Reverse engineering the ultrasound contrast agent

Abstract

In this review, a brief history and current state-of-the-art is given to stimulate the rational design of new microbubbles through the reverse engineering of current ultrasound contrast agents (UCAs). It is shown that an effective microbubble should be biocompatible, echogenic and stable. Physical mechanisms and engineering calculations have been provided to illustrate these properties and how they can be achieved. The reverse-engineering design paradigm is applied to study current FDA-approved and commercially available UCAs. Given the sophistication of microbubble designs reported in the literature, rapid development and adoption of ultrasound device hardware and techniques, and the growing number of revolutionary biomedical applications moving toward the clinic, the field of Microbubble Engineering is fertile for breakthroughs in next-generation UCA technology. It is up to current and future microbubble engineers and clinicians to push forward with regulatory approval and clinical adoption of advanced UCA technologies in the years to come.

Keywords: Coalescence; Dissolution; Drug delivery; Imaging; Microbubble; Surface forces.

Figure 1.

Ultrasound image enhancement with microbubble UCAs. Shown are a b-mode image of the rat kidney and Cadence Pulse Sequencing (CPS) mode images before and after UCA injection taken with a Siemens Sequoia ultrasound scanner. Note that the green boundary defining the kidney as the region of interest is drawn from the anatomical B-mode image, and that contrast is observed outside the kidney owing to nearby vasculature. Images from [33].

Figure 2.

Particle acoustic scattering cross section versus radius. Rayleigh theory (equation 1) was applied to estimate the cross sections for liquid (glycerin) and solid (steel) microspheres. The simple oscillator model (equations 2–4) was used to estimate the cross section for resonant gas bubbles - that is, the bubble is driven at its resonance frequency for each size. Solid lines show the cross sections at 1 MHz for liquid and solid particles. Dashed lines show the cross sections at 10 MHz for liquid and solid particles. Arrows show the cross sections for resonant gas bubbles at these frequency limits.

Figure 3.

Theoretical energy-distance profiles between two 3-μm diameter bubbles. a) Uncoated: van der Waals and hydrophobic interactions yield a purely attractive (negative) potential. b) Optison: the protein shell removes the hydrophobic attraction and imposes electrostatic and hydration repulsions, generating an energy barrier to coalescence. c) Sonovue: the lipid shell imposes electrostatic and protrusion repulsions, generating a purely repulsive (positive) potential. d) Defnity: the PEG brush on the lipid shell yields a long-range repulsion.

Figure 4.

Theoretical dissolution curves for a 3-μm diameter bubble. a) Uncoated microbubbles containing various gases in a saturated medium dissolving due to surface tension; gas parameters taken from [60]. B) Lipid-coated vs. uncoated air bubbles dissolving in an undersaturated medium (F = 0.8); lipid shell permeability is taken from [64] and elasticity is taken from [61].

Figure 5.

Cartoon schematic of shell and gas components for Optison, Sonovue and Definity. Molecular structures are not shown to scale.

Figure 6.

Methods of UCA manufacture: A) Optison is made by mechanical cavitation (mechanical shearing and hydrodynamic cavitation) in a rotor-stator homogenizer mill. B) Defnity is made by shaking back-and-forth at 4–5 kHz in a vial shaker. C) Sonovue is made by rehydrating a freeze-dried lipid powder.

Figure 7.

Commercialized next-generation microbubbles: A) Size-Isolated Microbubbles (SIMBs); graphic taken from AMB Labs (www.advancedmicrobubbles.com). B) Microfluidic microbubbles; graphic taken from Tide Microfluidics (www.tidemicrofluidics.com).