Characterizing Microbubble-Mediated Permeabilization in a Vessel-on-a-Chip Model.

Area of Science:

• Biomedical Engineering
• Drug Delivery
• Acoustic Medicine

Background:

• Ultrasound-activated microbubbles can increase vascular permeability for localized drug delivery.
• The precise mechanisms, including the impact of ultrasound cycle duration, remain incompletely understood.

Purpose of the Study:

• To investigate the mechanistic differences in vascular permeability increase induced by varying ultrasound cycle lengths.
• To develop and utilize a microvessel-on-a-chip model for studying ultrasound-microbubble interactions.
• To compare the effects of short (10 cycles) versus long (1000 cycles) ultrasound treatments on vascular permeability and sonoporation.

Main Methods:

• Development of a membrane-free microvessel-on-a-chip model with an extravascular space.
• Application of 2 MHz ultrasound with 10 or 1000 cycles at varying peak negative acoustic pressures (PNP).
• Assessment of vascular permeability changes, microvessel viability, and sonoporation, correlating with microbubble behavior.

Main Results:

• Distinct differences observed between 10 and 1000 ultrasound cycles.
• Slower onset rate of vascular permeability increase with 10 cycles compared to 1000 cycles.
• Lower vascular permeability increase and sonoporation at 750 kPa with 10 cycles versus 1000 cycles.
• Higher PNP thresholds for vascular permeability increase and sonoporation with fewer cycles.
• Vascular permeability increases did not correlate with αvβ3-targeted microbubble behavior, while sonoporation correlated with microbubble clustering.

Conclusions:

• The developed microvessel-on-a-chip model provides mechanistic insights into ultrasound-mediated vascular permeability.
• Ultrasound cycle length significantly influences the rate, extent, and thresholds of vascular permeability increase and sonoporation.
• Findings support the safe and efficient development of microbubble-mediated drug transport strategies.