Transient Electric Fields Can Suppress Flash Sparing during Ultra-High Dose Rate Electron Irradiation
Abstract
Purpose
FLASH radiotherapy, defined by ultra-high dose rates (UHDR; >40 Gy/s), can reduce normal-tissue toxicity while maintaining tumor control, yet reported FLASH effects show substantial variability across experimental and preclinical studies. Dielectric materials such as solid water are commonly used for backscatter and support in many in vitro and preclinical FLASH experiments, although recent work has shown that these materials can accumulate charge and generate transient electric fields when exposed to UHDR electron beams. We hypothesized that these UHDR-induced electric fields constitute a previously unrecognized experimental variable that modulates observable FLASH sparing.
Methods
Transient electric fields originating in underlying solid water were selectively suppressed using an electrostatic shield that blocks electric fields only when electrically grounded, while maintaining identical irradiation geometry, beam parameters, and dosimetry. Endpoints included γH2AX at 45 minutes post-irradiation, clonogenic survival, and membrane poration. Experiments were performed in 2D monolayers of normal human CCD-18Co colon fibroblasts and tumor cell lines HCT-116 and FaDu, comparing conventional dose rate, UHDR with electric fields, and UHDR with fields suppressed.
Results
In CCD fibroblasts, UHDR irradiation in the presence of E-fields showed no FLASH sparing relative to conventional dose rate. When E-fields were suppressed, FLASH sparing emerged, with significantly reduced γH2AX damage (<2-folds reduction, p = 0.002). HCT-116 and FaDu exhibited similar responses to each other and did not demonstrate FLASH sparing. Membrane poration in CCD fibroblasts under UHDR irradiation was substantially reduced with suppressed electric fields.
Conclusion
Transient electric fields generated during FLASH electron irradiation have a direct biological impact and can suppress FLASH sparing in normal cells. Suppressing these fields reveals a previously unrecognized physical–biological coupling that may explain variability across in vitro and preclinical FLASH studies. These findings necessitate careful consideration of experimental design and have important implications for small-animal and clinical FLASH implementations involving nearby dielectric materials.