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The blood-brain barrier (BBB) shields the brain from potentially harmful substances and forms a vital separation layer between the cerebral compartment and the circulatory system. While its integrity is essential to sustaining cerebral homeostasis and for brain survival, it also inhibits the transfer of most large molecules, thus severely limiting the usability of systemically administered drugs.

A treatment using microbubbles (MBs) in combination with focused ultrasound (FUS) has been proposed [1, 2] to bypass the BBB in a non-invasive, transient and spatially confined way. The comportment of these MBs inside capillary blood vessels when exposed to FUS has been studied by means of computational modeling (Figure 1). Numerical results [3, 4] indicate a significant increase in wall shear stress (WSS) and pressure as well as their respective spatial gradients in the affected vasculature. The goal of this project is the experimental assessment of bio-mechanical effect of such loading in an in-vitro BBB model.

The plan is to design and set up an experiment which is capable of monitoring the change of BBB permeability due to exposure to high frequency mechanical stresses. This setup consists of an in-vitro cerebral endothelial cell layer (Figure. 2), utilities to create oscillating WSS and pressure stimuli and assets to monitor the permeability of the BBB and measure the applied mechanical stresses (Figure. 3). The impacts of pressure, WSS and their respective spatial gradients will be separated in order to identify the most prominent factor. The final system should allow for microscopic visualization of BBB permeability and relate it to the magnitude and type of applied mechanical stimuli.

This project brings together competences in cell-biology, bio-chemistry, micro-engineering and physics and will serve to advance the knowledge about the process of mechanically induced BBB opening.

Over the course of this Master Thesis Sabrina successfully designed and built the experimental setup which is now being further developed and tested by Miles Aron.

References

1. Hynynen K. Ultrasound for drug and gene delivery to the brain Adv. Drug Delivery. Rev. 60 1209-17 (2008)
2. McDannold N et al. Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity Phys. Med. Biol. 51 793-807 (2006)
3. Wiedemair W et al. On ultrasound-induced microbubble oscillation in a capillary blood vessel and its implications for the blood-brain barrier Phys. Med. Biol. 57 1019-45 (2012)
4. Hosseinkhah N et al. A three-dimensional model of an ultrasound contrast agent gas bubble and its mechanical effects on microvessels Phys. Med. Biol. 57 785-808 (2012)