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Transient disruption of a blood-brain barrier on-chip using focused ultrasound and microbubbles

Wichers Schreur, J.H. (2022) Transient disruption of a blood-brain barrier on-chip using focused ultrasound and microbubbles.

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Abstract:Annually, 250,000 patients are diagnosed with primary brain tumors around the world for which clinicians have limited treatment strategies such as chemotherapy. However, the success of chemotherapy is limited due to the low permeability of the blood-brain barrier (BBB). The permeability of the BBB can be increased by microbubble (MB)-assisted BBB disruption, which can be a noninvasive, transient, tunable and targeted strategy to open specific regions of the BBB. In MB-assisted BBB disruption, MBs are excited by an ultrasound wave (US) which drives the bubbles into volumetric oscillations. The dynamic behavior of a MB depends on the size of MB, the shell viscoelasticity, and the surrounding environment. Moreover, the dynamic behavior of MBs oscillating next to a cellular layer could cause different biological responses (i.e. intercellular opening, sonoporation and endocytosis) in cells. In the process of understanding the mechanisms involved in the transient disruption of the BBB-onchip by monodisperse MBs and US, the behavior of MBs in the BBB-on-chip model with and without cellular monolayer was investigated. The resonance frequency, maximum amplitude at resonance and the damping were determined using ultra-high-speed imaging. The resonance frequency multiplied with the radius of the MB was larger in the model without cells. The maximum amplitude at resonance was smaller in the model with cells and damping increased in models with cells. Furthermore, barrier properties of different endothelial cell types were investigated, to study and optimize the BBB-on-chip. hiPSC-BMECs showed the highest continuous ZO-I expression located near the peripheral membrane. The ZO-I expression levels were also higher in a co-culture with astrocytes. Last, the effect of oscillating MBs on the cells cultured in BBB-on-chip was investigated. Trans endothelial electrical resistance (TEER), ZO-I and F-actin filaments were characterized to determine whether MB-assisted BBB disruption was induced by oscillating MBs. The TEER values decreased, the ZO-I expression was more localized to the nuclei and the F-actin filaments were less expressed after FUS+MB treatment. Therefore, it is suggested that FUS+MB treatment induced intercellular opening and sonoporation. More research needs to be performed in order to confirm these findings. Moreover, real-time imaging of FUS+MB treatments to the BBB-on-chip would profound knowledge into the mechanisms involved in the transient disruption of the BBB-on-chip, because the MB location and the dynamic effect on the cells nearby can be visualized.
Item Type:Essay (Master)
Faculty:EEMCS: Electrical Engineering, Mathematics and Computer Science
Subject:33 physics, 42 biology, 44 medicine
Programme:Biomedical Engineering MSc (66226)
Link to this item:https://purl.utwente.nl/essays/90531
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