Template-based formation of ultrasound microbubble contrast agents

Abstract

Precisely controlling microbubble size is critical for medical ultrasound imaging, where large microbubble contrast agents may lead to pulmonary microvascular embolization. In this study, we reported a facile method to fabricate the laminated ultrasound contrast agents with narrow size distribution. First, we prepared monodisperse silica particles (∼1.0 μm in diameter) as a core template. Then an amphiphilic shell was coated on the SiO2 particles surface via amine-anhydride modification. After etching the SiO2 cores by HF, the formed hollow structured particles were further PEGylated with free carboxylate residues. After dialysis and freeze-drying, the as-prepared microbubbles showed a narrow size distribution (diameter = 1.1 μm, PDI = 0.36). The microbubbles showed excellent stability for enhanced ultrasound contrast imaging for at least 20 minutes, resulting from the observed firm-shelling through electron microscopy. The laminated shells of the microbubbles have an average thickness of 100 nm composed of multiple aliphatic composites that efficiently reduce the leakage of inert gas. Further, these microbubbles also showed good biocompatibility when co-culturing with BNL CL2 cells in vitro. Based on the above evidence, this improved method for fabricating uniform ultrasound contrast agents can further translate into many biomedical applications.