The impact of geometry, intramural friction, and pressure on the antegrade longitudinal motion of the arterial wall: A phantom and finite element study.

Longitudinal motion of the carotid arterial wall, as measured with ultrasound, has shown promise as an indicator of vascular health. The underlying mechanisms are however not fully understood. We have found, in in vivo studies, that blood pressure has a strong relation to the antegrade longitudinal displacement in early systole. Further, we have identified that a tapered geometry and the intramural friction in-between two parts of a vessel wall influence the longitudinal displacement. We therefore studied the interaction between pressure, vessel geometry and intramural friction, tapered and straight ultrasound phantoms in a paralleled hydraulic bench study and corresponding numerical models. Profound antegrade longitudinal motion was induced in the innermost part of both tapered phantoms and the numerical models, but to a lesser extent when intramural friction was increased in the simulations. Strong correlations (R = 0.82-0.96; p < 1e-3; k = 9.3-14 µm/mmHg) between longitudinal displacement and pulse pressure were found in six of seven regions of interest in tapered phantoms. The motion of the straight phantom and the corresponding numerical model was smaller, on average zero or close to zero. This study demonstrates that tapering of the lumen, low intramural friction, and pressure might be important conducive features to the antegrade longitudinal motion of the arterial wall in vivo.

Contrast enhanced magneto-motive ultrasound in lymph nodes - modelling and pre-clinical imaging using magnetic microbubbles.

Despite advances in MRI, the detection and characterisation of lymph nodes in rectal cancer remains complex, especially when assessing the response to neo-adjuvant treatment. An alternative approach is functional imaging, previously shown to aid characterization of cancer tissues. We report proof-of-concept of the novel technique Contrast-Enhanced Magneto-Motive Ultrasound (CE-MMUS) to recover information relating to local perfusion and lymphatic drainage, and interrogate tissue mechanical properties through magnetically induced tissue deformations. The feasibility of the proposed application was explored using a combination of pre-clinical ultrasound imaging and finite element analysis. First, contrast enhanced ultrasound imaging on one wild type mouse recorded lymphatic drainage of magnetic microbubbles after bolus injection. Second, preliminary CE-MMUS data were acquired as a proof of concept. Third, the magneto-mechanical interactions of a magnetic microbubble with an elastic solid were simulated using finite element software. Accumulation of magnetic microbubbles in the inguinal lymph node was verified using contrast enhanced ultrasound, with peak enhancement occurring 3.7 s post-injection. Preliminary CE-MMUS indicates the presence of magnetic contrast agent in the lymph node. The finite element analysis explores how the magnetic force is transferred to motion of the solid, which depends on elasticity and bubble radius, indicating an inverse relation with displacement. Combining magnetic microbubbles with MMUS could harness the advantages of both techniques, to provide perfusion information, robust lymph node delineation and characterisation based on mechanical properties. Clinical Relevance- Robust detection and characterisation of lymph nodes could be aided by visualising lymphatic drainage of magnetic microbubbles using contrast enhanced ultrasound imaging and magneto-motion, which is dependent on tissue mechanical properties.

Evaluation of cellular stress responses in magnetomotive ultrasound.

Early and accurate diagnoses are important for successful cancer treatment. Lymph node involvement is often critical, and magnetomotive ultrasound (MMUS) has been proposed for its detection and characterization. MMUS relies on a magnetic contrast agent, for example, iron oxide nanoparticles, delivered to the tissue of interest, magnetically set in motion and detected using ultrasound. The magneto-mechanical interaction has not previously been evaluated on a cellular level. Here we demonstrate uptake and dose-dependent retention of magnetic nanoparticles in two human adenocarcinoma cell lines, with <10% cytotoxicity which did not increase following magnetic excitation. Further, the oxidative stress levels were not affected by magnetic particles or force. Thus, we found no evidence of adverse effects from the magneto-mechanical interactions under these conditions.

Modelling of magnetic microbubbles to evaluate contrast enhanced magnetomotive ultrasound in lymph nodes - a pre-clinical study.

OBJECTIVES: Despite advances in MRI the detection and characterisation of lymph nodes in rectal cancer remains complex, especially when assessing the response to neoadjuvant treatment. An alternative approach is functional imaging, previously shown to aid characterisation of cancer tissues. We report proof of concept of the novel technique Contrast-Enhanced Magneto-Motive Ultrasound (CE-MMUS) to recover information relating to local perfusion and lymphatic drainage, and interrogate tissue mechanical properties through magnetically induced deformations. METHODS: The feasibility of the proposed application was explored using a combination of experimental animal and phantom ultrasound imaging, along with finite element analysis. First, contrast-enhanced ultrasound imaging on one wild type mouse recorded lymphatic drainage of magnetic microbubbles after bolus injection. Second, tissue phantoms were imaged using MMUS to illustrate the force- and elasticity dependence of the magnetomotion. Third, the magnetomechanical interactions of a magnetic microbubble with an elastic solid were simulated using finite element software. RESULTS: Accumulation of magnetic microbubbles in the inguinal lymph node was verified using contrast enhanced ultrasound, with peak enhancement occurring 3.7 s post-injection. The magnetic microbubble gave rise to displacements depending on force, elasticity, and bubble radius, indicating an inverse relation between displacement and the latter two. CONCLUSION: Combining magnetic microbubbles with MMUS could harness the advantages of both techniques, to provide perfusion information, robust lymph node delineation and characterisation based on mechanical properties. ADVANCES IN KNOWLEDGE: (a) Lymphatic drainage of magnetic microbubbles visualised using contrast-enhanced ultrasound imaging and (b) magnetomechanical interactions between such bubbles and surrounding tissue could both contribute to (c) robust detection and characterisation of lymph nodes.

Development of Preclinical Ultrasound Imaging Techniques to Identify and Image Sentinel Lymph Nodes in a Cancerous Animal Model.

Lymph nodes (LNs) are believed to be the first organs targeted by colorectal cancer cells detached from a primary solid tumor because of their role in draining interstitial fluids. Better detection and assessment of these organs have the potential to help clinicians in stratification and designing optimal design of oncological treatments for each patient. Whilst highly valuable for the detection of primary tumors, CT and MRI remain limited for the characterization of LNs. B-mode ultrasound (US) and contrast-enhanced ultrasound (CEUS) can improve the detection of LNs and could provide critical complementary information to MRI and CT scans; however, the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines advise that further evidence is required before US or CEUS can be recommended for clinical use. Moreover, knowledge of the lymphatic system and LNs is relatively limited, especially in preclinical models. In this pilot study, we have created a mouse model of metastatic cancer and utilized 3D high-frequency ultrasound to assess the volume, shape, and absence of hilum, along with CEUS to assess the flow dynamics of tumor-free and tumor-bearing LNs in vivo. The aforementioned parameters were used to create a scoring system to predict the likelihood of a disease-involved LN before establishing post-mortem diagnosis with histopathology. Preliminary results suggest that a sum score of parameters may provide a more accurate diagnosis than the LN size, the single parameter currently used to predict the involvement of an LN in disease.

Displacement Patterns in Magnetomotive Ultrasound Explored by Finite Element Analysis.

Magnetomotive ultrasound is an emerging technique that enables detection of magnetic nanoparticles. This has implications for ultrasound molecular imaging, and potentially addresses clinical needs regarding determination of metastatic infiltration of the lymphatic system. Contrast is achieved by a time-varying magnetic field that sets nanoparticle-laden regions in motion. This motion is governed by vector-valued mechanical and magnetic forces. Understanding how these forces contribute to observed displacement patterns is important for the interpretation of magnetomotive ultrasound images. Previous studies have captured motion adjacent to nanoparticle-laden regions that was attributed to diamagnetism. While diamagnetism could give rise to a force, it cannot fully account for the observed displacements in magnetomotive ultrasound. To isolate explanatory variables of the observed displacements, a finite element model is set up. Using this model, we explore potential causes of the unexplained motion by comparing numerical models with earlier experimental findings. The simulations reveal motion outside particle-laden regions that could be attributed to mechanical coupling and the principle of mass conservation. These factors produced a motion that counterbalanced the time-varying magnetic excitation, and whose extent and distribution was affected by boundary conditions as well as compressibility and stiffness of the surroundings. Our findings emphasize the importance of accounting for the vector-valued magnetic force in magnetomotive ultrasound imaging. In an axisymmetric geometry, that force can be represented by a simple scalar expression, an oversimplification that rapidly becomes inaccurate with distance from the symmetry axis. Additionally, it results in an underestimation of the vertical force component by up to 30%. We therefore recommend using the full vector-valued force to capture the magnetic interaction. This study enhances our understanding of how forces govern magnetic nanoparticle displacement in tissue, contributing to accurate analysis and interpretation of magnetomotive ultrasound imaging.

Magnetomotive Ultrasound Imaging Systems: Basic Principles and First Applications.

This review discusses magnetomotive ultrasound, which is an emerging technique that uses superparamagnetic iron oxide nanoparticles as a contrast agent. The key advantage of using nanoparticle-based contrast agents is their ability to reach extravascular targets, whereas commercial contrast agents for ultrasound comprise microbubbles confined to the blood stream. This also extends possibilities for molecular imaging, where the contrast agent is labeled with specific targeting molecules (e.g., antibodies) so that pathologic tissue may be visualized directly. The principle of action is that an external time-varying magnetic field acts to displace the nanoparticles lodged in tissue and thereby their immediate surrounding. This movement is then detected with ultrasound using frequency- or time-domain analysis of echo data. As a contrast agent already approved for magnetic resonance imaging (MRI) by the US Food and Drug Administration, there is a shorter path to clinical translation, although safety studies of magnetomotion are necessary, especially if particle design is altered to affect biodistribution or signal strength. The external modulated magnetic field may be generated by electromagnets, permanent magnets, or a combination of the two. The induced nanoparticle motion may also reveal mechanical material properties of tissue, healthy or diseased, one of several interesting potential future aspects of the technique.

Tuning Viscoelasticity with Minor Changes in Speed of Sound in an Ultrasound Phantom Material.

The acoustic properties of ultrasound phantom materials have always been important, but with new applications interrogating tissue mechanical properties, viscoelasticity has also become an interesting feature to consider. Along with Young's modulus, the viscous component of tissue is affected by certain diseases and can therefore be used as a biomarker. Furthermore, viscoelasticity varies between tissue types and individuals, and therefore it would be useful with a phantom material that reflects this physiological range. Here we describe a gel for ultrasound imaging with a range of mechanical properties given by mixing different ratios of two oil-based gels, clear ballistic and styrene-ethylene/butylene-styrene (SEBS). The gels were mixed in five different proportions, ranging from 0-100% of either gel. For each of the gel compositions, we measured time of flight to determine speed of sound, narrowband ultrasound transmission for attenuation, stress-relaxation for viscoelasticity, mass and volume. Analysis of the stress-relaxation data using the generalized Maxwell model suggests that the material can be described by five parameters, E0, E1, E2, η1 and η2, and that each of these parameters decreases as more SEBS is incorporated into the mixed material. Instantaneous Young's modulus (the sum of E0, E1 and E2 in our model) ranges between 49 and 117 kPa for the different ratios, similar to values reported for cancerous tissue. Despite the large span of obtainable mechanical properties, speed of sound is relatively constant regardless of composition, with mean value estimates (± 95 % CI) between 1438 ± 9 and 1455 ± 3 m/s for pure and mixed gels. This was attributed to a variation in density and Poisson's ratio, following from the relation linking them to speed of sound and elasticity. Furthermore, both speed of sound and attenuation were within a suitable range for ultrasound phantoms. Combining this ballistic gel with SEBS copolymer in oil allows for control of mechanical properties, both elastic and viscous as evaluated by the material model. Furthermore, it does so without compromising ease of use, longevity and safety of the pre-made gel.

Design and Fabrication of a Conceptual Arterial Ultrasound Phantom Capable of Exhibiting Longitudinal Wall Movement.

The longitudinal movement of the arterial wall of large human arteries has shown promise to be an independent indicator of vascular health. Despite growing interest in this movement, its nature, causes, and implications are not fully understood, and existing phantoms have failed to show a pure longitudinal movement that is not secondary to the distension. An often overlooked aspect of the arterial wall is the interaction between the different layers. The longitudinal movement of the innermost layers, the intima and media, can be several hundred micrometers in the direction of flow during early systole. This is markedly larger than that of the adventitia, indicating that sliding occurs between the two layers. This feature was incorporated into a phantom by casting it in two parts. The molds were developed in-house using mainly a 3-D printer, a versatile and easy production method. Additionally, the phantom contains a tapered region. Using the phantom, we were able to demonstrate a pure longitudinal movement; when it was subjected to a pulsatile pressure, the wall displaced 220 [Formula: see text] (SD 40) radially and 560 [Formula: see text] (SD 74) longitudinally distal to the tapering. The motion followed the pressure variations. This paper serves as a guide for phantom production, explaining each step of the process.