Evaluation of the Reproducibility of Bolus Transit Quantification With Contrast-Enhanced Ultrasound Across Multiple Scanners and Analysis Software Packages-A Quantitative Imaging Biomarker Alliance Study.

OBJECTIVES: Contrast enhanced ultrasound (CEUS) is now broadly used clinically for liver lesion detection and characterization. Obstacles to the efforts to quantify perfusion with CEUS have been the lack of a standardized approach and undocumented reproducibility. The use of multiple scanners and different analysis software packages compounds the degree of variability. Our objectives were to standardize a CEUS-based approach for quantification of perfusion-related parameters of liver lesions and to evaluate the variability of bolus transit parameters (rise time [RT], mean transit time [MTT], peak intensity, and area under the curve) obtained from various clinical ultrasound scanners and analysis software. MATERIALS AND METHODS: Bolus transit as a way of evaluating perfusion has been investigated both in vivo and in vitro in the past but without establishing its reproducibility. We developed a tissue flow phantom that produces time-intensity curves very similar to those extracted from clinical cine loops of liver lesions. We evaluated the variability of the bolus transit parameters with 4 commercial scanners (Philips iU22, Philips EPIQ, GE LOGIQ E9, and Siemens Acuson Sequoia) and 3 different analysis software packages in multiple trials (15 per scanner). RESULTS: The variability (coefficient of variation) from repeated trials and while using a single scanner and software was less than 8% for RT, less than 12% for MTT, less than 49% for peak intensity, and less than 50% for area under the curve. Currently, it is not possible to directly compare amplitude values from different scanners and analysis software packages owing to the arbitrary linearization algorithm used among manufacturers; however, it is possible for time parameters (RT and MTT). The variability when using a different scanner with the same analysis software package was less than 9% for RT and less than 21% for MTT. The variability when using a different analysis software with the same scanner was less than 9% for RT and less than 15% for MTT. In all the evaluations we have performed, RT is the least variable parameter, while MTT is only slightly more variable. CONCLUSIONS: The present study will lay the groundwork for multicenter patient evaluations with CEUS quantification of perfusion-related parameters with the bolus transit technique. When using the protocol and method developed here, it is possible to perform perfusion quantification on different scanners and analysis software and be able to compare the results. The current work is the first study that presents a comparison of bolus transit parameters derived from multiple systems and software packages.

Engineered 3D Microvascular Networks for the Study of Ultrasound-Microbubble-Mediated Drug Delivery.

Localized and targeted drug delivery can be achieved by the combined action of ultrasound and microbubbles on the tumor microenvironment, likely through sonoporation and other therapeutic mechanisms that are not well understood. Here, we present a perfusable in vitro model with a realistic 3D geometry to study the interactions between microbubbles and the vascular endothelium in the presence of ultrasound. Specifically, a three-dimensional, endothelial-cell-seeded in vitro microvascular model was perfused with cell culture medium and microbubbles while being sonicated by a single-element 1 MHz focused transducer. This setup mimics the in vivo scenario in which ultrasound induces a therapeutic effect in the tumor vasculature in the presence of flow. Fluorescence and bright-field microscopy were employed to assess the microbubble-vessel interactions and the extent of drug delivery and cell death both in real time during treatment as well as after treatment. Propidium iodide was used as the model drug while calcein AM was used to evaluate cell viability. There were two acoustic parameter sets chosen for this work: (1) acoustic pressure: 1.4 MPa, pulse length: 500 cycles, duty cycle: 5% and (2) acoustic pressure: 0.4 MPa, pulse length: 1000 cycles, duty cycle: 20%. Enhanced drug delivery and cell death were observed in both cases while the higher pressure setting had a more pronounced effect. By introducing physiological flow to the in vitro microvascular model and examining the PECAM-1 expression of the endothelial cells within it, we demonstrated that our model is a good mimic of the in vivo vasculature and is therefore a viable platform to provide mechanistic insights into ultrasound-mediated drug delivery.