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Abstract
High-voltage pulsed electric fields (HV-PEF) delivered with invasive needle electrodes for electroporation applications is known to induce off-target blood–brain barrier (BBB) disruption. In this study, we sought to determine the feasibility of minimally invasive PEF application to produce BBB disruption in rat brain and identify the putative mechanisms mediating the effect. We observed dose-dependent presence of Evans Blue (EB) dye in rat brain when PEF were delivered with a skull mounted electrode used for neurostimulation application. Maximum region of dye uptake was observed while using 1500 V, 100 pulses, 100 µs and 10 Hz. Results of computational models suggested that the region of BBB disruption was occurring at thresholds of 63 V/cm or higher; well below intensity levels for electroporation. In vitro experiments recapitulating this effect with human umbilical vein endothelial cells (HUVEC) demonstrated cellular alterations that underlie BBB manifests at low-voltage high-pulse conditions without affecting cell viability or proliferation. Morphological changes in HUVECs due to PEF were accompanied by disruption of actin cytoskeleton, loss of tight junction protein—ZO-1 and VE-Cadherin at cell junctions and partial translocation into the cytoplasm. Uptake of propidium iodide (PI) in PEF treated conditions is less than 1% and 2.5% of total number of cells in high voltage (HV) and low-voltage (LV) groups, respectively, implying that BBB disruption to be independent of electroporation under these conditions. 3-D microfabricated blood vessel permeability was found to increase significantly following PEF treatment and confirmed with correlative cytoskeletal changes and loss of tight junction proteins. Finally, we show that the rat brain model can be scaled to human brains with a similar effect on BBB disruption characterized by electric field strength (EFS) threshold and using a combination of two bilateral HD electrode configurations.
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1 University of Massachusetts Amherst, Department of Mechanical and Industrial Engineering, Amherst, USA (GRID:grid.266683.f) (ISNI:0000 0001 2166 5835)
2 Memorial Sloan-Kettering Cancer Center, Department of Radiology, Interventional Radiology Service, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952)
3 Memorial Sloan-Kettering Cancer Center, Department of Radiology, Interventional Radiology Service, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952); Mie University, Department of Radiology, Tsu, Japan (GRID:grid.260026.0) (ISNI:0000 0004 0372 555X)
4 Amsterdam UMC, Department of Radiology and Nuclear Medicine, Amsterdam, Netherlands (GRID:grid.509540.d) (ISNI:0000 0004 6880 3010)
5 Harvard Medical School, Division of Neuromodulation, Department of Psychiatry, Massachusetts General Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Synchron Inc, Brooklyn, USA (GRID:grid.38142.3c); The City College of New York, Department of Biomedical Engineering, New York, USA (GRID:grid.254250.4) (ISNI:0000 0001 2264 7145)
6 The City College of New York, Department of Biomedical Engineering, New York, USA (GRID:grid.254250.4) (ISNI:0000 0001 2264 7145)
7 University of Massachusetts Amherst, Department of Mechanical and Industrial Engineering, Amherst, USA (GRID:grid.266683.f) (ISNI:0000 0001 2166 5835); University of Massachusetts Amherst, Institute for Applied Life Sciences, Amherst, USA (GRID:grid.266683.f) (ISNI:0000 0001 2166 5835)