3D computational model of oxygen depletion kinetics in brain vasculature during FLASH RT and its implications for in vivo oximetry experiments

Abstract

Ultra-high-dose-rate irradiation, also known as FLASH, has been shown to improve the therapeutic ratio of radiation therapy (RT). The mechanism behind this effect has been partially explained by the radiochemical oxygen depletion (ROD) hypothesis, which attributes the protection of the normal tissue to the induction of transient hypoxia by ROD. To better understand the contribution of oxygen to the FLASH effect, it is necessary to measure oxygen (O 2 ) in vivo during FLASH irradiation. This study's goal is to determine the temporal resolution required to accurately measure the rapidly changing oxygen concentration immediately after FLASH irradiation. Methods: We conducted a computational simulation of oxygen dynamics using a real vascular model that was constructed from a public fluorescence microscopy dataset.The dynamic distribution of oxygen tension (p o2 ) during and after FLASH RT was modeled by a partial differential equation (PDE) considering oxygen diffusion, metabolism, and ROD. The underestimation of ROD due to oxygen recovery was evaluated assuming either complete or partial depletion, and a range of possible values for parameters such as oxygen diffusion, consumption, vascular p o2 and vessel density. Result:The O 2 concentration recovers rapidly after FLASH RT. Assuming a temporal resolution of 0.5 s, the estimated ROD is only 50.7% and 36.7% of its actual value in cases of partial and complete depletion, respectively. Additionally, the underestimation of ROD is highly dependent on the vascular density. To estimate ROD rate with 90% accuracy, temporal resolution on the order of milliseconds is required considering the uncertainty in parameters involved, especially, the diverse vascular density of the tissue. Conclusion:The rapid recovery of O 2 poses a great challenge for in vivo ROD measurements during FLASH RT. Temporal resolution on the order of milliseconds is recommended for ROD measurements in the normal tissue. Further work is warranted to investigate whether the same requirements apply to tumors, given their irregular vasculature. K E Y W O R D S computational model, FLASH radiotherapy, in vivo oximetry, partial differential equations, radiochemical oxygen depletion 3914

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply

“…It is possible to obtain the oxygen depletion solution within a realistic tissue/vasculature 3D space with finite element method. Cui and Pratx ( 84 ) provided an example of mesh in 3D vasculature space in a mouse brain and worked on oxygen level recovery after the irradiation. To extend our current work into 3D vasculature space, it is imperative to perform the simulation on a representative collection of the animal tumor and normal tissue vasculature models to derive statistically meaningful results for FLASH sparing effects.…”

A potential revolution in cancer treatment: A topical review of FLASH radiotherapy

“…developed a 3D computation model to measure oxygen in vivo during FLASH‐RT. They concluded that the process on the order of milliseconds is recommended for radiochemical oxygen depletion measurements in normal tissues 28 . Rothwell et al.…”

“…They concluded that the process on the order of milliseconds is recommended for radiochemical oxygen depletion measurements in normal tissues. 28 Rothwell et al. presented their modeling work about oxygen depletion by implanted biological, radiochemical, and delivery parameters.…”

“…They concluded that the process on the order of milliseconds is recommended for radiochemical oxygen depletion measurements in normal tissues. 28 Rothwell et alpresented their modeling work about oxygen depletion by implanted biological, radiochemical, and delivery parameters. 29 Contrary to the oxygen depletion models raised by Pratx et al, 23 they used effective diffusivity to account for the porous nature of space between cells.…”

Real-time optical oximetry during FLASH radiotherapy using a phosphorescent nanoprobe

“…For CDR radiation, this depletion occurs slowly, and the loss of oxygen is counteracted by replenishment through diffusion from the vasculature. In contrast, UHDR radiation is rapid enough to induce a transient and measurable drop in the local concentration of oxygen in the irradiated tissues [14,15], which has the potential to alter radiobiological responses [18][19][20][21]. In addition, a second reason is that changes in oxygen levels within the irradiated tis-sues have been shown to modulate the ability of UHDR radiation to spare normal tissues, a clear indication that oxygen is involved in mediating the FLASH effect [8][9][10][22][23][24].…”