The OrganoPlate® as vessel-on-a-chip model to investigate increased microbubble-mediated vascular permeability

Abstract

The vessel wall is an important barrier modulating drug delivery to the underlying diseased tissue. Oscillating microbubbles can be used to locally enhance vascular permeability and sonoporate cells. As the mechanism is not fully understood, our aim was to grow 3D human vessels-on-a-chip in the OrganoPlate® 40 and use this model to investigate the effect of αvβ3-targeted microbubble and different ultrasound pressures (2 MHz, 100–850 kPa peak negative pressure) and cycle lengths (10×10 or 10×1000 cycles) on vascular permeability and sonoporation. The vascular permeability of 122 microvessels in 14 different conditions was quantified by microscopy imaging using the leakage pattern of a 150 kDa FITC-dextran dye. Furthermore, sonoporation was assessed using propidium iodide (PI). Upon microbubble and ultrasound treatment, an increase in vascular permeability was observed. Higher pressures and longer cycle length treatment showed a significantly higher vascular permeability and significant increase in PI uptake compared to all control groups (sham, ultrasound only, microbubble only), suggesting a simultaneous increase in vascular permeability and sonoporation correlating with higher pressure and longer cycle insonifications. In conclusion, the vessel-on-chip model is a suitable model to investigate how insonification with different ultrasound settings affects the microbubble-mediated vascular permeability increase and sonoporation.