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Development of a three-dimensional blood-brain barrier network with opening capillary structures for drug transport screening assays.

ABSTRACT: The blood-brain barrier (BBB), a selective barrier regulating the active and passive transport of solutes in the extracellular fluid of the central nervous system, prevents the delivery of therapeutics for brain disorders. The BBB is composed of brain microvascular endothelial cells (BMEC), pericytes and astrocytes. Current in vitro BBB models cannot reproduce the human structural complexity of the brain microvasculature, and thus their functions are not enough for drug assessments. In this study, we developed a 3D self-assembled microvascular network formed by BMEC covered by pericytes and astrocyte end feet. It exhibited perfusable microvasculature due to the presence of capillary opening ends on the bottom of the hydrogel. It also demonstrated size-selective permeation of different molecular weights of fluorescent-labeled dextran, as similarly reported for in vivo rodent brain, suggesting the same permeability with actual in vivo brain. The activity of P-glycoprotein efflux pump was confirmed using the substrate Rhodamine 123. Finally, the functionality of the receptor-mediated transcytosis, one of the main routes for drug delivery of large molecules into the brain, could be validated using transferrin receptor (TfR) with confocal imaging, competition assays and permeability assays. Efficient permeability coefficient (P_e) value of transportable anti-TfR antibody (MEM-189) was seven-fold higher than those of isotype antibody (IgG1) and low transportable anti-TfR antibody (13E4), suggesting a higher TfR transport function than previous reports. The BBB model with capillary openings could thus be a valuable tool for the screening of therapeutics that can be transported across the BBB, including those using TfR-mediated transport.

SUBMITTER: Piantino M

PROVIDER: S-EPMC9214798 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening recently entered clinical testing for targeted drug delivery to the brain. Sources of variability exist in the current procedures, motivating the development of real-time monitoring and control techniques to improve treatment safety and efficacy. Here we used three-dimensional (3D) transcranial microbubble imaging to calibrate FUS exposure levels for volumetric BBB opening. Methods: Using a sparse hemispherical transmit/receive ultrasound phased array, pulsed ultrasound was focused transcranially into the thalamus of rabbits during microbubble infusion and multi-channel 3D beamforming was performed online with receiver signals captured at the subharmonic frequency. Pressures were increased pulse-by-pulse until subharmonic activity was detected on acoustic imaging (psub), and tissue volumes surrounding the calibration point were exposed at 50-100%psub via rapid electronic beam steering. Results: Spatially-coherent subharmonic microbubble activity was successfully reconstructed transcranially in vivo during calibration sonications. Multi-point exposures induced volumetric regions of elevated BBB permeability assessed via contrast-enhanced magnetic resonance imaging (MRI). At exposure levels ≥75%psub, MRI and histological examination occasionally revealed tissue damage, whereas sonications at 50%psub were performed safely. Substantial intra-grid variability of FUS-induced bioeffects was observed via MRI, prompting future development of multi-point calibration schemes for improved treatment consistency. Receiver array sparsity and sensor configuration had substantial impacts on subharmonic detection sensitivity, and are factors that should be considered when designing next-generation clinical FUS brain therapy systems. Conclusion: Our findings suggest that 3D subharmonic imaging can be used to calibrate exposure levels for safe FUS-induced volumetric BBB opening, and should be explored further as a method for cavitation-mediated treatment guidance.

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Development of a three-dimensional blood-brain barrier network with opening capillary structures for drug transport screening assays.

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