The unique second wave phenomenon in contrast enhanced ultrasound imaging with nanobubbles

Abstract

Investigation of nanobubble (NB) pharmacokinetics in contrast-enhanced ultrasound (CEUS) at the pixel level shows a unique phenomenon where the first pass of the contrast agent bolus is accompanied by a second wave. This effect has not been previously observed in CEUS with microbubbles. The objective of this study was to investigate this second-wave phenomenon and its potential clinical applications. Seven mice with a total of fourteen subcutaneously-implanted tumors were included in the experiments. After injecting a bolus of NBs, the NB-CEUS images were acquired to record the time-intensity curves (TICs) at each pixel. These TICs are fitted to a pharmacokinetic model which we designed to describe the observed second-wave phenomenon. The estimated model parameters are presented as parametric maps to visualize the characteristics of tumor lesions. Histological analysis was also conducted in one mouse to compare the molecular features of tumor tissue with the obtained parametric maps. The second-wave phenomenon is evidently shown in a series of pixel-based TICs extracted from either tumor or tissues. The value of two model parameters, the ratio of the peak intensities of the second over the first wave, and the decay rate of the wash-out process present large differences between malignant tumor and normal tissue (0.04 < Jessen-Shannon divergence < 0.08). The occurrence of a second wave is a unique phenomenon that we have observed in NB-CEUS imaging of both mouse tumor and tissue. As the characteristics of the second wave are different between tumor and tissue, this phenomenon has the potential to support the diagnosis of cancerous lesions.

Fluorescence, ultrasonic and photoacoustic imaging for analysis and diagnosis of diseases

“…[127][128][129] Tumor localization using MBs is based on an imaging evaluation of the microvascular perfusion characteristics of abnormal tumors. 130,131 As a typical example, Dong et al combined conventional GSUS and Sonovue-based CEUS imaging modalities, as well as blood cell analysis to improve the diagnostic accuracy for different diseases, such as plasma cell mastitis, malignant small breast masses, and inflammatory mass stage periductal mastitis/duct ectasia. [127][128][129] In addition, Zlitni et al utilized emerging bioorthogonal reactions and technologies for the highly-selective capture of functionalized MBs to enhance ultrasonic image contrast and improve the quality of ultrasound molecular imaging in the diagnosis of tumors.…”

The use of speckle decorrelation OCT to detect nanobubbles in cell pellet aggregates

“…A NB has a gas core encapsulated within a stabilizing shell on the nanometer scale, offering a promising approach to enhance ultrasound imaging contrast and therapeutic agent delivery 1 . Their size, which allows for capillary bed perfusion and potential extravasation, combined with their echogenicity, makes them an ideal candidate for non-invasive diagnostic imaging and targeted treatment strategies 2 .…”

High-speed ultrasound imaging of bubbly flows and shear waves in soft matter

“…7 A further refinement of this technique occurred with the introduction of stabilized bulk nanobubbles (SBNB), currently used in tumor-targeted therapy. [8][9][10] One of the primary advantages of SBNB over other ultrasound contrast agents is that, due to their reduced size, nanobubbles may permeate extravascular tissues and intercellular spaces. In such cases, these bubbles are typically prepared with a phospholipid coating and/or specific gases at their core to prevent dissolution once injected into the bloodstream (i.e., ensuring 'in vivo' stability).…”