Engineering Responsive Ultrasound Contrast Agents Through Crosslinked Networks on Lipid‐Shelled Microbubbles

Abstract

Ultrasound imaging with contrast agents, especially with lipid‐shelled microbubbles, has become a vital tool in clinical diagnostics. Efforts to adapt these agents for molecular imaging have typically focused on targeted binding. More recently, crosslinking the lipid shell to alter its mechanical properties, followed by decrosslinking upon exposure to a stimulus, has been shown as a promising approach for imaging soluble molecular targets. Nevertheless, a systematic study of the influence of crosslinker concentration and structure on the mechanical properties of microbubbles has not been undertaken. An improved understanding of the role of these parameters is necessary to more effectively design contrast agents that detect proteases, an informative class of soluble disease markers. Here, the influence of crosslinker parameters on the acoustic properties of microbubbles, developing a model of crosslinker network formation on microbubble shells that explains the experimental observations, are studied. By incorporating cleavable elements that respond to UV light or proteolysis, kinetically resolved acoustic detection of these stimuli and the relevance of crosslinker design are demonstrated. The framework established in this study can be readily adapted to other protease‐cleavable units and provides a basis for the future development of responsive ultrasound contrast agents for molecular imaging of proteolytic activity.

In vivoapplications of micro/nanorobots

“…154 However, most of the micro/nanorobots do not hold this functionality, and this situation can lead to the need of specific contrast agents, e.g., iodine-and barium-based compounds, and/or swarming behavior to more easily discriminate them from the surrounding environment. [155][156][157] Additionally, combining different imaging modalities can be an attractive approach to overcome limitations of the currently used modalities, e.g., CT, MRI, US, PET, and SPECT. 135,158 Considering that most of the externally driven micro/nanorobots would be "blind" in the body without convenient imaging modalities, an effective approach for in vivo tracking should be an integral part of the micro/nanorobot design to enable the successful completion of their intended use.…”

“…, iodine- and barium-based compounds, and/or swarming behavior to more easily discriminate them from the surrounding environment. 155–157 Additionally, combining different imaging modalities can be an attractive approach to overcome limitations of the currently used modalities, e.g. , CT, MRI, US, PET, and SPECT.…”

Modulating Nonlinear Acoustic Response of Phospholipid-Coated Microbubbles with pH for Ultrasound Imaging

“…The type of lipid used allows the shell to buckle during compression or rupture during expansion, which increases the generation of harmonics. , Comparisons between theoretical simulations and experimental MB dynamic responses corroborate the observation that both MB shell composition and microstructure directly impact MB rheological properties, which are the main drivers of MB dynamic response, including oscillation amplitudes and resonant radii at harmonic and subharmonic resonances. Increasing shell stiffness and viscosity dampens MB oscillation amplitude, while a reduction in interfacial tension at the PFC–water interface that decreases shell viscosity and stiffness increases MB oscillation amplitude. − Because cross-linking shell lipids decreases or eliminates MB nonlinear response to ultrasound, most likely by restricting MB oscillation, utilizing cross-linkers that are cleavable by chemical, enzymatic, or other stimuli generates harmonics allowing detection of these bioresponsive MBs. − The successful demonstration of these approaches has paved the way to providing biomarker-responsive ultrasound contrast agents.…”

Superiorly Stable Three-Layer Air Microbubbles Generated by Versatile Ethanol–Water Exchange for Contrast-Enhanced Ultrasound Theranostics

“…Microbubbles are gas-filled spherical particles which are widely used in the food industry, − biomedicine, − sewage treatment, and photonic crystals owing to their large cavities, low specific gravity, large surface area, and acoustic scattering . In particular, microbubbles play increasingly important roles in biomedical fields, including ultrasound imaging, − drug delivery systems, biosensing, , ultrasound-targeted microbubble destruction, − and sonogenetics. , For example, air microbubbles, as ultrasound contrast agents, have long been used in the clinical diagnosis of vascular diseases, such as thrombosis and tumors, due to their high acoustic scattering characteristics and nonlinear interactions with ultrasound. − …”