Imperial College London

Professor MENGXING TANG

Faculty of EngineeringDepartment of Bioengineering

Professor of Biomedical Imaging
 
 
 
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Contact

 

+44 (0)20 7594 3664mengxing.tang Website

 
 
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Location

 

3.13Royal School of MinesSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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218 results found

Hirata S, Leow CH, Toulemonde MEG, Tang M-Xet al., 2021, Selection on Golay complementary sequences in binary pulse compression for microbubble detection, JAPANESE JOURNAL OF APPLIED PHYSICS, Vol: 60, ISSN: 0021-4922

Journal article

Cueto C, Cudeiro J, Agudo OC, Guasch L, Tang M-Xet al., 2021, Spatial Response Identification for Flexible and Accurate Ultrasound Transducer Calibration and its Application to Brain Imaging, IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, Vol: 68, Pages: 143-153, ISSN: 0885-3010

Journal article

Zhou X, Toulemonde M, Zhou X, Hansen-Shearer J, Senior R, Tang MXet al., 2021, Volumetric flow estimation in a coronary artery phantom using high frame rate contrast enhanced ultrasound, speckle decorrelation and Doppler flow direction detection, IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, ISSN: 0885-3010

Coronary flow reserve (CFR), relating to the volumetric flow rate, is an effective functional parameter to assess the stenosis in left anterior descending (LAD) coronary artery. We have recently proposed to use high frame rate (HFR) contrast enhanced ultrasound (CEUS) to estimate the volumetric flow rate using ultrasound speckle decorrelation (SDC) without any assumptions about the velocity profile. However, this method still has challenges in imaging deep and small vessels such as LAD. In this study we proposed to address the challenges and demonstrate the feasibility of volumetric flow rate measurement in a coronary mimicking phantom with pulsatile flow using a 1D array cardiac probe, vector Doppler and an optimal probe rotation/tilting for flow direction detection. Both simulations and in vitro experiments were conducted to validate the proposed method. It is shown that in-plane velocities estimated by vector Doppler under a 10-degree probe tilting resulted in smaller percentage error (+5.2%) in flow rate estimates than that in ultrasound imaging velocimetry (-20.2%) although their relative standard deviations were very close, being 2.6 ml/min and 2.8 ml/min, respectively. The flow rate estimated by SDC without direction detection had an error higher than 70%. A 10-degree tilting of the probe had the best results in flow rate estimation when compared to the 5 or 15-degree tilting. Realistic global motions in the LAD increased the flow rate estimation error from 5.2% to 14.2%. It is concluded that it is feasible to measure the volumetric flow rate in a coronary artery flow phantom with a conventional cardiac probe, using HFR acquisition, Doppler and SDC analysis. Potentially, this technique could also be applied to investigate the volumetric flow rate in other small vessels similar to the LAD.

Journal article

Davies HJ, Morse SV, Copping MJ, Sujarittam K, Bourgin VD, Tang M-X, Choi JJet al., 2021, Imaging with therapeutic acoustic wavelets–short pulses enable acoustic localization when time of arrival is combined with delay and sum, IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, Vol: 68, Pages: 178-190, ISSN: 0885-3010

—Passive acoustic mapping (PAM) is an algorithm that reconstructs the location of acoustic sourcesusing an array of receivers. This technique can monitor therapeutic ultrasound procedures to confirm the spatial distribution and amount of microbubble activity induced. CurrentPAM algorithms have an excellentlateral resolution but havea poor axial resolution, making it difficult to distinguishacoustic sources within the ultrasound beams. With recentstudies demonstrating that short-length and low-pressurepulses—acoustic wavelets—have the therapeutic function,we hypothesizedthat the axial resolution could be improvedwith a quasi-pulse-echo approach and that the resolutionimprovement would depend on the wavelet’s pulse length.This article describes an algorithm that resolves acousticsources axially using time of flight and laterally using delayand-sum beamforming, which we named axial temporalposition PAM (ATP-PAM). The algorithm accommodates arapid short pulse (RaSP) sequence that can safely deliverdrugs across the blood–brain barrier. We developed ouralgorithm with simulations (k-wave) and in vitro experiments for one-, two-, and five-cycle pulses, comparingour resolution against that of two current PAM algorithms.We then tested ATP-PAM in vivo and evaluated whether thereconstructed acoustic sources mapped to drug delivery

Journal article

Vos HJ, Voorneveld JD, Jebbink EG, Leow CH, Nie L, van den Bosch AE, Tang M-X, Freear S, Bosch JGet al., 2020, CONTRAST-ENHANCED HIGH-FRAME-RATE ULTRASOUND IMAGING OF FLOW PATTERNS IN CARDIAC CHAMBERS AND DEEP VESSELS, ULTRASOUND IN MEDICINE AND BIOLOGY, Vol: 46, Pages: 2875-2890, ISSN: 0301-5629

Journal article

Reavette RM, Sherwin SJ, Tang M, Weinberg PDet al., 2020, Comparison of arterial wave intensity analysis by pressure-velocity and diameter-velocity methods in a virtual population of adult subjects., Proceedings of the Institution of Mechanical Engineers Part H: Journal of Engineering in Medicine, Vol: 234, Pages: 1260-1276, ISSN: 0954-4119

Pressure-velocity-based analysis of arterial wave intensity gives clinically relevant information about the performance of the heart and vessels, but its utility is limited because accurate pressure measurements can only be obtained invasively. Diameter-velocity-based wave intensity can be obtained noninvasively using ultrasound; however, due to the nonlinear relationship between blood pressure and arterial diameter, the two wave intensities might give disparate clinical indications. To test the magnitude of the disagreement, we have generated an age-stratified virtual population to investigate how the two dominant nonlinearities 'viscoelasticity and strain-stiffening' cause the two formulations to differ. We found strong agreement between the pressure-velocity and diameter-velocity methods, particularly for the systolic wave energy, the ratio between systolic and diastolic wave heights, and older subjects. The results are promising regarding the introduction of noninvasive wave intensities in the clinic.

Journal article

Nie L, Minh Moo JT, Toulemonde M, Tang MX, Freear S, Harput Set al., 2020, Localization of a Scatterer in 3D with a Single Measurement and Single Element Transducer, ISSN: 1948-5719

Conventionally an A-mode scan, a single measurement with a single element transducer, is only used to detect the depth of a reflector or scatterer. In this case, a single measurement reveals only one-dimensional information; the axial distance. However, if the number of scatterers in the ultrasonic field is sparse, it is possible to detect the location of the scatter in multiple spatial dimensions. In this study, we developed a method to find the location of a scatterer in 3-D with a single-element transducer and single measurement. The feasibility of the proposed method was verified in 2-D with experimental measurements.

Conference paper

Choi J, Pouliopoulos A, Smith C, Bezer J, El Ghamrawy A, Boulding C, Morse SV, Meng-Xing Tet al., 2020, Doppler passive acoustic mapping, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 67, Pages: 2692-2703, ISSN: 0885-3010

In therapeutic ultrasound using microbubbles, it is essential to drive the microbubbles into the correct type of activity and the correct location to produce the desired biological response. Although passive acoustic mapping (PAM) is capable of locating where microbubble activities are generated, it is well known that microbubbles move rapidly within the ultrasound beam. We propose a technique that can image microbubble movement by estimating their velocities within the focal volume. Microbubbles embedded within a wall-less channel of a tissue-mimicking material were sonicated using 1-MHz focused ultrasound. The acoustic emissions generated by the microbubbles were captured with a linear array (L7-4). PAM with robust Capon beamforming was used to localize the microbubble acoustic emissions. We spectrally analyzed the time trace of each position and isolated the higher harmonics. Microbubble velocity maps were constructed from the position-dependent Doppler shifts at different time points during sonication. Microbubbles moved primarily away from the transducer at velocities on the order of 1 m/s due to primary acoustic radiation forces, producing a time-dependent velocity distribution. We detected microbubble motion both away and towards the receiving array, revealing the influence of acoustic radiation forces and fluid motion due to the ultrasound exposure. High-speed optical images confirmed the acoustically-measured microbubble velocities. Doppler PAM enables passive estimation of microbubble motion and may be useful in therapeutic applications, such as drug delivery across the blood-brain barrier, sonoporation, sonothrombolysis and drug release.

Journal article

Riemer K, Rowland EM, Leow CH, Tang MX, Weinberg PDet al., 2020, Determining haemodynamic wall shear stress in the rabbit aorta in vivo using contrast-enhanced ultrasound image velocimetry, Annals of Biomedical Engineering, Vol: 48, Pages: 1728-1739, ISSN: 0090-6964

Abnormal blood flow and wall shear stress (WSS) can cause and be caused by cardiovascular disease. To date, however, no standard method has been established for mapping WSS in vivo. Here we demonstrate wide-field assessment of WSS in the rabbit abdominal aorta using contrast-enhanced ultrasound image velocimetry (UIV). Flow and WSS measurements were made independent of beam angle, curvature or branching. Measurements were validated in an in silico model of the rabbit thoracic aorta with moving walls and pulsatile flow. Mean errors over a cardiac cycle for velocity and WSS were 0.34 and 1.69%, respectively. In vivo time average WSS in a straight segment of the suprarenal aorta correlated highly with simulations (PC = 0.99) with a mean deviation of 0.29 Pa or 5.16%. To assess fundamental plausibility of the measurement, UIV WSS was compared to an analytic approximation derived from the Poiseuille equation; the discrepancy was 17%. Mapping of WSS was also demonstrated in regions of arterial branching. High time average WSS (TAWSSxz = 3.4 Pa) and oscillatory flow (OSIxz = 0.3) were observed near the origin of conduit arteries. In conclusion, we have demonstrated that contrast-enhanced UIV is capable of measuring spatiotemporal variation in flow velocity, arterial wall location and hence WSS in vivo with high accuracy over a large field of view.

Journal article

Christensen-Jeffries K, Couture O, Dayton PA, Eldar YC, Hynynen K, Kiessling F, O'Reilly M, Pinton IGF, Schmitz G, Tang M-X, Tanter M, Van Sloun RJGet al., 2020, SUPER-RESOLUTION ULTRASOUND IMAGING, ULTRASOUND IN MEDICINE AND BIOLOGY, Vol: 46, Pages: 865-891, ISSN: 0301-5629

Journal article

Guasch L, Calderon Agudo O, Tang M-X, Nachev P, Warner Met al., 2020, Full-waveform inversion imaging of the human brain, npj Digital Medicine, Vol: 3, Pages: 1-12, ISSN: 2398-6352

Magnetic resonance imaging and X-ray computed tomography provide the two principal methods available for imaging the brain at high spatial resolution, but these methods are not easily portable and cannot be applied safely to all patients. Ultrasound imaging is portable and universally safe, but existing modalities cannot image usefully inside the adult human skull. We use in silico simulations to demonstrate that full-waveform inversion, a computational technique originally developed in geophysics, is able to generate accurate three-dimensional images of the brain with sub-millimetre resolution. This approach overcomes the familiar problems of conventional ultrasound neuroimaging by using the following: transcranial ultrasound that is not obscured by strong reflections from the skull, low frequencies that are readily transmitted with good signal-to-noise ratio, an accurate wave equation that properly accounts for the physics of wave propagation, and adaptive waveform inversion that is able to create an accurate model of the skull that then compensates properly for wavefront distortion. Laboratory ultrasound data, using ex vivo human skulls and in vivo transcranial signals, demonstrate that our computational experiments mimic the penetration and signal-to-noise ratios expected in clinical applications. This form of non-invasive neuroimaging has the potential for the rapid diagnosis of stroke and head trauma, and for the provision of routine monitoring of a wide range of neurological conditions.

Journal article

Dewey M, Siebes M, Kachelrieß M, Kofoed KF, Maurovich-Horvat P, Nikolaou K, Bai W, Kofler A, Manka R, Kozerke S, Chiribiri A, Schaeffter T, Michallek F, Bengel F, Nekolla S, Knaapen P, Lubberink M, Senior R, Tang M-X, Piek JJ, van de Hoef T, Martens J, Schreiber L, Quantitative Cardiac Imaging Study Groupet al., 2020, Clinical quantitative cardiac imaging for the assessment of myocardial ischaemia, Nature Reviews Cardiology, Vol: 17, Pages: 427-450, ISSN: 1759-5002

Cardiac imaging has a pivotal role in the prevention, diagnosis and treatment of ischaemic heart disease. SPECT is most commonly used for clinical myocardial perfusion imaging, whereas PET is the clinical reference standard for the quantification of myocardial perfusion. MRI does not involve exposure to ionizing radiation, similar to echocardiography, which can be performed at the bedside. CT perfusion imaging is not frequently used but CT offers coronary angiography data, and invasive catheter-based methods can measure coronary flow and pressure. Technical improvements to the quantification of pathophysiological parameters of myocardial ischaemia can be achieved. Clinical consensus recommendations on the appropriateness of each technique were derived following a European quantitative cardiac imaging meeting and using a real-time Delphi process. SPECT using new detectors allows the quantification of myocardial blood flow and is now also suited to patients with a high BMI. PET is well suited to patients with multivessel disease to confirm or exclude balanced ischaemia. MRI allows the evaluation of patients with complex disease who would benefit from imaging of function and fibrosis in addition to perfusion. Echocardiography remains the preferred technique for assessing ischaemia in bedside situations, whereas CT has the greatest value for combined quantification of stenosis and characterization of atherosclerosis in relation to myocardial ischaemia. In patients with a high probability of needing invasive treatment, invasive coronary flow and pressure measurement is well suited to guide treatment decisions. In this Consensus Statement, we summarize the strengths and weaknesses as well as the future technological potential of each imaging modality.

Journal article

Zhang G, Toulemonde M, Riemer K, Zhu J, Harput S, Christensen-Jeffries K, Zhu Z, Wang B, Leow CH, Weinberg P, Dunsby C, Tang M-Xet al., 2020, Effects of Mechanical Index on Repeated Sparse Activation of Nanodroplets In Vivo, IEEE International Ultrasonics Symposium (IEEE IUS), Publisher: IEEE, ISSN: 1948-5719

Conference paper

Riemer K, Toulemonde M, Rowland EM, Leow CH, Tang M-X, Weinberg PDet al., 2020, 4D Blood Flow and Wall Shear Stress measured using Volumetric Ultrasound Image Velocimetry, IEEE International Ultrasonics Symposium (IEEE IUS), Publisher: IEEE, ISSN: 1948-5719

Conference paper

Harput S, Toulemonde M, Ramalli A, Christensen-Jeffries K, Boni E, Tortoli P, Dunsby C, Tang M-Xet al., 2020, Quantitative Microvessel Analysis with 3-D Super-Resolution Ultrasound and Velocity Mapping, IEEE International Ultrasonics Symposium (IEEE IUS), Publisher: IEEE, ISSN: 1948-5719

Conference paper

Toulemonde M, Harput S, Tiennot T, Zhou X, Tang M-Xet al., 2020, 3D super localized flow with locally and acoustically activated nanodroplets and high frame rate imaging using a matrix array, IEEE International Ultrasonics Symposium (IEEE IUS), Publisher: IEEE, ISSN: 1948-5719

Conference paper

Zhang G, Harput S, Toulemonde M, Broughton-Venner J, Zhu J, Riemer K, Christensen-Jeffries K, Brown J, Eckersley RJ, Weinberg P, Dunsby C, Tang M-Xet al., 2019, Acoustic wave sparsely-activated localization microscopy (AWSALM): in vivo fast ultrasound super-resolution imaging using nanodroplets, IEEE International Ultrasonics Symposium (IUS), Publisher: IEEE, Pages: 1930-1933, ISSN: 1948-5719

Current localization-based super-resolution ultrasound imaging requires a low concentration of flowing microbubbles to visualize microvasculature beyond the diffraction limit and acquisition is slow. Nanodroplets offer a promising solution as they can be sparsely activated and deactivated on-demand. In this study, acoustic wave sparsely-activated localization microscopy (AWSALM) using activation and deactivation of nanodroplets, an acoustic counterpart of photo-activated localization microscopy (PALM) which is less dependent on agent concentration and the presence of flow, is demonstrated for super-resolution imaging in deep tissues in vivo. An in vivo super-resolution image of a rabbit kidney is obtained in 1.1 seconds using AWSALM, where micro-vessels with apparent sizes far below the half-wavelength of 220 μm were visualized. This preliminary result demonstrates the feasibility of applying AWSALM for in vivo super-resolution imaging.

Conference paper

Zhou X, Zhou X, Leow CH, Tang Met al., 2019, Measurement of flow volume in the presence of reverse flow with ultrasound speckle decorrelation, Ultrasound in Medicine and Biology, Vol: 45, Pages: 3056-3066, ISSN: 0301-5629

Direct measurement of volumetric flow rate in the cardiovascular system with ultrasound is valuable but has been a challenge because most current 2-D flow imaging techniques are only able to estimate the flow velocity in the scanning plane (in-plane). Our recent study demonstrated that high frame rate contrast ultrasound and speckle decorrelation (SDC) can be used to accurately measure the speed of flow going through the scanning plane (through-plane). The volumetric flow could then be calculated by integrating over the luminal area, when the blood vessel was scanned from the transverse view. However, a key disadvantage of this SDC method is that it cannot distinguish the direction of the through-plane flow, which limited its applications to blood vessels with unidirectional flow. Physiologic flow in the cardiovascular system could be bidirectional due to its pulsatility, geometric features, or under pathologic situations. In this study, we proposed a method to distinguish the through-plane flow direction by inspecting the flow within the scanning plane from a tilted transverse view. This method was tested on computer simulations and experimental flow phantoms. It was found that the proposed method could detect flow direction and improved the estimation of the flow volume, reducing the overestimation from over 100% to less than 15% when there was flow reversal. This method showed significant improvement over the current SDC method in volume flow estimation and can be applied to a wider range of clinical applications where bidirectional flow exists.

Journal article

Zhou X, Vincent P, Zhou X, Leow CH, Tang M-Xet al., 2019, Optimization of 3-D Divergence-Free Flow Field Reconstruction Using 2-D Ultrasound Vector Flow Imaging, Ultrasound in Medicine and Biology, Vol: 45, Pages: 3042-3055, ISSN: 0301-5629

Abstract- 3D blood Vector Flow Imaging (VFI) is of great value for understanding and detecting cardiovascular diseases. Currently 3D Ultrasound (US) VFI requires 2D matrix probes which are expensive and suffer from sub-optimal image quality. Our recent study proposed an interpolation algorithm to obtain a divergence free reconstruction of the 3D flow field from 2D velocities obtained by High Frame Rate US Particle Imaging Velocimetry (HFR echo-PIV, also known as HFR UIV), using a 1D array transducer. This work aims to significantly improve the accuracy and reduce the time-to-solution of our previous approach thereby paving the way for clinical translation. More specifically, accuracy was improved by optimising the divergence free basis to reduce Runge-phenomena near domain boundaries, and time-to-solution was reduced by demonstrating that under certain conditions the resulting system could be solved using widely available and highly optimized Generalized Minimum Residual (GMRES) algorithms. To initially demonstrate the utility of the approach, coarse 2D sub-samplings of an analytical unsteady Womersely flow solution and a steady helical flow solution obtained using Computational Fluid Dynamics (CFD) were used to successfully reconstruct full flow solutions, with 0.82% and 4.8% average relative errors in the velocity field respectively. Subsequently, multi-plane 2D velocity fields were obtained through HFR UIV for a straight tube phantom and a carotid bifurcation phantom, from which full 3D flow fields were reconstructed. These were then compared with flow fields obtained via CFD in each of the two configurations, and average relative errors of 6.01% and 12.8% in the velocity field were obtained. These results reflect 15%-75% improvements in accuracy and 53~874 fold acceleration of reconstruction speeds for the four cases, when compared with the previous divergence free flow reconstruction method. In conclusion the proposed method provides an effective and fast metho

Journal article

Zhu J, Lin S, Leow CH, Rowland E, Kai R, Harput S, Weinberg P, Tang Met al., 2019, High Frame Rate Contrast-Enhanced Ultrasound Imaging for Slow Lymphatic Flow: Influence of Ultrasound Pressure and Flow Rate on Bubble Disruption and Image Persistence, Ultrasound in Medicine and Biology, Vol: 45, Pages: 2456-2470, ISSN: 0301-5629

Contrast enhanced ultrasound (CEUS) utilising microbubbles shows great potential for visualising lymphatic vessels and identifying sentinel lymph nodes (SLN) which is valuable for axillary staging in breast cancer patients. However, current CEUS imaging techniques have limitations that affect the accurate visualisation and tracking of lymphatic vessels and SLN. (1) Tissue artefacts and bubble disruption can reduce the image contrast. (2) Limited spatial and temporal resolution diminishes the amount of information that can be captured by CEUS. (3) The slow lymph flow makes Doppler based approaches less effective. This work evaluates on a lymphatic vessel phantom the use of high frame-rate (HFR) CEUS for the detection of lymphatic vessels where flow is slow. Specifically the work particularly investigates the impact of key factors in lymphatic imaging, including ultrasound pressure and flow velocity as well as probe motion during vessel tracking, on bubble disruption and image contrast. A trail was also conducted to apply HFR CEUS imaging on vasculature in a rabbit popliteal lymph node (LN). Our results show that (1) HFR imaging and SVD filtering can significantly reduce tissue artefacts in the phantom; (2) the slow flow rate within the phantom makes image contrast and signal persistence more susceptible to changes in ultrasound amplitude/MI, and an MI value can be chosen to reach a compromise between images contrast and bubble disruption under slow flow condition; (3) probe motion significantly decreases image contrast of the vessel, which can be improved by applying motion correction prior to SVD filtering; (4) the optical observation of the impact of ultrasound pressure in HFR CEUS further confirm the importance of optimising ultrasound amplitude MI; (5) Vessels inside rabbit LN with blood flow less than 3 mm/s are clearly visualised.

Journal article

Christensen-Jeffries K, Brown J, Harput S, Zhang G, Zhu J, Tang M-X, Dunsby C, Eckersley RJet al., 2019, Poisson statistical model of ultrasound super-resolution imaging acquisition time, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 66, Pages: 1246-1254, ISSN: 0885-3010

A number of acoustic super-resolution techniques have recently been developed to visualize microvascular structure and flow beyond the diffraction limit. A crucial aspect of all ultrasound (US) super-resolution (SR) methods using single microbubble localization is time-efficient detection of individual bubble signals. Due to the need for bubbles to circulate through the vasculature during acquisition, slow flows associated with the microcirculation limit the minimum acquisition time needed to obtain adequate spatial information. Here, a model is developed to investigate the combined effects of imaging parameters, bubble signal density, and vascular flow on SR image acquisition time. We find that the estimated minimum time needed for SR increases for slower blood velocities and greater resolution improvement. To improve SR from a resolution of λ/10 to λ/20 while imaging the microvasculature structure modeled here, the estimated minimum acquisition time increases by a factor of 14. The maximum useful imaging frame rate to provide new spatial information in each image is set by the bubble velocity at low blood flows (<;150 mm/s for a depth of 5 cm) and by the acoustic wave velocity at higher bubble velocities. Furthermore, the image acquisition procedure, transmit frequency, localization precision, and desired super-resolved image contrast together determine the optimal acquisition time achievable for fixed flow velocity. Exploring the effects of both system parameters and details of the target vasculature can allow a better choice of acquisition settings and provide improved understanding of the completeness of SR information.

Journal article

Ahmadzadeh SMH, Chen X, Hagemann H, Tang M-X, Bull AMJet al., 2019, Developing and using fast shear wave elastography to quantify physiologically-relevant tendon forces, Medical Engineering and Physics, Vol: 69, Pages: 116-122, ISSN: 1350-4533

Direct quantification of physiologically-relevant tendon forces can be used in a wide range of clinical applications. However, tendon forces have usually been estimated either indirectly by computational models or invasively using force transducers, and direct non-invasive measurement of forces remains a big challenge. The aim of this study was to investigate the feasibility of using Shear Wave Elastography (SWE) for quantifying human tendon forces at physiological levels. An experimental protocol was developed to measure Shear Wave Speed (SWS) and tensile force in a human patellar tendon using SWE and conventional tensile testing to quantify the correlation between SWS and load. The SWE system was customised to allow imaging of fast shear waves expected in human tendons under physiological loading which is outside the normal range of the existing SWE systems. SWS increased from 10.8 m/s to 36.1 m/s with the increasing tensile load from 8 N to 935 N and a strong linear correlation between SWS and load (r = 0.99, p < 0.01) was observed. The findings in this study suggest that SWE can be used as a potential non-invasive method for direct quantification of physiologically-relevant tendon forces, as well as for validating the estimated forces from other methods such as computational models.

Journal article

Zhu J, Rowland E, Harput S, Riemer K, Leow CH, Clark B, Cox K, Lim A, Christensen-Jeffries K, Zhang G, Brown J, Dunsby C, Eckersley R, Weinberg P, Tang Met al., 2019, 3D super-resolution ultrasound imaging of rabbit lymph node vasculature in vivo using microbubbles, Radiology, Vol: 291, Pages: 642-650, ISSN: 0033-8419

Background: Variations in lymph node (LN) microcirculation can be indicative of metastasis. Identifying and quantifying metastatic LNs remains essential for prognosis and treatment planning but a reliable non-invasive imaging technique is lacking. 3D super-resolution (SR) ultrasound has shown potential to noninvasively visualize microvascular networks in vivo.Purpose: To study the feasibility of 3D SR ultrasound imaging of rabbit lymph node (LN) microvascular structure and blood flow using microbubbles.Materials and Methods: In vivo studies were carried out to image popliteal LNs of two healthy male New Zealand White rabbits aged 6-8 weeks. 3D high frame rate contrast enhanced ultrasound was achieved by mechanically scanning a linear imaging probe. Individual microbubbles were identified, localized, and tracked to form 3D SR images and super-resolved velocity maps. Acoustic sub-aperture processing (ASAP)was used to improve image contrast and generateenhanced power Doppler (PD) and color Doppler (CD) images. Vessel size and blood flow velocity distributions were evaluated and assessed by Student’s paired t-test. Results:SR images revealed micro-vessels in the rabbitLN, with branches clearly resolved when separated by 30 μm, which is less than half of the acoustic wavelength and not resolvable by power or color Doppler. The apparent size distribution of most vessels in the SR images was below 80 μm and agrees with micro-CT data whereas most of those detected by Doppler techniques were larger than 80 μm. The blood flow velocity distribution indicated that most of the blood flow in the rabbit popliteal LN was at velocities lower than 5mm/s. Conclusion: 3D super-resolution ultrasound imaging using microbubbles allows non-invasive and non-ionizing visualization and quantification of rabbit lymph node microvascular structures and blood flow dynamics with resolution below the wave diffraction limit.

Journal article

Zhang G, Harput S, Hu H, Christensen-Jeffries K, Zhu J, Brown J, Leow CH, Eckersley R, Dunsby C, Tang M-Xet al., 2019, Fast acoustic wave sparsely activated localization microscopy (fast-AWSALM): ultrasound super-resolution using plane-wave activation of nanodroplets, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 66, Pages: 1039-1046, ISSN: 0885-3010

Localization-based ultrasound super-resolution imaging using microbubble contrast agents and phase-change nano-droplets has been developed to visualize microvascular structures beyond the diffraction limit. However, the long data acquisition time makes the clinical translation more challenging. In this study, fast acoustic wave sparsely activated localization microscopy (fast-AWSALM) was developed to achieve super-resolved frames with sub-second temporal resolution, by using low-boiling-point octafluoropropane nanodroplets and high frame rate plane waves for activation, destruction, as well as imaging. Fast-AWSALM was demonstrated on an in vitro microvascular phantom to super-resolve structures that could not be resolved by conventional B-mode imaging. The effects of the temperature and mechanical index on fast-AWSALM was investigated. Experimental results show that sub-wavelength micro-structures as small as 190 lm were resolvable in 200 ms with plane-wave transmission at a center frequency of 3.5 MHz and a pulse repetition frequency of 5000 Hz. This is about a 3.5 fold reduction in point spread function full-width-half-maximum compared to that measured in conventional B-mode, and two orders of magnitude faster than the recently reported AWSALM under a non-flow/very slow flow situations and other localization based methods. Just as in AWSALM, fast-AWSALM does not require flow, as is required by current microbubble based ultrasound super resolution techniques. In conclusion, this study shows the promise of fast-AWSALM, a super-resolution ultrasound technique using nanodroplets, which can generate super-resolution images in milli-seconds and does not require flow.

Journal article

Hernandez-Gil J, Braga M, Harriss B, Carroll LS, Leow CH, Tang M-X, Aboagye EO, Long NJet al., 2019, Development of Ga-68-labelled ultrasound microbubbles for whole-body PET imaging, Chemical Science, Vol: 10, Pages: 5603-5615, ISSN: 2041-6520

Microbubble (MB) contrast agents have revolutionalised the way ultrasound (US) imaging can be used clinically and pre-clinically. Contrast-enhanced US offers improvements in soft-tissue contrast, as well as the ability to visualise disease processes at the molecular level. However, its inability to provide in vivo whole-body imaging can hamper the development of new MB formulations. Herein, we describe a fast and efficient method for achieving 68Ga-labelling of MBs after a direct comparison of two different strategies. The optimised approach produces 68Ga-labelled MBs in good yields through the bioorthogonal inverse-electron-demand Diel–Alder reaction between a trans-cyclooctene-modified phospholipid and a new tetrazine-bearing HBED-CC chelator. The ability to noninvasively study the whole-body distribution of 68Ga-labelled MBs was demonstrated in vivo using positron emission tomography (PET). This method could be broadly applicable to other phospholipid-based formulations, providing accessible solutions for in vivo tracking of MBs.

Journal article

Leow CH, Bush N, Stanziola A, Braga M, Shah A, Hernández-Gil J, Long NJ, Aboagye E, Bamber J, Tang Met al., 2019, 3D microvascular imaging using high frame rate ultrasound and ASAP without contrast agents: development and initial in vivo evaluation on non-tumour and tumour models, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 66, Pages: 939-948, ISSN: 0885-3010

Three-dimensional imaging is valuable to non-invasively assess angiogenesis given the complex 3D architecture of vascular networks. The emergence of high frame rate (HFR) ultrasound, which can produce thousands of images per second, has inspired novel signal processing techniques and their applications in structural and functionalimaging of blood vessels. Although highly sensitive vascular mapping has been demonstrated using ultrafast Doppler, the detectability of microvasculature from the background noise may be hindered by the low signal to noise ratio (SNR) particularly in deeper region and without the use of contrast agents. We have recently demonstrated a coherence based technique, acoustic sub-aperture imaging (ASAP), for super-contrast vascular imaging and illustrated the contrast improvement using HFR contrast-enhanced ultrasound. In this work, we provide a feasibility study for microvascular imaging using ASAP without contrast agents, and extend its capability from 2D to volumetric vascular mapping. Using an ultrasound research system and a pre-clinical probe, we demonstrated the improved visibility of microvascular mapping using ASAP in comparison to ultrafast Power Doppler (PD) on a mouse kidney, liver and tumour without contrast agent injection. The SNR of ASAP images improves in average by 10dB when compared to PD. Besides, directional velocity mappings were also demonstrated by combining ASAP with the phase information extracted from lag-1 autocorrelation. Three-dimensional vascular and velocity mapping of the mouse kidney, liver and tumour were demonstrated by stackingthe ASAP images acquired using 2D ultrasound imaging and a trigger-controlled linear translation stage. The 3D results depicted clear micro-vasculature morphologies and function

Journal article

Zhang G, Lin S, Leow CH, Pang KT, Hernandez Gil J, Long N, Eckersley R, Matsunaga T, Tang Met al., 2019, Quantification of vaporized targeted nanodroplets using high-frame-rate ultrasound and optics, Ultrasound in Medicine and Biology, Vol: 45, Pages: 1131-1142, ISSN: 0301-5629

Owing to their ability to efficiently deliver biological cargo and sense the intracellular milieu, vertical arrays of high aspect ratio nanostructures, known as nanoneedles,are being developed as minimally invasive tools for cell manipulation. However, little is known of the mechanisms of cargo transfer across the cell membrane-nanoneedle interface. Particularly,the contributions of membrane piercing, modulation of membrane permeability and endocytosis to cargo transfer remain largelyunexplored. Here, combining state-of-the-art electron and scanning ion conductance microscopy with molecular biology techniques, we show that porous silicon nanoneedle arrays concurrently stimulate independent endocytic pathways which contribute to enhanced biomolecule delivery into human mesenchymal stem cells. Electron microscopy of the cell membrane at nanoneedle sites shows an intact lipid bilayer, accompanied by an accumulation of clathrin-coated pits and caveolae. Nanoneedles enhance the internalisation of biomolecular markers of endocytosis, highlighting the concurrent activation of caveolae-and clathrin-mediated endocytosis, alongside macropinocytosis. These events contribute to the nanoneedle-mediated delivery (nanoinjection) of nucleic acids into human stem cells, which distribute across the cytosol and the endolysosomal system. This data extends the understanding of how nanoneedles modulate biological processes to mediate interaction with the intracellular space, providing indications for the rational design of improved cell-manipulation technologies.

Journal article

Brown J, Christensen-Jeffries K, Harput S, Zhang G, Zhu J, Dunsby C, Tang M-X, Eckersley RJet al., 2019, Investigation of microbubble detection methods for super-resolution imaging of microvasculature, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 66, Pages: 676-691, ISSN: 0885-3010

Ultrasound super-resolution techniques use the response of microbubble contrast agents (MBs) to visualize the microvasculature. Techniques that localize isolated bubble signals first require detection algorithms to separate the MB and tissue responses. This work explores the three main MB detection techniques for super-resolution of microvasculature. Pulse inversion (PI), differential imaging (DI) and singular value decomposition (SVD) filtering were compared in terms of the localization accuracy, precision and contrast to tissue ratio (CTR). MB responses were simulated based on the properties of Sonovue™ and using the Marmottant model. Non-linear propagation through tissue was modelled using the k-Wave software package. For the parameters studied, the results show that PI is most appropriate for low frequency applications, but also most dependent on transducer bandwidth. SVD is preferable for high frequency acquisition where localization precision on the order of a few microns is possible. PI is largely independent of flow direction and speed compared to SVD and DI, so is appropriate for visualizing the slowest flows and tortuous vasculature. SVD is unsuitable for stationary MBs and can introduce a localization error on the order of hundreds of microns over the speed range 0- 2 mm/s and flow directions from lateral (parallel to probe) to axial (perpendicular to probe). DI is only suitable for flow rates > 0.5 mm/s or as flow becomes more axial. Overall, this study develops a MB and tissue non-linear simulation platform to improve understanding of how different MB detection techniques can impact the super-resolution process and explores some of the factors influencing the suitability of each.

Journal article

Zhou X, Papadopoulou V, Leow CH, Vincent P, Tang M-Xet al., 2019, 3-D flow reconstruction using divergence-free interpolation of multiple 2-D contrast-enhanced ultrasound particle imaging velocimetry measurements, Ultrasound in Medicine and Biology, Vol: 45, Pages: 795-810, ISSN: 0301-5629

Quantification of 3-D intravascular flow is valuable for studying arterial wall diseases but currently there is a lack of effective clinical tools for this purpose. Divergence-free interpolation (DFI) using radial basis function (RBF) is an emerging approach for full-field flow reconstruction using experimental sparse flow field samples. Previous DFI reconstructs full-field flow from scattered 3-D velocity input obtained using phase-contrast magnetic resonance imaging with low temporal resolution. In this study, a new DFI algorithm is proposed to reconstruct full-field flow from scattered 2-D in-plane velocity vectors obtained using ultrafast contrast-enhanced ultrasound (>1000 fps) and particle imaging velocimetry. The full 3-D flow field is represented by a sum of weighted divergence-free RBFs in space. Because the acquired velocity vectors are only in 2-D and hence the problem is ill-conditioned, a regularized solution of the RBF weighting is achieved through singular value decomposition (SVD) and the L-curve method. The effectiveness of the algorithm is determined via numerical experiments for Poiseuille flow and helical flow with added noise, and it is found that an accuracy as high as 95.6% can be achieved for Poiseuille flow (with 5% input noise). Experimental feasibility is also determined by reconstructing full-field 3-D flow from experimental 2-D ultrasound image velocimetry measurements in a carotid bifurcation phantom. The method is typically faster for a range of problems compared with computational fluid dynamics, and has been found to be effective for the three flow cases.

Journal article

Cox K, Tang M-X, Zhu J, 2019, Diagnosing and Managing the Malignant Axilla in Breast Cancer, CURRENT BREAST CANCER REPORTS, Vol: 11, Pages: 1-8, ISSN: 1943-4588

Journal article

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