Maria Evertsson

Frequency- and phase-sensitive magnetomotive ultrasound imaging of superparamagnetic iron oxide nanoparticles

It has recently been demonstrated that superparamagnetic iron oxide nanoparticles can be used as magnetomotive ultrasound contrast agents. A time-varying external magnetic field acts to move the particles and, thus, the nanoparticle-laden tissue. However, the difficulty of distinguishing this magnetomotive motion from undesired movement induced in regions without nanoparticles or other motion artifacts has not been well reported. Using a high-frequency linear-array system, we found that displacements outside nanoparticle-laden regions can be similar in magnitude to those in regions containing nanoparticles. We also found that the displacement outside the nanoparticle regions had a phase shift of approximately π radians relative to that in the nanoparticle regions. To suppress signals arising from undesirable movements, we developed an algorithm based on quadrature detection and phase gating at the precise frequency of nanoparticle displacement. Thus, clutter at other frequencies can be filtered out, and the processed signal can be color-coded and superimposed on the B-mode image. The median signal-to-clutter ratio improvement using the proposed algorithm was 36 dB compared with simply summing the movement energy at all frequencies. This clutter rejection is a crucial step to move magnetomotive ultrasound imaging of nanoparticles toward in vivo investigations.

Multimodal Detection of Iron Oxide Nanoparticles in Rat Lymph Nodes Using Magnetomotive Ultrasound Imaging and Magnetic Resonance Imaging

Detection and removal of sentinel lymph nodes (SLN) is important in the diagnosis and treatment of cancer. The SLN is the first regional lymph node draining the primary tumor, and if the cancer has spread, it is most likely to find metastases in the SLN. In this study, we have for the first time been able to image the very same contrast agent, superparamagnetic iron oxide nanoparticles (SPIO-NPs), in rat SLNs by using both our frequency- and phase-gated magnetomotive ultrasound (MMUS) algorithm and conventional magnetic resonance imaging (MRI); MMUS post mortem, MRI in vivo. For both higher NP-concentration and smaller NPs, we found that the MMUS data showed a larger magnetomotive displacement (1.56 ± 0.43 and 1.94 ± 0.54 times larger, respectively) and that the MR-images were affected to a higher degree. The MMUS displacement also increased with lower excitation frequency (1.95 ± 0.64 times larger for 5 Hz compared with 15 Hz) and higher excitation voltage (2.95 ± 1.44 times larger for 30 V compared with 10 V). The results show that MMUS has potential to be used as bedside guidance during SLN surgery, imaging the same particles that were used in prior staging with other imaging techniques.

Combined Magnetomotive ultrasound, PET/CT, and MR imaging of 68 Ga-labelled superparamagnetic iron oxide nanoparticles in rat sentinel lymph nodes in vivo

Current methods for intra-surgical guidance to localize metastases at cancer surgery are based on radioactive tracers that cause logistical challenges. We propose the use of a novel ultrasound-based method, magnetomotive ultrasound (MMUS) imaging that employ a nanoparticle-based contrast agent that also may be used for pre-operative PET/MRI imaging. Since MMUS is radiation free, this eliminates the dependence between pre- and intra-operative imaging and the radiation exposure for the surgical staff. This study investigates a hypothetical clinical scenario of pre-operative PET imaging, combined with intra-operative MMUS imaging, implemented in a sentinel lymph node (SLN) rat model. At one-hour post injection of 68Ga-labelled magnetic nanoparticles, six animals were imaged with combined PET/CT. After two or four days, the same animals were imaged with MMUS. In addition, ex-vivo MRI was used to evaluate the amount of nanoparticles in each single SLN. All SLNs were detectable by PET. Four out of six SLNs could be detected with MMUS, and for these MMUS and MRI measurements were in close agreement. The MRI measurements revealed that the two SLNs undetectable with MMUS contained the lowest nanoparticle concentrations. This study shows that MMUS can complement standard pre-operative imaging by providing bedside real-time images with high spatial resolution.

Induced tissue displacement in magnetomotive ultrasound imaging - simulations and experiments

Magnetomotive ultrasound imaging is an emerging technique where superparamagnetic iron oxide nanoparticles can be used as an ultrasound contrast agent. A time-varying external magnetic field acts to move the particles lodged in tissue, and ultrasound is used to detect the resulting tissue movement. In phantom studies we have observed opposite phase motion next to regions containing nanoparticles. We hypothesize that this motion is caused by mechanical coupling from regions where nanoparticles are located. The present study compares experimental data to a numerical simulation with identical geometry as the experimental set-up. The magnetic force acting on particles was modeled as emanating from a coil with a cone shaped iron core, and applied as a body load in nanoparticle-laden regions. The simulation showed opposed motion in-between nanoparticle-laden phantom inserts, in a manner similar to the experimental situation. There is a slight mismatch in the extent of vertical movement, which we interpret as a result of the modeled slip condition tangentially to the surface, which in reality presumably is a combination of slip and stick due to friction.

Normalization of Magnetic Field Effects: Towards Quantitative Magnetomotive Ultrasound Imaging

In magnetomotive ultrasound (MMUS) imaging superparamagnetic iron oxide nanoparticles (NP) are used as contrast agents and a time-varying external magnetic field acts to move the particles and thereby the nanoparticle-laden tissue. Recently we proposed a frequency and phase sensitive algorithm to reduce motion artifacts. However, the method is not quantitative as the particle movement induced is dependent not only on the field strength, but also on the field gradient, plus material parameters. Here we assess the measured nanoparticle movement across the image plane in comparison with simulations of the magnetic force, to evaluate the potential for image normalization of magnetic field effects. We found that the movement decreased with distance to the iron core tip, from which the magnetic field was extending, and approaches zero at the transducer face. This finding did not coincide with the simulation and may make it difficult to enable quantification. The coefficient of variation between measurements on the homogeneous phantom was typically in the order of 15% for all frequencies, indicating the expected accuracy for quantitative measurements.

In vivo magnetomotive ultrasound imaging of rat lymph nodes - a pilot study

The drive to gain a better understanding of how diseases arise and how to provide ever-earlier detection are some of the key factors for the development of molecular imaging. Compared to other imaging modalities ultrasound has not received the same attention for molecular imaging mainly due to its limited contrast resolution, together with contrast agents confined to the intravascular space. To overcome these issues, new nano-sized contrast agents and new ultrasound imaging techniques e.g. photo acoustic imaging, have been developed. Another such imaging technique under development is magnetomotive ultrasound imaging (MMUS). We have previously developed a frequency and phase tracking algorithm which is able to detect superparamagnetic iron oxide nanoparticles (SPIO NPs) using MMUS, where our suggested first clinical application is to detect sentinel lymph nodes (SLNs) in breast cancer surgery. Recently we have shown detection of SPIO laden rat SLNs in situ. Here we present the feasibility of in vivo detection of SLNs in rats. The algorithm clearly pinpoints the NP laden SLN, even in presence of significant artefactual tissue movement. The magnetomotive displacement increased when a higher voltage was applied on the coil creating the magnetic field (e.g. 56.6% increasing the voltage from 20V to 50V). An uneven concentration distribution of NPs in the SLN was found. The maximum magnetomotive displacement difference between two different cross sections in one SLN was 9.76 times. The study also showed that for a higher concentration of NPs a lower magnetic coil excitation voltage could be used in order to create a magnetomotive displacement of a certain magnitude. The result from this in vivo study shows that the method has potential for future clinical use.

Towards real-time magnetomotive ultrasound imaging

Magnetomotive ultrasound (MMUS) imaging indirectly enables visualization of magnetic nanoparticles (MNPs) with ultrasound. An external time varying magnetic field displaces MNPs and thus their closest surrounding, the induced displacement is tracked in the US data and color-coded on B-mode images. However, images are currently processed offline, which is time consuming and precludes clinical use of MMUS. In this work, the previously proposed MMUS algorithm (DOI: TUFFC.2013.2591) is automated and implemented online on the ULA-OP scanner.

Cross-correlation detection improves spatial delineation and enables high resolution tracking of temporal events in magnetomotive ultrasound imaging

Magnetomotive ultrasound (MM US) imaging is a method whereby superparamagnetic iron oxide nanoparticles (SPIO NP) are used as a contrast agent. By applying an external magnetic field the particles are set in motion together with their surroundings. The induced movement is detected with ultrasound, and for the case of harmonic excitation of the magnetic source, quadrature detection (lock-in plus phase gating) can recover the magnetomotive signal (doi:10.1109/TUFFC.2013.2591). Here, we propose instead the use of cross-correlation for detection, and report the potential benefits compared to the previous approach.

Effect of nanoparticle size and magnetic field strength on the displacement signal in magnetomotive ultrasound imaging

Magnetomotive ultrasound imaging is an emerging technique where superparamagnetic iron oxide nanoparticles can be used as an ultrasound contrast agent. A time-varying external magnetic field acts to move tissue embedded particles, and ultrasound is used to detect the resulting tissue movement. In this experimental phantom study we observed a variation in the magnetomotive response in respect to physical size of the embedded superparamagnetic iron oxide nanoparticles. Given the same Fe concentration a weaker response, by a factor of 2, was detected with the larger nanoparticles. However, approximately seven times larger response remains, given the volume ratio between particles, implying a seven times larger response per binding event. We hypothesize that this can have bearing in molecular imaging.

B-field energy dependent phase lag dispersion in magnetomotive ultrasound imaging

Magnetomotive ultrasound imaging is an emerging technique where superparamagnetic iron oxide nanoparticles can be used as an ultrasound contrast agent. A time-varying external magnetic field acts to move tissue embedded particles, and ultrasound is used to detect the resulting tissue movement. In experimental phantom studies we have observed a phase lag dispersion in the magnetomotive response in respect to applied time-varying magnetic field (B-field). We hypothesize that this dispersion is triggered by the strength of the applied B-field in combination with concentration of embedded nanoparticles in the region. The cohort response of the nanoparticles aligns as the magnetic field gets more energetic. Moreover, the tightening of the phase response indicate an asymptotic tapering towards a phase limit.