Author: David J. Gladstone, P. Jack Hoopes, David I Hunter, Brian W Pogue, Jacob Pierce Sunnerberg, Armin Tavakkoli 👨🔬
Affiliation: Thayer School of Engineering, Dartmouth College, University of Wisconsin - Madison, Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Geisel School of Medicine, Dartmouth College 🌍
Purpose: The FLASH effect, characterized by normal tissue sparing under ultra-high dose rate (UHDR) radiation delivery, remains mechanistically unclear. This study investigated the relationship between local tissue oxygenation and FLASH sparing by examining radiation response under controlled tissue oxygenation conditions.
Methods: Forty-eight mice received 25 Gy single-fraction irradiation to flank skin under either UHDR (225 Gy/s) or conventional dose rate (CDR, 0.15 Gy/s) delivery. Tissue pO2 was modulated using four breathing conditions: room air, 100% oxygen, carbogen (95% O2/5% CO2), or vascular compression. Real-time tissue oximetry was performed using the PdG4 phosphorescent probe, enabling direct measurement of radiation-induced oxygen depletion during UHDR beam delivery. Local tissue oxygenation was maintained within specific ranges (2 - 44 mmHg) across treatment conditions. Skin response was monitored daily for ulceration through a standardized scoring system.
Results: Statistically significant FLASH sparing was observed exclusively under room air conditions (Log-rank p = 0.0140), with reduced ulceration in the UHDR group compared to CDR. Despite complete protection in UHDR compression (0% ulceration vs 50% CDR), this difference did not reach significance at the 5% level (p = 0.0578). No significant differences were observed between UHDR and CDR under 100% oxygen (p = 0.1189) or carbogen (p = 0.9782) conditions. Real-time oximetry revealed distinct oxygen consumption patterns between UHDR and CDR delivery.
Conclusion: These findings establish a novel tissue oxygenation requirement for FLASH effect expression, demonstrating optimal sparing under physiological oxygen conditions. This work provides crucial mechanistic insight into the oxygen-dependent nature of the FLASH effect, suggesting a fundamental shift in the radiation-induced oxygen enhancement ratio under UHDR delivery.