Objective
Contrast-enhanced ultrasound (CEUS) presents distinct advantages in diagnostic echography. Utilizing microbubbles (MBs) as conventional contrast agents enhances vascular visualization and organ perfusion, facilitating real-time, non-invasive procedures. There is a current tendency to replace traditional polydisperse MBs with novel monodisperse formulations in an attempt to optimize contrast enhancement and guarantee consistent behavior and reliable imaging outcomes. This study investigates the contrast enhancement achieved using various-sized monodisperse MBs and their influence on non-linear imaging artifacts observed in traditional CEUS.

Methods
To explore the differences between monodisperse and polydisperse populations without excessive experimentation, numerical simulations are employed for delivering precise, objective and expeditious results. The iterative non-linear contrast source (INCS) method has previously demonstrated efficacy when simulating ultrasound propagation in large populations in which each bubble has individual properties and several orders of multiple scattering are significant. Therefore, this method is employed to realistically simulate both monodisperse and polydisperse MBs.

Results
Our findings in CEUS imaging indicate that scattering from resonant monodisperse MBs is 11.8 dB stronger than scattering from polydisperse MBs. Furthermore, the amplitude of non-linear imaging artifacts downstream of the monodisperse population is 19.4 dB stronger compared with polydisperse suspension.

Conclusion
Investigating the impact of multiple scattering on polydisperse populations compared with various monodisperse suspensions has revealed that monodisperse MBs are more effective contrast agents, especially when at resonance. Despite the strong signal-to-noise ratio of monodisperse populations, imaging artifacts caused by non-linear wave propagation are also enhanced, resulting in further mis-classification of MBs as tissue.@en

The field of contrast-enhanced ultrasound (CEUS) combines nonlinearly oscillating microbubbles (MBs) with dedicated pulse sequences to reveal the vascular function of organs. Clinical ultrasound contrast agents consist of polydisperse MB suspensions with diameters ranging from 0.5 to 10 μ⁢m and resonance frequencies ranging from 1 to 15 MHz. As a result, just a small fraction of MBs resonates at a given ultrasound frequency. MB suspensions with narrow size distributions can be tuned for a specific imaging frequency, boost CEUS sensitivity, and enable deeper vascular imaging. However, their enhanced nonlinear behavior makes imaging susceptible to nonlinear-wave-propagation artifacts. Here we numerically investigate the impact of the acoustic wavefront shape on the imaging of nonlinearly oscillating, monodisperse MBs. Specifically, our approach relies on an extension of the iterative nonlinear-contrast-source method that accounts for all nonlinear effects in CEUS. We demonstrate that supersonic X-shaped wavefronts referred to as “X waves” can be used to generate ultrasound images of monodisperse MBs without nonlinear-wave-propagation artifacts. In contrast, imaging based on focused, planar, and diverging wavefronts leads to significant nonlinear artifacts. Taken together, our results show that X waves can harness the full potential of monodisperse MBs by enabling their sensitive and specific detection in a tissue context.@en

For over 50 years, medical ultrasound has been a pioneering force in healthcare, seamlessly blending diagnostic and therapeutic applications. In diagnostics, ultrasound reveals intricate internal structures based on the generation of acoustic pressure waves in the human body and capturing reflections from tissue and body structures, enabling precise anomaly identification. Simultaneously, in therapy, ultrasound utilizes its acoustic prowess for targeted interventions and submillimeter localization in unconventional cancer treatments like proton therapy. The field has shifted significantly with the advent of nonlinear acoustics, exploring wave propagation phenomena. Contrast agents marked a revolutionary leap, enhancing the specificity, sensitivity, and efficiency of diagnostic and therapeutic ultrasound. Microbubbles, as the most conventionally used agents, exhibit strong nonlinear scattering under ultrasonic excitation, making them suitable for CEUS applications. @en

In contrast-enhanced echography, the simulation of nonlinear propagation of ultrasound through a population of oscillating microbubbles imposes a computational challenge. Also, the numerical complexity increases because each scatterer has individual properties. To address these problems, the Iterative Nonlinear Contrast Source (INCS) method has been extended to include a large population of nonlinearly responding microbubbles. The original INCS method solves the Westervelt equation in a four-dimensional spatiotemporal domain by generating increasingly accurate field corrections to iteratively update the acoustic pressure. The field corrections are computed by the convolution of a nonlinear contrast source with the Green's function of the linear background medium. Because the convolution integral allows a coarse discretization, INCS can efficiently deal with large-scale problems. To include a population of microbubbles, these are considered as individual contrast point sources with their own nonlinear response. The field corrections are computed as before, but now, in each iteration, the temporal signature of each contrast point source is computed by solving the bubble's Marmottant equation. Physically, each iteration adds an order of multiple scattering. Here, the performance of the extended INCS method and the significance of multiple scattering is demonstrated through various results from different configurations.

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An in vivo range verification technology for proton beam cancer therapy, preferably in real-time and with submillimeter resolution, is desired to reduce the present uncertainty in dose localization. Acoustical imaging technologies exploiting possible local interactions between protons and microbubbles or nanodroplets might be an interesting option. Unfortunately, a theoretical model capable of characterising the acoustical field generated by an individual proton on nanometer and micrometer scales is still missing. In this work, such a model is presented. The proton acoustic field is generated by the adiabatic expansion of a region that is locally heated by a passing proton. To model the proton heat deposition, secondary electron production due to protons has been quantified using a semi-empirical model based on Rutherford's scattering theory, which reproduces experimentally obtained electronic stopping power values for protons in water within 10% over the full energy range. The electrons transfer energy into heat via electron-phonon coupling to atoms along the proton track. The resulting temperature increase is calculated using an inelastic thermal spike model. Heat deposition can be regarded as instantaneous, thus, stress confinement is ensured and acoustical initial conditions are set. The resulting thermoacoustic field in the nanometer and micrometer range from the single proton track is computed by solving the thermoacoustic wave equation using k-space Green's functions, yielding the characteristic amplitudes and frequencies present in the acoustic signal generated by a single proton in an aqueous medium. Wavefield expansion and asymptotic approximations are used to extend the spatial and temporal ranges of the proton acoustic field.

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