Static response of coated microbubbles:Modeling simulations and parameter estimation

AbstractThe mechanical response of contrast agent microbubbles subject to a static load was investigated in force-deformation curves. Asymptotic relations are fitted with experimental AFM measurements of polymeric microbubbles available in the literature. The elastic modulus and shell thickness are estimated based on the transition from the classical linear (Reissner) to the nonlinear (Pogorelov) regime. The estimated value of the elastic modulus is in the order of GPa and the shell thickness in the order of nm, in good agreement with independent estimates. Numerical simulations recover the above transition and identify a third regime, dominated by the compressibility of the enclosed gas

Mechanical properties of phospholipid coated microbubbles

Phospholipid coated, inert gas filled microbubbles (MBs) are currently in widespread use in medical applications for the enhancement of diagnostic ultrasound images, and they are promising candidates for use in the area of targeted drug/gene delivery and uptake. As phospholipid coated MBs were developed for use with diagnostic ultrasound, their behaviour under acoustic loading is well investigated, however much less is known about their response to direct mechanical loading, which will potentially prove important as the range of uses of MBs expands. This is particularly true of the existing commercially available MB products. In this thesis, atomic force microscopy (AFM) was used to investigate the mechanical behaviour of three types of commercially produced phospholipid coated MBs, Definity®, BR14 and Sonovue®, at small deformations. Force spectroscopy was used to produce force-deformation (F-Δ) curves showing how the MBs deform under mechanical loading. Definity® MBs were deformed with tipless cantilevers at high deformations (though still less than 30% of the initial height of the MB); BR14 and Sonovue® MBs were probed with both tipless and tipped cantilevers to investigate both whole-bubble deformation and also shell indentation. BR14 was limited to low deformations; Sonovue® included both low and high deformations. The F-Δ curves were used to evaluate MB stiffness and also in combination with up to four mechanical models to predict the Young’s modulus of the MBs. The suitability of Reissner, Hertz, Elastic Membrane and De Jong theories for the prediction of the Young’s modulus of the MBs was explored. In the case of Definity® MBs no correlation between MB size and stiffness was observed; however an unexpected size dependence was observed in the Young’s modulus values, possibly due to variations in the thickness of the phospholipid shell. The membrane stretching component of elastic membrane theory was found to be the most applicable model on these MBs in this higher deformation regime. However, in this regime, gas compressibility could play a role and this is not included in the model. We studied the mechanical properties of BR14 MBs at very low deformations using ‘soft’ cantilevers. In this regime, gas compressibility should play a minimal role and there are several mechanical models which may be used. These MBs demonstrated decreasing stiffness with increasing diameter, and little variation in Young’s modulus with diameter. Hertz and De Jong theories showed more realistic Young’s modulus values (compared to other models) with little observable trend. Sonovue® MBs were used for a more comprehensive study of the small and very small deformation regimes using ‘soft’, ‘hard’ and tipped cantilevers. They showed no definitive trend in MB stiffness with MB diameter. Hertz and De Jong theory were again found to be most suitable. Analysis of curves acquired with tipped cantilevers indicated that the stiffness of a localised area of the shell membrane is similar to the overall stiffness of the MB and that the apparent Young’s modulus of the membrane according to the Hertz theory is also similar to that of the MB as a whole. Generally, considering all systems, Reissner theory was found to produce large overestimates of Young’s modulus, exceeding expected values by several orders of magnitude. Hertz and De Jong theories produced underestimates, though by a much smaller margin. Elastic membrane theory worked well and produced realistic Young’s modulus values only at relatively high deformation (the stretching term) in spite of the fact that gas compressibility is not taken into account. The suitability of the models is therefore very dependent on the deformation regime of the experiment. It seems that there is scope for better models at low deformation taking into account the soft shell of the MB and possibly its specific structure. Precise structural information of the MB shells does not exist; it is not trivial to attain and should certainly be a topic of future work with additional instrumentation

Differentiation of Vascular Characteristics Using Contrast-Enhanced Ultrasound Imaging

Ultrasound contrast imaging has been used to assess tumour growth and regression by assessing the flow through the macro- and micro-vasculature. Our aim was to differentiate the blood kinetics of vessels such as veins, arteries and microvasculature within the limits of the spatial resolution of contrast-enhanced ultrasound imaging. The highly vascularised ovine ovary was used as a biological model. Perfusion of the ovary with SonoVue was recorded with a Philips iU22 scanner in contrast imaging mode. One ewe was treated with prostaglandin to induce vascular regression. Time-intensity curves (TIC) for different regions of interest were obtained, a lognormal model was fitted and flow parameters calculated. Parametric maps of the whole imaging plane were generated for 2 × 2 pixel regions of interest. Further analysis of TICs from selected locations helped specify parameters associated with differentiation into four categories of vessels (arteries, veins, medium-sized vessels and micro-vessels). Time-dependent parameters were associated with large veins, whereas intensity-dependent parameters were associated with large arteries. Further development may enable automation of the technique as an efficient way of monitoring vessel distributions in a clinical setting using currently available scanners.Agência financiadora Medical Research Council UK (MRC) 30800896 Science & Technology Facilities Council (STFC) ST/M007804/1 British Heart Foundation PG/10/021/28254 Life Sciences Discovery Fund 3292512 United States Department of Defense CA160415/PRCRPinfo:eu-repo/semantics/publishedVersio

Improved microbubble (MB) Localisation Using Particle Detecting algorithm:Evaluation of Algorithm Performance for Different Beamforming Methods

International audienceThe performance of image analysis techniques (particle detection) on contrast enhanced ultrasound (CEUS) images could be enhanced by using it in combination with the right beamformer (BF). The current study investigates the best performing combination of a particle detecting algorithm (Kanoulas et al. 2019) with four beamformers (BFs), classical and adaptive. In a series of in silico experiments, adjacent MBs are placed in distances comparable to the lateral resolution limit, the CEUS images of the MBs were simulated in FieldII, and finally beamformed with the four methods. The images were processed with the MB detection algorithm and the results were evaluated by the true detections (TD), missed MBs, spurious detections, and localisation uncertainty (LU). For the smallest distances all methods deteriorate but the MV methods provided 4-12% more TD. For the intermediate distances the TD were comparable for all BFs but the adaptive methods provided lower LU. When a set of evaluation metrics is used, the adaptive methods provide marginally but systematically improved results which suggests that, under the appropriate imaging conditions, they could be used to enhance vessel mapping