieved in vivo in an injury model of the mouse carotid artery. Intravascular gene targeting can be combined with positioning of the transduced cells via nanomagnetic particles, thereby combining gene- and cell-based therapies.