Development of an In Vitro Model to Study Mechanisms of Ultrasound-Targeted Microbubble Cavitation–Mediated Blood–Brain Barrier Opening

并行传输 跨细胞 血脑屏障 磁导率 微气泡 内皮干细胞 生物物理学 细胞生物学 化学 药物输送 紧密连接 体外 超声波 材料科学 生物 纳米技术 医学 神经科学 生物化学 中枢神经系统 放射科
作者
Grace E. Conway,Anurag N. Paranjape,Xucai Chen,Flordeliza S. Villanueva
出处
期刊:Ultrasound in Medicine and Biology [Elsevier]
标识
DOI:10.1016/j.ultrasmedbio.2023.12.005
摘要

Ultrasound-targeted microbubble cavitation (UTMC)-mediated blood-brain barrier (BBB) opening is being explored as a method to increase drug delivery to the brain. This strategy has progressed to clinical trials for various neurological disorders, but the underlying cellular mechanisms are incompletely understood. In the study described here, a contact co-culture transwell model of the BBB was developed that can be used to determine the signaling cascade leading to increased BBB permeability.This BBB model consists of bEnd.3 cells and C8-D1A astrocytes seeded on opposite sides of a transwell membrane. Pulsed ultrasound (US) is applied to lipid microbubbles (MBs), and the change in barrier permeability is measured via transendothelial electrical resistance and dextran flux. Live cell calcium imaging (Fluo-4 AM) is performed during UTMC treatment.This model exhibits important features of the BBB, including endothelial tight junctions, and is more restrictive than the endothelial cell (EC) monolayer alone. When US is applied to MBs in contact with the ECs, BBB permeability increases in this model by two mechanisms: UTMC induces pore formation in the EC membrane (sonoporation), leading to increased transcellular permeability, and UTMC causes formation of reversible inter-endothelial gaps, which increases paracellular permeability. Additionally, this study determines that calcium influx into ECs mediates the increase in BBB permeability after UTMC in this model.Both transcellular and paracellular permeability can be used to increase drug delivery to the brain. Future studies can use this model to determine how UTMC-induced calcium-mediated signaling increases BBB permeability.
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