Super-Resolution Ultrasound Bubble Tracking for Preclinical and Clinical Multiparametric Tumor Characterization

Abstract

Super-resolution imaging methods promote tissue characterization beyond the spatial resolution limits of the devices and bridge the gap between histopathological analysis and non-invasive imaging. Here, we introduce Ultrasound Bubble Tracking (UBT) as an easily applicable and robust new tool to morphologically and functionally characterize fine vascular networks in tumors at super-resolution. In tumor-bearing mice and for the first time in patients, we demonstrate that within less than one minute scan time UBT can be realized using conventional preclinical and clinical ultrasound devices. In this context, next to highly detailed images of tumor microvascularization and the reliable quantification of relative blood volume and perfusion, UBT provides access to multiple new functional and morphological parameters that showed superior performance in discriminating tumors with different vascular phenotypes.Furthermore, our initial clinical results indicate that UBT is a highly translational technology with strong potential for the multiparametric characterization of tumors and the assessment of therapy response.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Ultrasound Localization Microscopy and Super-Resolution: A State of the Art

“…A series of parameters are important such as the maximum distance a microbubble can propagate between two images, the intensity threshold to include or exclude the next microbubble, the criteria's to initiate and the criteria's to terminate a track. More refined tracking algorithms were introduced such as Markov chain combined with Monte Carlo approaches [111] [112] or involving Hungarian assignment [105] [113]. The Hungarian assignment resolution implies linear operations on the cost matrix of the problem to solve the assignment problem of dimension n with an order of n 3 time complexity instead of an order of n!…”

“…A very important debate in the ULM community is the frame rate necessary to create super-resolved images. Indeed, subwavelength resolutions were obtained both with ultrafast frame rates (500Hz and up [83], [97], [99], [115]- [117]) and conventional frame rates (around 30Hz [95], [96], [106], [111], [112], [118], [119] [111]). Is ultrafast imaging at kHz frame rates really necessary for ULM?…”

“…Especially since most available clinical scanners have yet to attain high frame rates, reducing the potential impact of the method in patient imaging. Opacic et al [111] propose to exploit ULM tracking at conventional frame rates to reconstruct super-resolved vessels. Not only were they able to track microbubbles in vessels with a short acquisitions of 40s (2000 images), but they were also able to extract parameters such as median distance between vessels, flow direction entropy and other parameters that appear to change between tumor types in-vivo.…”

“…Opacic et al [111], exploiting ULM tracking at conventional frame rates, also established new parameters for tumor characterization through microvessel imaging. They compared three different tumor types in mice, which were expected to display a diversity of vascular density (A431, MLS and A546).They showed that they could extract biomarkers such as flow direction entropy and distances to the closest vessel, which differed in a statistically significant fashion between the different tumor types.…”

Advanced Ultrasound Technologies for Diagnosis and Therapy

“…However, initial clinical data indicate that this translation is challenging and requires a refined imaging protocol and inplane and out-of-plane motion correction ( Fig. 2D) (19). The latter may be addressed by postprocessing data from 3D matrix transducers, which will also enable 3D assessment of vascular architecture in healthy and pathologic tissues.…”