Magnetomotive ultrasound for nanomedicine : a mechanistic approach to detection, evaluation and safety assessment

Cancer is one of the leading causes of death worldwide, but reliable diagnosis and staging can contribute to optimal treatment planning, and is a crucial factor in reducing mortality and maintaining quality of life. Soft tissue mechanical properties are promising indicators of cancer that can be assessed non-invasively using functional imaging. Additionally, lymphatic involvement is considered a key aspect in staging of many types, including colorectal and breast cancer. Magnetomotive ultrasound, MMUS, is an imaging technique proposed for cancer staging and treatment. It relies on magnetically induced motion, transferred from a contrast agent to the tissue of interest. The tissue response to this perturbation is related to its mechanical properties, and thereby to cancer progression. Typically, the contrast agent consists of magnetic nanoparticles; These can be incorporated into microbubbles, that could allow for drug transport and site-specific delivery. Exploring these properties and possibilities of MMUS clarifies its clinical potential. The aim of this work was therefore to examine (a) the relation between tissue mechanical properties and magnetomotion, (b) the feasibility of magnetic microbubbles as a contrast agent and (c) the cellular response to magnetic nanoparticles and forces. Points (a) and (b) were addressed by comparing MMUS images conducted on real and phantom tissue to finite element analysis outputs; Transmission electron microscopy and quantitative cell based assays were used in exploring point (c). Magnetomotion was found to depend on tissue compressibility and elasticity, both potential cancer indicators. Tissue elasticity was also found to affect the tissue deformations induced by magnetic microbubbles. Furthermore, lymphatic drainage of magnetic microbubbles was demonstrated, validating their potential as a contrast agent in cancer imaging. Finally, cells were confirmed to take up nanoparticles, and no adverse effects of magnetic excitation was detected. In summary, there is merit to further development of MMUS for cancer diagnostics and treatment

Design and Fabrication of Ultrasound Phantoms to Identify the Actuator of Arterial Wall Longitudinal Movement

Trots att ett decennium har gått sedan artärernas longitudinella rörelse visades in vivo är bakgrunden till denna multifasiska rörelse fortfarande inte fastställd. Att trycket skulle kunna driva rörelsen har ledigt avfärdats. Resonemanget har varit att eftersom trycket verkar vinkelrätt mot väggen kan det endast påverka den radiella töjningen. I följande arbete har vi visat i en förenklad teoretisk modell samt i fantom-modeller att trycket kan orsaka en longitudinell rörelse hos kärlfantomer med vissa specifika geometrier. En kombination av traditionella och nyskapande tekniker användes för att skapa de sammansatta fantomerna. Fantomerna gjordes i två delar och PVA användes till båda. Ett system för att koppla samman fantomen med en pump utvecklades. Fantomerna designades så att en eventuell tryckdriven rörelse kunde isoleras. Resultatet visade att geometrin påverkade storleken av den longitudinella rörelsen. En jämförelse av rörelsens omfattning mellan tre olika fantomer visade att rörelsen var minst för den fantom där trycket inte skulle kunna orsaka en stor framåtrörelse enligt teorin. Geometrin för denna fantom var en cylinder med konstant diameter och förlängningen uppmättes till 0.186 mm med en standardavvikelse på 0.057. De andra geometrierna hade en minskande diameter, den ena gradvis, den andra abrupt. Förlängningen var 3.258 ± 0.077 respektive 5.375 ± 0.392 mm. Rörelsemönstret längst med en av fantomerna är också en stark indikation på att större delen av rörelsen härrör från den position där trycket skulle ha störst påverkan. Detta tyder på att trycket verkligen kan driva en framåtriktad rörelse av kärlväggen.Although a decade has passed since the longitudinal movement of arteries was shown in vivo, the cause for this multiphasic movement has not yet been established. Pressure as a force driving the forward motion has been repeatedly dismissed on the grounds that pressure acts perpendicular to the wall and therefore solely in the radial direction. In this work we have shown in a simplified theoretical model and phantom models that pressure can cause a longitudinal movement of vessel phantoms of some specific geometries. The compound phantoms were produced using a combination of traditional and innovatory techniques. The phantoms were in two parts and PVA was used for both. A system to connect the phantom inlet to a pump was also developed. The phantoms where designed such that any movement due to pressure could be isolated. The result showed that the geometry and position influenced the longitudinal movement. A comparison of the magnitude of the movements of three different phantoms showed that the movement was smallest in the phantom where pressure could not generate a large forward movement according to the theory. The geometry of this particular phantom was a cylinder of constant diameter, and the lengthening was measured to 0.186 mm with a standard deviation of 0.057. The other geometries involved a decrease of the diameter, one gradual and another abrupt. The lengthening was 3.258 ± 0.077 and 5.375 ± 0.392 mm respectively. The movement pattern along the length of one of the phantoms strongly indicate that the largest part of the movement originates where pressure would have the greatest influence. This implies that the pressure can drive the forward motion of the vessel wall.The Moving Artery Phantom Illnesses related to the heart and blood vessels are a common cause of death in the world. A relatively new discovery is that the arterial wall moves back and forth along with the blood flow. To understand if this motion is related to these illnesses, researchers like to know its origin. We have designed and fabricated phantoms to be used in investigating if varying the pressure of the flow can give rise to this motion. Many people suffer and die from illnesses related to the heart and blood vessels. To understand whom is in the risk group researchers try to learn all about these organs. Arteries are the blood vessels transporting blood from the heart out to the body. The arteries are elastic and they move when the heart is pumping. The arteries widen due to the incoming blood, but the arterial wall also moves along the blood flow back and forth. This second movement has only been known for a little more than a decade. The reason for the movement is not yet known. We want to see if varying the pressure can give rise to a motion. The pressure acts at a 90 degrees angle to the wall, widening the vessel by pushing it out. But if the vessels diameter becomes narrower the pressure could act along the direction of flow. We want to investigate if the pressure can drive the motion. Inside the human body there are so many variables that can affect the motion of the vessels. It is impossible to design a test that investigates how just one of all of these parameters affect it. Therefore we have designed and fabricated models, also called phantoms to investigate the movement in a much simpler system. The phantom is fabricated in two parts. One part is representing the moving artery and the second part the surrounding tissue. These two elastic, slightly slimy, parts are assembled under water and viewed with an ultrasound equipment. Ultrasound is a high frequency sound and an image is created from the echoes. It is frequently used in medical diagnosis, for example on babies before they are born. To cast the phantom we use 3D-printed molds. The printer prints from the bottom up, one layer at the time. Each print is drawn in a computer program, and it takes approximately three hours from the printer starting until the plastic part is in our hands. We compare three different geometries. One straight, one with an abrupt diameter change, making the phantom vessel narrower and one with a more gradual diameter change, also making the vessel narrower. The assembled phantoms are connected to a tube from the pump. The pump is taking the place of the heart, but instead of using blood we pump water into the phantom. The pressure is varied. By using the ultrasound equipment the movement of the vessel phantom could be seen and later analyzed. The results show that the straight vessel did not move much along the vessel wall but both of the vessels with changing diameter move

Contrast-enhanced magnetomotive ultrasound imaging (CE-MMUS) for colorectal cancer staging : assessment of sensitivity and resolution to detect alterations in tissue stiffness

A key challenge in the treatment of colorectal cancer is identification of the sentinel draining lymph node. Magnetomotive ultrasound, MMUS, has identified lymph nodes in rat models: superparamagnetic iron oxide nanoparticles (SPIONs) accumulated in the lymph are forced to oscillate by an external magnetic field; the resulting axial displacement is recovered allowing structure delineation with potential to indicate alterations in tissue stiffness, but it is limited by small vibration amplitudes. We propose CE-MMUS using SPION loaded microbubbles (SPION-MBs) to enhance sensitivity, reduce toxicity, and offer additional diagnostic or perfusion information. Laser doppler vibrometry measurements was performed on SPION containing tissue mimicking material during magnetic excitation. These measurements show a vibration amplitude of 279 ± 113 μm in a material with Young's modulus of 24.3 ± 2.8 kPa, while the displacements were substantially larger, 426 ± 9 μm, in the softer material, with a Young's modulus of 9.6 ± 0.8 kPa. Magnetic field measurement data was used to calibrate finite element modelling of both MMUS and CE-MMUS. SPION-MBs were shown to be capable of inducing larger tissue displacements under a given magnetic field than SPIONs alone, leading to axial displacements of up to 2.3x larger. A doubling in tissue stiffness (as may occur in cancer) reduces the vibration amplitude. Thus, there is potential for CE-MMUS to achieve improved stiffness sensitivity. Our aim is to define the potential contribution of CE-MMUS in colorectal cancer diagnosis and surgical guidance

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

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

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

Search for anomalous t t-bar production in the highly-boosted all-hadronic final state

A search is presented for a massive particle, generically referred to as a Z', decaying into a t t-bar pair. The search focuses on Z' resonances that are sufficiently massive to produce highly Lorentz-boosted top quarks, which yield collimated decay products that are partially or fully merged into single jets. The analysis uses new methods to analyze jet substructure, providing suppression of the non-top multijet backgrounds. The analysis is based on a data sample of proton-proton collisions at a center-of-mass energy of 7 TeV, corresponding to an integrated luminosity of 5 inverse femtobarns. Upper limits in the range of 1 pb are set on the product of the production cross section and branching fraction for a topcolor Z' modeled for several widths, as well as for a Randall--Sundrum Kaluza--Klein gluon. In addition, the results constrain any enhancement in t t-bar production beyond expectations of the standard model for t t-bar invariant masses larger than 1 TeV.Comment: Submitted to the Journal of High Energy Physics; this version includes a minor typo correction that will be submitted as an erratu

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe

Measurement of the t t-bar production cross section in the dilepton channel in pp collisions at sqrt(s) = 7 TeV

The t t-bar production cross section (sigma[t t-bar]) is measured in proton-proton collisions at sqrt(s) = 7 TeV in data collected by the CMS experiment, corresponding to an integrated luminosity of 2.3 inverse femtobarns. The measurement is performed in events with two leptons (electrons or muons) in the final state, at least two jets identified as jets originating from b quarks, and the presence of an imbalance in transverse momentum. The measured value of sigma[t t-bar] for a top-quark mass of 172.5 GeV is 161.9 +/- 2.5 (stat.) +5.1/-5.0 (syst.) +/- 3.6(lumi.) pb, consistent with the prediction of the standard model.Comment: Replaced with published version. Included journal reference and DO

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters