Radiation damage to normal mammalian tissue in vivo with laser-driven protons at ultra-high instantaneous dose rate

Abstract: The differential sparing of normal tissues relative to tumor control observed at ultra-high dose rates, referred to as the FLASH effect, has recently gained considerable attention. The therapeutic advantages of FLASH radiotherapy are expected to be further amplified through the use of protons and ions, which enable precise dose deposition at tumor depth while minimizing irradiation of healthy tissues proximal and distal to the target. Nevertheless, the mechanism underlying this sparing effect remains poorly understood. Laser-driven proton accelerators are capable of delivering uniquely high instantaneous dose rates in ultrashort bunches. Here, we report the first in vivo investigation of normal tissue response to laser-driven proton irradiation. Our findings reveal a reduction in tissue swelling following laser-driven proton treatment compared with X-ray irradiations at conventional dose rates. RNA sequencing identified differential gene expression associated with immune and epidermal programs following laser-driven proton irradiations at two different dose levels.