Functional and Molecular Ultrasound Imaging: Concepts and Contrast Agents

Abstract

Contrast-enhanced ultrasound has shown convincing results for monitoring vessel morphology, surrogate markers of vascularization and changes in molecular marker expression in oncological and cardiovascular diseases. Ultrasound contrast agents have the ability to increase the backscattering signal intensity of an ultrasound pulse. An interesting class of ultrasound contrast agents are gas filled microbubbles, which can be synthesized by external bubble encapsulation using sugar matrices or microspheres consisting of lipids or polymers with or without surfactant and by selecting gases with low blood solubility and diffusion coefficient such as perfluorocarbons or sulphur hexafluoride. Ultrasound contrast agents can be classified according to the rigidity of their shell. Soft-shell microbubbles are coated with a thin monolayer of surfactant molecules such as palmitic acid or phospholipids and are very sensitive to pressure changes. Hard-shell microbubbles have a rigid shell made of polymers such as polycyanoacrylate, which dramatically increases their stability. Depending on the acoustic properties of the microbubbles and on the purpose of the examination either destructive or non destructive methods are preferred for their detection. Microbubbles can be detected by destructive and non-destructive methods. Both soft- and hard-shell microbubbles coated with target-specific molecules can also be used for molecular imaging. Using target-specific approaches, the expression of several angiogenic markers such as VEGFR2, alphavbeta3 Integrins, ICAM, and E-selectin has been investigated in neoplastic and vascular diseases. This article summarizes the synthesis and properties of contrast agents as well as the indications, limitations and future potential of contrast-enhanced functional and molecular ultrasound.

Squamous Cell Carcinoma Xenografts: Use of VEGFR2-targeted Microbubbles for Combined Functional and Molecular US to Monitor Antiangiogenic Therapy Effects

“…Gas-filled microbubbles are routinely used to enhance the contrast of tumors and for the functional assessment of vascularization (11,12). In this context, functional assessment includes the visualization of vessels and the quantification of blood velocity, perfusion and relative blood volume (rBV).…”

Tissue perfusion rate estimation with compression-based photoacoustic-ultrasound imaging

“…The reperfusion of these contrast agents is observed and signals are fit to models to estimate spatially resolved reperfusion times. [13][14][15] While the destruction-reperfusion ultrasound imaging technique is a powerful means of imaging tissue perfusion, some work has shown that the destruction of microbubbles may damage microvascular walls. 16,17 Other preclinical methods of measuring perfusion rates such as dynamic contrast-enhanced MRI also typically require contrast agents and are not sufficiently low cost or high throughput for widespread screening tasks.…”

Tumor blood vessel visualization

“…In the destructive mode with pulsed waves the shell of the microbubble even cracks and the gas is emitted explosively, enhancing the ultrasound backscatter. To increase their selectivity, targeted ligands like peptides or antibodies have been conjugated to the surface of microbubbles to assess for example processes of inflammation or angiogenesis (Klibanov, 2006;Kiessling et al, 2009). This approach has improved the properties of ultrasound up to a molecular imaging technique.…”