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Register a new userModeling of cellular response after FLASH irradiation: a quantitative analysis based on the radiolytic oxygen depletion hypothesis
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Purpose: Recent studies suggest ultra-high dose rate (FLASH) irradiation can spare normal tissues from radiotoxicity, while efficiently controlling the tumor, and this is known as the FLASH effect. This study performed theoretical analyses about the impact of radiolytic oxygen depletion (ROD) on the cellular responses after FLASH irradiation. Methods: Monte Carlo simulation was used to model the ROD process, determine the DNA damage, and calculate the amount of oxygen depleted (LROD) during FLASH exposure. A mathematical model was applied to analyze oxygen tension (pO2) distribution in human tissues and the recovery of pO2 after FLASH irradiation. DNA damage and cell survival fractions (SFs) after FLASH irradiation were calculated. The impact of initial cellular pO2, FLASH pulse number, pulse interval, and radiation quality of the source particles on ROD and subsequent cellular responses were systematically evaluated. Results: The simulated electron LROD range was 0.38-0.43 {mu}M/Gy when pO2 ranged from 7.5-160 mmHg. The calculated DNA damage and SFs show that radioprotective effect is only evident in cells with a lower pO2. Different irradiation setups alter the cellular responses by modifying the pO2. Single pulse delivery or multi-pulse delivery with pulse intervals shorter than 10-50 ms resulted in fewer DNA damages and higher SFs. Source particles with a low radiation quality have a higher capacity to deplete oxygen, and thus, lead to a more conspicuous radioprotective effect. Conclusions: The FLASH radioprotective effect due to ROD may only be observed in cells with a low pO2. Single pulse delivery or multi-pulse delivery with short pulse intervals are suggested for FLASH irradiation to avoid oxygen tension recovery during pulse intervals. Source particles with low radiation quality are preferred for their conspicuous radioprotective effects.
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Background: Experiments have reported low normal tissue toxicities during FLASH radiation, but the mechanism has not been elaborated. Several hypotheses have been proposed to explain the mechanism. The oxygen depletion hypothesis has been introduced and mostly studied qualitatively. Methods: We present a computational model to describe the time-dependent change of oxygen concentration in the tissue. The kinetic equation of the model is solved numerically using the finite difference method. The model is used to analyze the FLASH effect with the oxygen depletion hypothesis, and the brain tissue is chosen as an example. Results: The oxygen distribution is determined by the oxygen consumption rate of the tissue and the distance between capillaries. The change of oxygen concentration with time after radiation has been found to follow a negative exponential function, and the time constant is determined by the distance between capillaries. When the dose rate is high enough, the same dose results in the same change of oxygen concentration regardless of dose rate. The analysis of FLASH effect in the brain tissue based on this model does not support the explanation of the oxygen depletion hypothesis. Conclusions: The oxygen depletion hypothesis remains controversial because oxygen in most normal tissues cannot be depleted by FLASH radiation according to the mathematical analysis with this model and experiments on the expression and distribution of the hypoxia-inducible factors.
Although cone-beam CT (CBCT) has been used to guide irradiation for pre-clinical radiotherapy(RT) research, it is limited to localize soft tissue target especially in a low imaging contrast environment. Knowledge of target shape is a fundamental need for RT. Without such information to guide radiation, normal tissue can be irradiated unnecessarily, leading to experimental uncertainties. Recognition of this need led us to develop quantitative bioluminescence tomography (QBLT), which provides strong imaging contrast to localize optical targets. We demonstrated its capability of guiding conformal RT using an orthotopic bioluminescent glioblastoma (GBM) model. With multi-projection and multi-spectral bioluminescence imaging and a novel spectral derivative method, our QBLT system is able to reconstruct GBM with localization accuracy <1mm. An optimal threshold was determined to delineate QBLT reconstructed gross target volume (GTV_{QBLT}), which provides the best overlap between the GTV_{QBLT} and CBCT contrast labeled GBM (GTV), used as the ground truth for the GBM volume. To account for the uncertainty of QBLT in target localization and volume delineation, we also innovated a margin design; a 0.5mm margin was determined and added to GTV_{QBLT} to form a planning target volume (PTV_{QBLT}), which largely improved tumor coverage from 75% (0mm margin) to 98% and the corresponding variation (n=10) of the tumor coverage was significantly reduced. Moreover, with prescribed dose 5Gy covering 95% of PTV_{QBLT}, QBLT-guided 7-field conformal RT can irradiate 99.4 pm 1.0% of GTV vs. 65.5 pm 18.5% with conventional single field irradiation (n=10). Our QBLT-guided system provides a unique opportunity for researchers to guide irradiation for soft tissue targets and increase rigorous and reproducibility of scientific discovery.
Purpose: To investigate experimentally, if FLASH irradiation depletes oxygen within water for different radiation types such as photons, protons and carbon ions. Methods: This study presents measurements of the oxygen consumption in sealed, 3D printed water phantoms during irradiation with X-rays, protons and carbon ions at varying dose rates up to 340 Gy/s. The oxygen measurement was performed using an optical sensor allowing for non-invasive measurements. Results: Oxygen consumption in water only depends on dose, dose rate and linear energy transfer (LET) of the irradiation. The total amount of oxygen depleted per 10 Gy was found to be 0.04 - 0.18 % atm for 225 kV photons, 0.04 - 0.25 % atm for 224 MeV protons and 0.09 - 0.17 % atm for carbon ions. consumption depends on dose rate by an inverse power law and saturates for higher dose rates because of self-interactions of radicals. Higher dose rates yield lower oxygen consumption. No total depletion of oxygen was found for clinical doses. Conclusions: FLASH irradiation does consume oxygen, but not enough to deplete all the oxygen present. For higher dose rates, less oxygen was consumed than at standard radiotherapy dose rates. No total depletion was found for any of the analyzed radiation types for 10 Gy dose delivery using FLASH.
In modern surgery, a multitude of minimally intrusive operational techniques are used which are based on the punctual heating of target zones of human tissue via laser or radio-frequency currents. Traditionally, these processes are modeled by the bioheat equation introduced by Pennes, who considers Fouriers theory of heat conduction. We present an alternative and more realistic model established by the hyperbolic equation of heat transfer. To demonstrate some features and advantages of our proposed method, we apply the obtained results to different types of tissue heating with high energy fluxes, in particular radiofrequency heating and pulsed laser treatment of the cornea to correct refractive errors. Hopefully, the results of our approach help to refine surgical interventions in this novel field of medical treatment.
We present an effective method to model empirical action potentials of specific patients in the human atria based on the minimal model of Bueno-Orovio, Cherry and Fenton adapted to atrial electrophysiology. In this model, three ionic are currents introduced, where each of it is governed by a characteristic time scale. By applying a nonlinear optimization procedure, a best combination of the respective time scales is determined, which allows one to reproduce specific action potentials with a given amplitude, width and shape. Possible applications for supporting clinical diagnosis are pointed out.
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