Abstract
Ultrasound localization microscopy (ULM) permits the reconstruction of super-resolved microvascular images at clinically relevant penetration depths, which can be potentially leveraged to provide non-invasive quantitative measures of tissue hemodynamics and hypoxic status. We demonstrate that ULM microbubble data processing methods, applied to images acquired with a Verasonics Vantage 256 system, can provide a non-invasive imaging surrogate biomarker of tissue oxygenation status. This technique was applied to evaluate the microvascular structure, vascular perfusion, and hypoxia of a renal cell carcinoma xenograft model grown in the chorioallantoic membrane of chicken embryos. Histological microvascular density was significantly correlated to ULM measures of intervessel distance (R = −0.92, CI95 = [−0.99,−0.42], p = 0.01). The Distance Metric, a measure of vascular tortuosity, was found to be significantly correlated to hypoxyprobe quantifications (R = 0.86, CI95 = [0.17, 0.99], p = 0.03). ULM, by providing non-invasive in vivo microvascular structural information, has the potential to be a crucial clinical imaging modality for the diagnosis and therapy monitoring of solid tumors.
Highlights
Ultrasound localization microscopy (ULM) permits the reconstruction of super-resolved microvascular images at clinically relevant penetration depths, which can be potentially leveraged to provide noninvasive quantitative measures of tissue hemodynamics and hypoxic status
In this paper we explore the utility of ULM imaging for providing a surrogate imaging biomarker for intratumoral hypoxia in a renal cell carcinoma xenograft model (ATCC CRL-2947, Mus musculus renal adenocarcinoma) grown in the chorioallantoic membrane (CAM) of chicken embryos[31]
We evaluated the utility of ULM imaging on a chicken embryo chorioallantoic membrane tumor xenograft model of renal cell carcinoma
Summary
Ultrasound localization microscopy (ULM) permits the reconstruction of super-resolved microvascular images at clinically relevant penetration depths, which can be potentially leveraged to provide noninvasive quantitative measures of tissue hemodynamics and hypoxic status. Recent developments in imaging technologies and techniques have allowed for the localization and tracking of individual contrast microbubbles in vivo, such as ultrasound localization microscopy or ULM22–25, permitting the reconstruction of higher resolution images to reveal tissue microvascular structure This processing technique retains the imaging penetration, non-invasiveness, and safety profile of clinically used contrast-enhanced ultrasound, achieving a substantial improvement in spatial resolution in exchange for increased imaging acquisition times. Resolving microvascular features is of paramount importance for informing tissue vascular supply and oxygenation status, as the main site of gas- and nutrient-exchange occurs at the capillary bed This revolutionary technological advance can be potentially leveraged to provide noninvasive quantitative measures of tissue hemodynamics and oxygenation within clinically-relevant decision times, thereby permitting tailored therapy selection based on tumor hypoxia status. ULM has shown great promise in characterizing and classify tumor microvasculature, the application of ULM for measurement tumor hypoxia is relatively unexplored, which is surprising given that conventional CEUS has been shown to provide surrogate biomarkers for intratumoral oxygenation[30]
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