Ultrasound localization microscopy of renal tumor xenografts in chicken embryo is correlated to hypoxia

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. 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.