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Ultrasound-assisted drug delivery with targeted-microbubbles in blood vessels on a chip

Ultrasound contrast imaging using micron-sized bubbles (less than 8 μm in diameter) has demonstrated detectable echogenic signals in vivo. However, challenges remain in terms of producing monodisperse microbubbles stable against destruction from aggregation and gas dissolution for improving blood circulation times and reducing clogging of small blood vessels. In the case of drug delivery, it is crucial to control destruction to release encapsulated contents only to the targeted area with minimal prior passive leakage of drug. Polymerizable lipid mixtures were used as microbubble shell materials. The monodisperse Polymerized Shell Microbubbles (PSM) containing 25 mol% of polymerizable diacetylene lipids were more stable than commercially acquired microbubbles or non-polymerizable shell microbubbles in terms of dissolution. The PSM showed a significantly slower decrease in intensity of gray-scale ultrasound image brightness than the two. In addition, the bubbles that were polymerized to different extents showed variable destruction rates at different ultrasound power levels, suggesting that polymerization can not only provide passive bubble longevity but tunable rupture capability. Lastly, drug-loaded targeted microbubbles have been observed in the in vitro blood vessels on a chip under ultrasound application to test drug delivery to the vessels. Compared to control targeted microbubbles with no drug, the drug-loaded targeted microbubbles kill the cells on the vessel wall selectively with ultrasound assistance.