Modeling Gasotransmitter Availability to Brain Capillary Endothelial Cells with Ultrasound-sensitive Microbubbles

Area of Science:

• Biomedical Engineering
• Computational Biology
• Neuroscience

Background:

• Vascular cognitive impairment and dementia stem from a compromised blood-brain barrier (BBB).
• Current treatments manage neuronal damage but not the root cause of BBB disruption.
• Existing therapies often involve temporarily disrupting the BBB, which can have adverse effects.

Purpose of the Study:

• To computationally assess the feasibility of using carbon monoxide (CO) delivered from ultrasound-sensitive microbubbles (MBs) to repair and enhance BBB integrity.
• To investigate the controlled release and transport of CO to brain capillary endothelial cells (BCECs).

Main Methods:

• Simulated ultrasound activation in the internal carotid artery to trigger MB rupture and CO release.
• Modeled CO transport dynamics, including hemodynamics, mass transport, and binding kinetics, to predict CO dose at the BBB.
• Utilized axisymmetric and patient-specific models to analyze CO availability to BCECs under various conditions.

Main Results:

• CO released from MBs remains available to interact with BCECs for several cardiac cycles.
• Predicted concentrations of CO and CO-hemoglobin (COHb) are within non-toxic levels, with free hemoglobin available.
• Biologically relevant CO concentrations can be achieved and sustained in BCECs through controlled ultrasound activation, even in tortuous vasculature.

Conclusions:

• The computational findings support the feasibility of the CO/MB strategy for BBB repair.
• Controlled ultrasound-mediated delivery of CO is crucial for the therapeutic viability of this approach.