Formulation and Characterization of Chemically Cross-linked Microbubble Clusters

The purpose of this study is to introduce a new concept of chemically cross-linked microbubble clusters (CCMCs), which are individual microbubble ultrasound contrast agents (UCAs) physically tethered together. We demonstrate a facile means of their production, characterize their size and stability, and describe how they can potentially be used in biomedical applications. By tethering UCAs together into CCMCs, we propose that novel methods of ultrasound mediated imaging and therapy can be developed through unique interbubble interactions in an ultrasound field. One of the major challenges in generating CCMCs is controlling aggregate sizes and maintaining stability against Ostwald ripening and coalescence. In this study, we demonstrate that chemically cross-linked microbubble clusters can produce small (<10 μm) quasi-stable complexes that slowly fuse into bubbles with individual gas cores. Furthermore, we demonstrate that this process can be driven with low-intensity ultrasound pulses, enabling a rapid fusion of clusters which could potentially be used to develop novel ultrasound contrast imaging and drug delivery strategies in future studies. The development of novel microbubble clusters presents a simple yet robust process for generating novel UCAs with a design that could allow for more versatility in contrast-enhanced ultrasound (CEUS), molecular imaging, and drug delivery applications. Additionally, microbubble clustering is a unique way to control size, shell, and gas compositions that can be used to study bubble ripening and coalescence in a highly controlled environment or study the behavior of mixed-microbubble populations.