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

Pharm Res. 2023 Oct;40(10):2399-2411. doi: 10.1007/s11095-023-03606-w. Epub 2023 Oct 2.


Background: Vascular cognitive impairment and dementia results from blood components passing through disrupted blood brain barriers (BBBs). Current treatments can reduce further progress of neuronal damage but do not treat the primary cause. Instead, these treatments typically aim to temporarily disrupt the BBB. Alternatively, this study computationally assessed the feasibility of delivering carbon monoxide (CO) from ultrasound-sensitive microbubbles (MBs) as a strategy to promote BBB repair and integrity. CO can interact with heme-containing compounds within cells and promote cell growth. However, careful dose control is critical for safety and efficacy because CO also binds at high affinity to hemoglobin (Hb).

Methods: Ultrasound activation was simulated at the internal carotid artery, and CO released from the resulting MB rupture was tracked along the shortest path to the BBB for several activation times and doses. The CO dose available to brain capillary endothelial cells (BCECs) was predicted by considering hemodynamics, mass transport, and binding kinetics.

Results: The half-life of CO binding to Hb indicated that CO is available to interact with BCECs for several cardiac cycles. Further, MB and COHb concentrations would not be near toxic levels and free Hb would be available. The axisymmetric model indicated that biologically-relevant CO concentrations will be available to BCECs, and these levels can be sustained with controlled ultrasound activation. A patient-specific geometry shows that while vessel tortuosity provides a heterogeneous response, a relevant CO concentration could still be achieved.

Conclusions: This computational study demonstrates feasibility of the CO / MB strategy, and that controlled delivery is important for viability of this strategy.

Keywords: carbon monoxide; drug delivery; microbubble; ultrasound; vascular cognitive impairment.

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Drug Delivery Systems
  • Endothelial Cells / metabolism
  • Gasotransmitters* / metabolism
  • Humans
  • Microbubbles
  • Rats
  • Rats, Sprague-Dawley


  • Gasotransmitters