An organ-on-a-chip investigation into dose-dependent, temporal dynamic effects of radiosurgery on the blood–brain barrier and its immunological response

PURPOSE: This work used an organ-on-a-chip (OOC) model of the blood-brain barrier (BBB) to study effects of clinical radiation on barrier permeability and cytokine concentrations. METHODS: Gravity-perfused OOC devices developed in house for modeling the BBB were prepared with human endothelial cells, astrocytes, and pericytes. The devices were then irradiated to 0, 2, or 20 Gy with a 6 MV X-ray beam from a medical linear accelerator. At 0, 6, 24, and 48 h post irradiation, barrier permeability was assessed by measuring the diffusion across the barrier of Alexa Fluor-labeled dextran perfused into the vascular chamber. At these same time points, effluent was drawn from both the vascular and brain chambers and analyzed using a 10-cytokine panel. RESULTS: A statistically significant increase in barrier permeability was observed at 24 and 48 h and appeared similar between 2 and 20 Gy. For 20 Gy but not 2 Gy, a large initial increase was observed in the concentration of Granulocyte-Macrophage Colony-Stimulating Factor in the vascular chamber at 6 h, which subsequently decreased. An increase was also observed in the concentration of Interleukin-1α in the brain chamber starting at 24 h and continuing to 48 h. The concentration of Vascular Endothelial Growth Factor was observed to increase starting at 6 h and 24 h in the vascular chamber and brain chamber, respectively, and to subsequently decrease in both chambers. CONCLUSIONS: Radiation effects on the BBB including barrier permeability and cytokine concentration can be observed in a dose- and time-dependent manner using an OOC.