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Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US-enhanced drug delivery. Polymeric MB are highly suitable for these applications because of their acoustic responsiveness, high drug loading capability, and ease of surface functionalization. While many studies have focused on using polymeric MB for diagnostic and therapeutic purposes, relatively little attention has thus far been paid to improving their inherent imaging and drug delivery features. This study here shows that manipulating the polymer chemistry of poly(butyl cyanoacrylate) (PBCA) MB via temporarily mixing the monomer with the monomer-mimetic butyl cyanoacetate (BCC) during the polymerization process improves the drug loading capacity of PBCA MB by more than twofold, and the in vitro and in vivo acoustic responses of PBCA MB by more than tenfold. Computer simulations and physisorption experiments show that BCC manipulates the growth of PBCA polymer chains and creates nanocavities in the MB shell, endowing PBCA MB with greater drug entrapment capability and stronger acoustic properties. Notably, because BCC can be readily and completely removed during MB purification, the resulting formulation does not include any residual reagent beyond the ones already present in current PBCA-based MB products, facilitating the potential translation of next-generation PBCA MB., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Ultrasound localization microscopy is becoming well established in preclinical applications. For its translation into clinical practice, the localization precision achievable with commercial ultrasound scanners is crucial - especially with volume imaging, which is essential for dealing with out-of-plane motion. Here, we propose an easy-to-perform method to estimate the localization precision of 3D ultrasound scanners. With this method, we evaluated imaging sequences of the Philips Epiq 7 ultrasound device using the X5-1 and the XL14-3 matrix transducers, and also tested different localization methods. For the X5-1 transducer, the best lateral, elevational, and axial precision was 109 μm, 95 μm, and 55 μm for one contrast mode, and 29 μm, 22 μm, and 19 μm for the other. The higher frequency XL14-3 transducer yielded precisions of 17 μm, 38 μm, and 6 μm using the harmonic imaging mode. Although the center of mass was the most robust localization method also often providing the best precision, the localization method has only minor influence on the localization precision compared to the impact by the imaging sequence and transducer. The results show that with one of the imaging modes of the X5-1 transducer, precisions comparable to the XL14-3 transducer can be achieved. However, due to localization precisions worse than 10 μm, reconstruction of the microvasculature at the capillary level will not be possible. These results show the importance to evaluate the localization precision of imaging sequences from different ultrasound transducers or scanners in all directions before using them for in vivo measurements.

With the widespread interest and uptake of super-resolution ultrasound (SRUS) through localization and tracking of microbubbles, also known as ultrasound localization microscopy (ULM), many localization and tracking algorithms have been developed. ULM can image many centimeters into tissue in-vivo and track microvascular flow non-invasively with sub-diffraction resolution. In a significant community effort, we organized a challenge, Ultrasound Localization and TRacking Algorithms for Super-Resolution (ULTRA-SR). The aims of this paper are threefold: to describe the challenge organization, data generation, and winning algorithms; to present the metrics and methods for evaluating challenge entrants; and to report results and findings of the evaluation. Realistic ultrasound datasets containing microvascular flow for different clinical ultrasound frequencies were simulated, using vascular flow physics, acoustic field simulation and nonlinear bubble dynamics simulation. Based on these datasets, 38 submissions from 24 research groups were evaluated against ground truth using an evaluation framework with six metrics, three for localization and three for tracking. In-vivo mouse brain and human lymph node data were also provided, and performance assessed by an expert panel. Winning algorithms are described and discussed. The publicly available data with ground truth and the defined metrics for both localization and tracking present a valuable resource for researchers to benchmark algorithms and software, identify optimized methods/software for their data, and provide insight into the current limits of the field. In conclusion, Ultra-SR challenge has provided benchmarking data and tools as well as direct comparison and insights for a number of the state-of-the art localization and tracking algorithms.

Objective: Ultrasound localization microscopy (ULM) has gained increasing attention in recent years because of its ability to visualize blood vessels at super-resolution. The field of oncology, in particular, could benefit from detailed vascular characterization, for example, for diagnosis and therapy monitoring. This study was aimed at refining ULM for breast cancer patients by optimizing the measurement protocol, identifying translational challenges and combining ULM and shear wave elastography., Methods: We computed ULM images of 11 patients with breast cancer by recording contrast-enhanced ultrasound (CEUS) sequences and post-processing them in an offline pipeline. For CEUS, two different doses and injection speeds of SonoVue were applied. The best injection protocol was determined based on quantitative parameters derived from so-called occurrence maps. In addition, a suitable measurement time window was determined, also considering the occurrence of motion. ULM results were compared with shear wave elastography and histological vessel density., Results: At the higher dose and injection speed, the highest number of microbubbles, number of tracks and vessel coverage were achieved, leading to the most detailed representation of tumor vasculature. Even at the highest concentration, no significant overlay of microbubble signals occurred. Motion significantly reduced the number of usable frames, thus limiting the measurement window to 3.5 min. ULM vessel coverage was comparable to the histological vessel fraction and correlated significantly with mean tumor elasticity., Conclusion: The settings for microbubble injection strongly influence ULM images, thus requiring optimized protocols for different indications. Patient and examiner motion was identified as the main translational challenge for ULM., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)