Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering

Abstract

Microbubble contrast agents and the associated imaging systems have developed over the past twenty-five years, originating with manually-agitated fluids introduced for intra-coronary injection. Over this period, stabilizing shells and low diffusivity gas materials have been incorporated in microbubbles, extending stability in vitro and in vivo. Simultaneously, the interaction of these small gas bubbles with ultrasonic waves has been extensively studied, resulting in models for oscillation and increasingly sophisticated imaging strategies. Early studies recognized that echoes from microbubbles contained frequencies that are multiples of the microbubble resonance frequency. Although individual microbubble contrast agents cannot be resolved—given that their diameter is on the order of microns—nonlinear echoes from these agents are used to map regions of perfused tissue and to estimate the local microvascular flow rate. Such strategies overcome a fundamental limitation of previous ultrasound blood flow strategies; the previous Doppler-based strategies are insensitive to capillary flow. Further, the insonation of resonant bubbles results in interesting physical phenomena that have been widely studied for use in drug and gene delivery. Ultrasound pressure can enhance gas diffusion, rapidly fragment the agent into a set of smaller bubbles or displace the microbubble to a blood vessel wall. Insonation of a microbubble can also produce liquid jets and local shear stress that alter biological membranes and facilitate transport. In this review, we focus on the physical aspects of these agents, exploring microbubble imaging modes, models for microbubble oscillation and the interaction of the microbubble with the endothelium.

Sonochemical synthesis of nanomaterials

“…Their use as echo contrast agents for improved sonography (e.g., echocardiography) has become standard. 83 Protein microspheres have also been developed as 19 F-MRI contrast agents, 84 as in vivo MRI temperature probes, 85 as optical coherence tomography contrast agents, 86 for encapsulation and drug release, [87][88][89] and as multifunctional, multimodal cancer imaging contrast agents. 90 The combination of chemical and physical effects of ultrasound can also be applied to prepare organic latex beads in a one-pot fashion.…”

The role of acoustofluidics in targeted drug delivery

“…Since then, microbubbles are widely used as Ultrasound Contrast Agents (UCA) in medical imaging, [2][3][4][5][6][7][8] owing to their capability of enhancing the reflection of ultrasound (US) waves. 9,10 Besides their use as contrast agents in diagnostics purposes, these microbubbles in conjunction with ultrasound have been off late used as a tool for targeted drug delivery and gene therapy. [11][12][13][14][15][16] UCA or ultrasound contrast microbubbles are small (typically 1-8 lm in diameter) gasfilled microspheres and are coated with an adsorbed layer of proteins, 17 polymers, 18 or lipids.…”

Automating tumor classification with pixel-by-pixel contrast-enhanced ultrasound perfusion kinetics

“…These properties allow for highly specific time-resolved imaging of tumor vasculature a) Electronic mail: akummel@ucsd.edu and perfusion. [9][10][11][12] Since cancers exhibit accelerated metabolism, they promote the development of new blood vessels; different types of cancers will often possess characteristic patterns to their vasculature which allow identification of the tumor type with CEUS. [13][14][15] Previous reports have shown that analysis of timeintensity curves (TICs) can produce hemodynamic measurements such as the area under the curve (AUC) and time to peak (TTP) that have statistical significance between benign and malignant lesions of various types of tumors.…”