Ultra-short pulse source of ionizing radiation with a dose rate of Gy/ps based on direct laser acceleration of electrons for studying the FLASH effect

Ultra-short pulse source of ionizing radiation with a dose rate of Gy/ps based on direct laser acceleration of electrons for studying the FLASH effect | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Ultra-short pulse source of ionizing radiation with a dose rate of Gy/ps based on direct laser acceleration of electrons for studying the FLASH effect Mikhail Gyrdymov, Vratislav Fabian, Nikolai Bukharskii, Michael Häfner, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7391364/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Results of the pilot experiment on the ultra-intense irradiation of the water phantom and various biological media with laser-driven beams of relativistic electrons in context of the FLASH effect are presented. Directed high-current beams of MeV electrons were generated by the interaction of sub-ps high-energy PHELIX laser pulses with low-density polymer foam, which was converted into a plasma of near-critical density by an additional nanosecond laser pulse. The combination of 20–50 Gy of ionizing radiation delivered by the relativistic electron beam in a single laser shot and the world's highest dose rate of 70 Gy/ps makes this source unique for studying the FLASH effect and for applications. The picosecond duration of the electron beam allows the separation of the process of ultrafast (instantaneous) oxygen ionization and the subsequent chemical reactions. In each laser shot, a sudden drop in oxygen saturation as a function of the delivered dose was measured in water and biological media. The dependence obtained is consistent with the results of the Monte Carlo simulation. Physical sciences/Optics and photonics Physical sciences/Physics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction FLASH radiotherapy Modern radiotherapy employs high-energy photons, protons, and electrons to treat cancer, but collateral damage to healthy tissue remains a major clinical limitation. Low linear energy transfer (LET) radiation such as X-rays and electrons induces DNA damage predominantly through the radiolysis of water, leading to the formation of reactive oxygen species (ROS). The presence of oxygen in normal tissues amplifies this effect — a phenomenon known as the oxygen effect — which contributes to radiation-induced toxicities such as inflammation and fibrosis [ 1 , 2 ]. To improve the therapeutic ratio, innovative approaches are being pursued to reduce normal tissue injury without compromising tumor control. One promising strategy is ultra-high dose-rate irradiation, known as FLASH radiotherapy, which delivers a therapeutic dose within a fraction of a second (typically > 40 Gy/s). Preclinical studies have shown that FLASH can significantly spare normal tissue while maintaining tumor control — a phenomenon referred to as the FLASH effect [ 3 – 9 ]. Although the underlying mechanisms are not fully understood, it is hypothesized that rapid radiolytic depletion of oxygen and altered ROS dynamics contribute to this transient radioresistance. Achieving FLASH-compatible dose rates remains a technical challenge with conventional accelerators, prompting interest in alternative delivery systems such as high-intensity laser-driven particle sources. The PHELIX laser ( P etawatt H igh E nergy L aser for Heavy I on E x periments), for example, can generate ultra-short, high-dose electron of bursts, achieving instantaneous dose rates over 10 Gy/ps (10¹³ Gy/s) and absolute dose values of several tens of Gy, offering a unique platform to investigate FLASH effects under controlled conditions [ 10 ]. Since biological tissues consist primarily of water, radiation-induced chemical processes in vivo are largely mediated by water radiolysis and the subsequent formation of ROS, such as hydroxyl radicals (·OH), superoxide anions (O₂·⁻), and hydrogen peroxide (H₂O₂) [ 11 – 14 ]. These reactive species account for the majority of indirect radiation damage to DNA and other biomolecules. Importantly, aqueous solutions saturated with oxygen undergo similar radical chemistry and oxygen consumption dynamics as biological tissues during irradiation, making them a robust first approximation for studying oxygen-dependent radiochemical processes. This includes key phenomena relevant to FLASH, such as radiolytic oxygen depletion and transient shifts in ROS balance. Accordingly, the PHELIX experiments employ water and aqueous media as model systems to probe the fundamental chemistry underlying the FLASH effect and its potential biological implications. The results of this study — assuming further improvements in dosimetric accuracy — pave the way for benchmarking the chemical-stage predictions of Monte Carlo track-structure codes [ 12 ], which simulate intricate reaction dynamics and offer valuable insights into the radiochemistry underlying the FLASH effect. Of particular interest is the role of inter-track radical recombination under ultra-high radiation intensities, a phenomenon that has been theoretically anticipated but remains experimentally unverified. Typical benchmarking scenarios involve ultra-short irradiations in aqueous systems or solutions containing homogeneously distributed target molecules. However, experimental data under such conditions are scarce, especially in oxygenated environments, which are representative of biological systems. A major challenge lies in detecting measurable radical concentrations on sub-microsecond timescales — the critical window for radiation-induced chemical transformations, see Fig. 1 . The use of laser-accelerated electron bunches with durations on the order of 1 picosecond enables separation between the ultrafast ionization of oxygen — occurring at the end of the physical stage and onset of the pre-chemical stage — and the ensuing chemical reactions. This temporal decoupling presents a significant advantage for Monte Carlo simulations, such as those performed with the TRAX-CHEM code, which can model these conditions with high fidelity [ 12 ]. In this study, the depletion of dissolved oxygen during irradiation with a laser-driven electron beam (mean kinetic energy: 10 MeV) is quantitatively compared to TRAX-CHEM simulations as a function of delivered dose. Electron acceleration in low-density polymer foam targets, enabled by the 200 TW short-pulse PHELIX laser system [ 10 , 16 , 17 ], provides a unique platform for generating highly charged, collimated MeV-range electron beams capable of depositing several tens of Gy in biological targets within a single picosecond-scale laser shot. The amount of oxygen consumed during irradiation is directly linked to the yield of radiation-induced radical species and can therefore serve as a benchmark for Monte Carlo-based simulation tools. This approach contributes to a deeper understanding of the spatiotemporal complexity of radiation chemistry under ultra-high dose rate conditions. Here, we demonstrate – for the first time — the applicability of this novel ionizing radiation source for radiochemical investigations. Specifically, we quantified the rate of oxygen consumption via the key reaction channels e aq ⁻ + O 2 → O 2 ⁻ and H · + O 2 → HO 2 in both pure water and biologically relevant aqueous media at instantaneous dose rates of 50–70 Gy/ps and per-shot doses of up to 50 Gy — a uniquely high-value achievement in this context. Direct laser accelerated electrons as an ultra-high dose rate source of ionizing radiation. Multiple types of ionizing radiation, including particle and X-ray beams generated by conventional high-frequency (RF) accelerators, have been employed to investigate and demonstrate the FLASH effect, see Table 1 in [ 18 ]. Reported dose rates from these conventional sources — including electron, proton, X-ray, and ion beams — range from 40 Gy/s [ 19 ] to as high as 10⁹ Gy/s [ 20 ], with total doses of 10–20 Gy being delivered over time spans from 10 nanoseconds to several hundred milliseconds. Among these different ionization sources, relativistic electron beams offer advantageous characteristics: higher energy deposition per unit path length compared to X-rays, while achieving more uniform volumetric energy deposition compared to protons and ions. Unlike conventional accelerator-based beams, which operate with pulse durations in the nanosecond to sub-second range, laser-driven sources are capable of producing particle and X-ray bursts on sub-picosecond timescales. This enables instantaneous dose rates that far exceed those achievable with standard technologies, thus offering new opportunities for exploring the biological and chemical underpinnings of the FLASH effect [ 21 ]. Direct laser acceleration (DLA) of electrons interacting with plasmas at near-critical electron densities (NCD) offers a promising mechanism for generating ultra-high dose rate ionizing radiation. When sub-picosecond laser pulses interact with NCD plasmas, DLA electrons with kinetic energies exceeding 7.5 MeV (approximately five times the ponderomotive potential) can be produced, exhibiting beam charges of several tens of nC, sub-picosecond pulse durations, and high directional stability [ 10 , 16 , 17 , 22 ]. These properties enable localized delivery of both high radiation doses and ultra-high dose rates within target materials. At the PHELIX facility, experiments conducted at moderate relativistic intensities (10¹⁹ W/cm²) demonstrated the generation of DLA electron beams through the interaction of sub-ps laser pulses with pre-ionized, low-density polymer foam targets. Pre-ionization was achieved using an auxiliary nanosecond laser pulse, which converted the foam into plasma with electron densities approaching 6×10²⁰ cm⁻³ – conditions suitable for effective DLA electron generation [ 10 , 16 , 17 , 22 ]. Experimental measurements and numerical simulations confirm that the DLA-generated electron beam is collimated within a half angle of 13 ± 2° and its energy distribution follows an exponential energy distribution characterized by an effective temperature in the range of 10–15 MeV, which is an order of magnitude higher than those achieved with conventional solid-foil targets irradiated under comparable laser conditions. The picosecond duration of the electron pulse closely matches the laser pulse length, enabling temporally confined dose delivery. Figure 2 illustrates the experimental setup, including up to four 0.99 T magnetic spectrometers positioned at various angles relative to the laser axis (a), the measured electron spectra for 800 ± 50 µm thick polymer foam targets with a mean density of 2 mg/cm³ (b) [ 23 ]. Additionally, the angular distribution of electrons with energies exceeding 7.5 MeV was recorded using a cylindrical detector composed of three 3 mm steel layers interleaved with imaging plates (IP) (c) [ 10 ]. The electron beam displays an exponential spectral shape with effective temperatures of approximately 13 MeV at − 10° and up to 16 MeV along the laser axis, confined within a solid angle of 0.1 sr in case of electrons with energies > 7.5 MeV. The experiments performed at the PHELIX facility demonstrate that such DLA electron beams are capable of delivering radiation doses of 20–50 Gy to aqueous or cellular targets within a single picosecond pulse. This temporal confinement provides a unique opportunity to distinguish between the immediate physical ionization of oxygen and the subsequent chemical reaction cascades. The unprecedented combination of high absolute dose and ultra-high dose rates exceeding 70 Gy/ps renders the resulting data exceptionally valuable for benchmarking Monte Carlo simulations of radiation chemistry under extreme conditions. Experimental setup Primary target and laser parameters The experiment was conducted in single-shot mode at the PHELIX laser facility, Helmholtzzentrum GSI Darmstadt. A well-controlled nanosecond (ns) pulse with an intensity of ~ 10¹³ W/cm² (corresponding to 0.3% of E tot in Fig. 4 ) was first used to transform a foam target into a plasma with near-critical electron density (NCD), n cr = 10²¹ cm⁻³ for λ = 1.053 µm. After a delay of 3–5 ns, the main laser pulse, with a duration of 750 ± 250 fs and an energy of 70 ± 10 J (measured before the compressor), interacted with the plasma target. The measured laser energy within the FWHM of the focal spot was 20 ± 2 J, corresponding to an intensity of ~ 10¹⁹ W/cm². Nanosecond and sub-picosecond pulses were focused onto the target by the same off-axis parabolic mirror with a focal length of 150 cm (f/5). The foam targets were CHO polymer aerogels with an initial average density of 2–5 mg/cm³ and a thickness of 300–1500 µm, grown inside a copper washer with an inner diameter of 2.5 mm. In the case of full ionization of CHO-atoms, the electron density of the resulting plasma corresponds to 0.65n cr [ 22 , 24 ]. Secondary targets for FLASH irradiation Secondary targets included various liquids such as deionized water, phosphate-buffered saline (PBS), cell culture medium (F-12 Nutrient Medium, or Ham’s F12), and lysed cells, which were placed in airtight cylindrical tanks suitable for vacuum operation. All samples were fully oxygenated prior to irradiation. Experimental setup for irradiation of the secondary targets The schematic arrangement is shown in Fig. 3 , with additional details in Fig. 6 a. DLA electrons irradiated the tank containing a water-like medium, which was positioned between two magnets providing a 0.4 T magnetic field. This configuration deflected electrons with energies below 7 MeV and ensured homogeneous irradiation of the tank, where O₂ concentration measurements were performed. A carbon collimator was employed to improve quasi-uniform irradiation conditions by absorbing low-energy electrons propagating at larger angles. The tank, with an internal volume of 5 × 5 × 5 mm³, was equipped with a 2 mm diameter optical fiber connected to an oxygen meter located outside the target chamber. Further details are provided in the “Methods” section. Reconstruction of the radiation dose inside the tank The objective of the experiment was to establish a correlation between the decrease in O₂ concentration in the tank, induced by ultra-high flux laser-driven relativistic electrons, and the corresponding deposited dose. Figure 3 presents an example of the dose generated by relativistic electron beams penetrating a radiochromic film (RCF) for shot #9. In this case, DLA electrons were produced via the interaction of a PHELIX laser pulse, with an intensity of 10¹⁹ W/cm², with a 1000 µm CHO-foam target of 2 mg/cm³ density, pre-ionized by a nanosecond pulse. As direct dose measurements within the tank were not feasible, the dose was reconstructed using RCF data recorded outside the tank, along the electron beam path. Figure 4 presents a diagram of doses recorded on RCF#1 and RCF#2, averaged over a 5 × 5 mm² area corresponding to the tank position (blue box in Fig. 3 ), for laser shots using foam targets with volume densities of 2–5 mg/cm³ and thicknesses of 400–1500 µm. Comparison of RCF#1 and RCF#2 data indicates that protons with initial energies exceeding 10 MeV dominate the signal at RCF#1 after passing through the shielding. The proton-induced dose on RCF#1 increases from approximately 50 Gy to 150 Gy with increasing foam areal density. The relative dose variation due to inhomogeneous distribution on RCF#1 in front of the tank ranged from 10–40% across different laser shots, with the primary contribution from MeV protons. On RCF#2, located behind the tank, the dose originates from MeV electrons and soft X-rays, with relative deviations between 5% and 18% across different shots. In Fig. 4 , laser shots are grouped by similar foam and laser pulse parameters; the average dose values and variation intervals (for RCF#2) are shown for each group. Dose differences within each group can be attributed to several factors: the laser energy before the compressor varied from 60 to 80 J between shots, and the focusing quality changed significantly over the course of the day due to heating of the Nd:glass gain medium. Both the energy and intensity of the laser pulse influence the charge of the DLA electrons and, consequently, the ionizing radiation dose. RCF#2 and RCF#3 represent doses from DLA electrons emerging from the tank and exhibit the same trend with increasing foam areal density as RCF#1. The lateral shift of the RCF signal relative to the laser axis (see marked areas 1, 2 on RCF#2 and areas 4, 5 on RCF#3 in Fig. 3 ) confirms the predominant role of electrons deflected in the 0.4 T static magnetic field. Protons with energies above 10 MeV, detected via the Time-of-Flight method [ 25 ], are fully stopped by the 2 mm-thick tank wall. For this reason, only the RCF#2 and RCF#3 signals were used for dose evaluation. Absolute calibration of EBT-3 and EBT-XD films was performed using an X-ray source. In the experiment, simultaneous measurements of the O₂ concentration, the dose inside the tank, and the energy and angular distribution of the DLA electrons were not possible. Therefore, a reconstruction method was developed to estimate the dose at six selected positions on RCF#2 and RCF#3 (Fig. 3 ) by optimizing the assumed energy and angular distribution of the electrons. From previous measurements (Fig. 2 and [ 10 , 22 ]), the energy distribution of the DLA electrons can be approximated by an exponential function with two effective temperatures: $$\:f={\frac{{d}^{2}N}{dE\bullet\:d\varOmega\:}|}_{\alpha\:}={N}_{0}\left(\lambda\:\bullet\:exp\left(-\frac{E}{{T}_{1}}\right)\:+(1-\lambda\:)\bullet\:exp\left(-\frac{E}{{T}_{2}}\right)\right)\bullet\:exp\left(-{\left(\frac{\alpha\:-{\alpha\:}_{0}}{\varDelta\:\alpha\:}\right)}^{2}\right)$$ 1 , where \(\:{N}_{0}\) (for E > 2 MeV) is the total number of the DLA electrons, \(\:\lambda\:\) and \(\:\left(1-\lambda\:\right)\) are the fractions of electrons with effective temperatures \(\:{T}_{1}\) and \(\:{T}_{2}\) , \(\:{\alpha\:}_{0}\:\) is the angle between the laser axis and the electron beam, and \(\:\varDelta\:\alpha\:\) is the divergence parameter related to the half-angle of FWHM: \(\:{\varDelta\:\alpha\:}_{1/2FWHM}=\varDelta\:\alpha\:\bullet\:\sqrt{ln\left(2\right)}\) (see Fig. 2 c). As a first step in dose evaluation for the secondary target, the parameters of Eq. ( 1 ) were taken from the reference shot in Fig. 2 . Iterative optimization was then performed to determine the six parameters in Eq. ( 1 ) that yielded the best match between the calculated and measured doses at all six positions on RCF#2 and RCF#3 for each laser shot. It is important to note that the stopping powers for water (or water-like media), the RCF material (active and protective layers), and PEEK (tank wall material) are very similar, as shown in Fig. 6 d in Methods. This similarity implies comparable doses inside the tank for different aqueous media, provided that the experimental conditions – such as target-laser parameters and relative positioning of the primary and secondary targets – remain unchanged. The irradiation dose was calculated based on the optimized electron energy distribution, ensuring the best agreement between measured RCF doses and the corresponding stopping power of the biological medium. Details of the reconstruction method are provided in “Supplementary Information”. Results and discussion Measurement of the O 2 concentration During the laser shots, a prompt decrease in the O₂ concentration was observed. An example of the recorded O₂ concentration drop is shown in Fig. 5 a for irradiation of water with a beam of DLA electrons. This rapid oxygen depletion, induced by ultra-high dose rates, contrasts with the behavior at low dose rates, where a gradual decline is typically observed, as in the case of X-ray sources [ 26 ] The measurements were conducted with a time resolution of 1 s, as determined by the detector [ 26 ]. Figure 5 b presents the dependence of the O₂ concentration drop on the dose deposited by the DLA electrons. This dependence can be approximated by a linear fit with a slope of 0.33 µM/Gy (red line in Fig. 5 b), while the experimentally determined values are 0.35 ± 0.05 µM/Gy for water and 0.37 ± 0.05 µM/Gy for the culture medium. For these approximations, the point with coordinates (0, 0) was fixed. Monte Carlo track structure simulations, which can model the physical-chemical stage of electron and ion tracks in water, are useful for estimating radiochemical yields in the early stages of radiation-induced chemical evolution. In this work, the experimental results are compared with predictions of the TRAX-CHEM code [ 11 ]. This code calculates the yields of molecular species and radicals in oxygenated aqueous solutions and has been used to estimate molecular oxygen removal as a function of the dose delivered by 1 MeV electrons in sealed oxygenated solutions [ 12 ]. However, both the complexity of the underlying processes and technological limitations necessitate several assumptions and approximations when comparing simulations with experimental results. Most Monte Carlo codes assume that the dose is delivered instantaneously and that the entire track evolution is completed within the first microsecond. In contrast, irradiation times typically required in medical or FLASH accelerator facilities to achieve the high doses needed for measurable oxygen depletion are on the same order of magnitude – or even longer – than the simulated chemical stage timescale. Oxygen depletion and tissue-sparing effects A leading hypothesis for the normal tissue-sparing effect observed at ultra-high dose rates is rapid oxygen depletion during the radiation pulse, which in turn reduces oxidative damage. When a FLASH dose is delivered almost instantaneously, local oxygen in tissues is consumed by radiation-induced radical reactions faster than it can be replenished by diffusion or blood flow [ 27 ]. This transient drop in oxygen tension is critical because oxygen is a potent radiosensitizer: under conventional dose rates, oxygen “fixes” DNA damage by forming peroxyl radicals, making oxygen-rich normal tissues highly susceptible to radiation injury [ 27 ]. In FLASH irradiation, the sudden hypoxia renders normal cells more radioresistant during the pulse, curtailing the yield of harmful ROS. Experimental evidence strongly supports this mechanism. For example, FLASH-irradiated mouse brains were found to have significantly lower levels of ROS and hydrogen peroxide, with correspondingly less DNA damage in neurons and glia compared to brains irradiated at conventional dose rates [ 2 ]. In cell culture studies, human normal lung fibroblasts exposed to proton FLASH showed fewer senescent cells and lower TGF-β1 expression — a marker of fibrosis and oxidative stress — than cells exposed to the same dose at a standard dose rate [ 2 ]. Likewise, in mouse models, FLASH dramatically reduces classic radiation toxicity: Favaudon et al. reported that a 15–20 Gy dose to the lungs caused severe fibrosis and activation of TGF-β pathways when delivered conventionally, but no lung fibrosis or complications when administered as a < 1 s FLASH pulse [ 2 ]. Such findings indicate that ultra-rapid dosing spares normal tissue by minimizing ongoing radical generation and damage fixation — essentially outpacing the biological processes that normally amplify radiation injury. The implications for therapy are profound — by blunting oxygen-dependent damage in healthy tissues, FLASH could allow for higher tumor doses or enable the treatment of tumors located near sensitive organs with far fewer side effects [ 28 ]. In other words, rapid oxygen depletion widens the therapeutic window of radiotherapy, as normal tissues tolerate ultra-high dose-rate exposure markedly better than conventional irradiation. The PHELIX study exemplifies these advantages: using a laser-driven beam, it achieves FLASH doses that spare normal cells via the oxygen depletion effect while still effectively ablating tumor cells. Going forward, this approach could transform clinical practice by enabling aggressive radiation treatments that maximize tumor kill while minimizing long-term damage to healthy tissue — leveraging the unique radiobiology of FLASH to improve patient outcomes [ 2 , 27 ]. Conclusion In conclusion, we propose the use of high-current directed beams of DLA electrons generated by the interaction of relativistic intense laser pulses with pre-ionized low-density polymer foams for studying the FLASH effect and its potential application in FLASH therapy. Relativistic electron bursts provide higher energy deposition in matter compared to X-rays, are easier to transport and handle than protons, and maintain short pulse durations over long distances due to their relativistic energies. High-current MeV electron beams, accelerated via direct laser acceleration, can deliver doses up to 1–2 Gy per joule of focused laser energy per shot (20–50 Gy for the PHELIX laser) at an unprecedented dose rate. The picosecond pulse duration allows separation of instantaneous oxygen ionization from subsequent chemical reactions. A sudden drop in oxygen saturation was observed in water and culture media during each laser shot, correlating with the delivered dose. Therefore, this approach is unique and offers promising opportunities for benchmarking Monte Carlo track structure codes and for application in FLASH therapy, provided the accuracy of dose measurements is improved. Methods A detailed schematic of the experimental setup is shown in Fig. 6 a. To ensure uniform irradiation of the 5 mm diameter tank by DLA electrons, electrons with energies below 7 MeV were deflected using a static magnetic field of 0.4 T. This measure was crucial for performing O₂ concentration measurements under quasi-uniform irradiation conditions. Additionally, a carbon collimator was employed to attenuate low-energy electrons propagating at angles greater than 5° relative to the laser axis (see Fig. 3 and Fig. 6 a). The tank was shielded by three layers of EBT-3 radiochromic films (RCFs) to stop ions and protons (Fig. 6 b). A 150 µm thick aluminum foil was used to attenuate soft X-rays. This shielding was sufficient to stop protons with energies up to 10 MeV and to reduce the X-ray signal at 6 keV to 10% of its initial intensity [ 30 ]. For O₂ concentration measurements, an oxygen meter was used. It transmitted light at 505 nm through a 2 mm diameter optical fiber to a sensor spot (SP-Pst3-SA23-D5-OIW-US) containing luminophores [ 26 ]. The sensor spot was placed on the inner wall of the 5 × 5 × 5 mm³ tank filled with the medium, allowing light penetration (Fig. 6 c). Due to photoluminescence quenching, oxygen molecules in the medium reduce luminescence from the sensor spot [ 31 ]. The resulting signal was sent back to the oxygen meter for analysis, which was connected to a PC for real-time data recording. To protect the PC and optical sensor from electromagnetic pulses during laser shots, both were housed inside a Faraday cage located adjacent to the target chamber. A remote connection to the PC was established via an internal network for control from the control room. The tank parts (Fig. 6 c) were glued to ensure airtightness, allowing operation under vacuum conditions. The tank walls were made from polyetheretherketone (PEEK), a radiation- and chemically-resistant material that does not leach chemicals or oxygen when irradiated. Before sealing, the tank was completely filled with the sample, ensuring no air bubbles were trapped. Importantly, the stopping powers of water (or water-like media), the active and protective layers of the RCFs, and PEEK are very similar, as shown in Fig. 6 d. This similarity allows us to assume comparable doses within the tank for different contents, provided the experimental conditions – such as target, laser parameters, and tank position – are kept constant. GEANT4 simulation of dose distribution for the optimized experimental setup. An alternative design of the setup with the water tank, shown in Fig. 7 a, allows avoiding complications caused by low-energy electrons (< 7 MeV), which carry the main beam charge, and protons with energies ≤ 15 MeV in dose measurements inside and outside the tank – eliminating the need for a magnetic deflection and enabling more precise dose determination within the irradiated medium. In this setup, one half of the tank contains the liquid samples, while the second, open part houses RCFs positioned on the left and right sides of the optical fiber. Both parts share common 2 mm thick PEEK walls and are separated by a sealed optical window (Fig. 7 a). Dose distribution simulations induced by electrons in water were performed using the GEANT4 Monte Carlo code. The input parameters included electron energy and angular distributions measured during the interaction of a 10¹⁹ W/cm² PHELIX laser pulse with pre-ionized, 2 mg/cm³, 800 µm thick CHO-foam. To achieve more homogeneous irradiation of the 5 mm diameter water tank by high-current DLA electrons, electrons were passed through 80 µm thick gold and 2 mm thick PEEK plates (Fig. 7 a). These plates convert and scatter the low-energy electron fraction, reducing its dose contribution per solid angle and thus homogenizing the dose distribution within the water tank. The corresponding electron spectra are shown in Fig. 7 b. Radiochromic films placed around the optical fiber recorded doses of 45 Gy (RCF#1) and 32 Gy (RCF#2), corresponding to an estimated dose of 39 ± 3 Gy deposited in the water within the measurement area. Declarations Competing interests The authors declare no competing interests. Additional information “Supplementary Information”. The online version contains supplementary material available at …. Funding This work was funded by the German Ministry for Education and Research (BMBF) under contract No. 05P21SJFA2 and supported by the Czech Ministry of Education, Youth and Sports (Project No. CZ.02.2.69/0.0/0.0/18_053/0016980) and the Grant Agency of the Czech Republic (Grant No. GM23-05027M). Author Contribution O.N.R., S.Z., M.G. conceived and designed the experiment. Pha.K. developed the diagnostic for measurement of oxygen concentration. M.G. constructed and developed the construction for measurement of radiation dose from particles in a magnetic field. N.G.B. produced and prepared polymer foam targets. M.G., J.C., Pha.K., N.B., S.Z. and O.N.R. performed the experiment, M.G., Pha.K., M.H. and O.N.R. analyzed the data. M.H. and M.G. performed and guided python simulations, N.B. performed and guided simulations in GEANT4. M.G., O.N.R., V.F, M.F., D.B. wrote the manuscript with revisions by all co-authors. N.E.A. and O.N.R. provided overall supervision. Acknowledgement The results presented here are based on Experiment P213 performed at the PHELIX facility at the GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany, in the framework of FAIR Phase-0 in 2021. The authors are very grateful for the support provided by the PHELIX laser team. This work was funded by the German Ministry for Education and Research (BMBF) under contract No. 05P21SJFA2 and supported by the Czech Ministry of Education, Youth and Sports (Project No. CZ.02.2.69/0.0/0.0/18_053/0016980) and the Grant Agency of the Czech Republic (Grant No. GM23-05027M).The authors express their sincere gratitude to Martina K. Fuss and Daria Boscolo for their invaluable contributions to the development and realization of this project. Their expertise was instrumental to the success of this study. Data Availability The data supporting the plots of this article and other results of this study are available from the corresponding authors on reasonable request. References Prasanna, P. G. et al. Normal tissue injury induced by photon and proton therapies: Gaps and opportunities. Int. J. Radiat. Oncol. Biol. Phys. 110 (5), 1325–1340. https://doi.org/10.1016/j.ijrobp.2021.02.043 (2021). Gao, Y. et al. A potential revolution in cancer treatment: A topical review of FLASH radiotherapy. J. Appl. Clin. Med. Phys. 23 (10), e13790. https://doi.org/10.1002/acm2.13790 (2022). Favaudon, V. et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Translat Med. 6 , 245. https://doi.org/10.1126/scitranslmed.3008973 (2014). Vozenin, M. C., Hendry, J. H. & Limoli, C. L. Biological benefits of ultrahigh dose rate FLASH radiother-apy: sleeping beauty awoken. Clin. Oncol. 31 , 407–415. https://doi.org/10.1016/j.clon.2019.04.001 (2019). Vozenin, M. C. et al. The advantage of FLASH confirmed in mini-pig and cat-cancer patientsю. Clin. Canc Res. 25 , 35–42. https://doi.org/10.1158/1078-0432.ccr-17-3375 (2019). Montay-Gruel, P. et al. Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species. Proc. Natl. Acad. Sci. USA 116, 10943–10951. (2019). https://doi.org/10.1073/pnas.1901777116 Adrian, G. et al. The FLASH effect depends on oxygen concentration. Brit J. Radiol. 93 , 20190702. https://doi.org/10.1259/bjr.20190702 (2020). Bourhis, J. et al. Treatment of a first patient with FLASH-radiotherapy. Radiother Oncol. 139 , 18–22. https://doi.org/10.1016/j.radonc.2019.06.019 (2019). Orobeti, S. et al. First in vitro cell co-culture experiments using laser-induced high-energy electron FLASH irradiation for the development of anti-cancer therapeutic strategies. Sci. Rep. 14 , 14866. https://doi.org/10.1038/s41598-024-65137-7 (2024). Rosmej, O. N. et al. High-current laser-driven beams of relativistic electrons for high energy density research. Plasma Phys. Control Fusion . 62 , 115024. https://doi.org/10.1088/1361-6587/abb24e (2020). Boscolo, D., Krämer, M., Fuss, M. C., Durante, M. & Scifoni, E. Impact of Target Oxygenation on the Chemical Track Evolution of Ion and Electron Radiation. Int. J. Mol. Sci. 21 , 424. https://doi.org/10.3390/ijms21020424 (2020). Boscolo, D., Scifoni, E., Durante, M., Krämer, M. & Fuss, M. C. May oxygen depletion explain the FLASH effect? A chemical track structure analysis. Radiother. Oncol. 162 , 68–75. https://doi.org/10.1016/j.radonc.2021.06.031 (2021). Rosini, G., Ciarrocchi, E., Ciarrocchi, E. & D’Orsi, B. Mechanisms of the FLASH effect: current insights and advances. Front Cell. Dev. Biol. : Sec Cancer Cell. Biology . 13 https://doi.org/10.3389/fcell.2025.1575678 (2025). Marshall, K. L., Velayutham, M., Khramtsov, V. V., Mizener, A. & Cifarelli, C. P. Enhancing radiation-induced reactive oxygen species generation through mitochondrial transplantation in human glioblastoma. Sci. Rep. 15 , 7618. https://doi.org/10.1038/s41598-025-91331-2 (2025). Weber, U. A., Scifoni, E. & Durante, M. FLASH radiotherapy with carbon ion beams. Med. Phys. 49 , 1974–1992. https://doi.org/10.1002/mp.15135 (2022). Rosmej, O. N. et al. Interaction of relativistically intense laser pulses with long-scale near critical plasmas for optimization of laser based sources of MeV electrons and gamma-rays. New. J. Phys. 21 , 043044. https://doi.org/10.1088/1367-2630/ab1047 (2019). Günther, M. M. et al. Forward-looking insights in laser-generated ultra-intense γ-ray and neutron sources for nuclear application and science. Nat. Commun. 13 , 170. https://doi.org/10.1038/s41467-021-27694-7 (2022). Lin, B. et al. Mechanisms of FLASH effect. Front. Oncol. 12 , 995612. https://doi.org/10.3389%2Ffonc.2022.995612 (2022). Fouillade, C. et al. FLASH irradiation spares lung progenitor cells and limits the incidence of radio-induced senescence. Clin. Cancer Res. 26 (6), 1497–1506. https://doi.org/10.1158/1078-0432.ccr-19-1440 (2020). Yang, G. et al. Association of cancer stem cell radio-resistance under ultra-high dose rate FLASH irradiation with lysosome-mediated autophagy. Front. Cell. Dev. Biol. 9 , 672693. https://doi.org/10.3389/fcell.2021.672693 (2021). Kacem, H., Almeida, A., Cherbuin, N. & Vozenin, M. C. Understanding the FLASH effect to unravel the potential of ultra-high dose rate irradiation. Int. J. Radiat. Biol. 98 (3), 506–516. https://doi.org/10.1080/09553002.2021.2004328 (2022). Rosmej, O. N. et al. Advanced plasma target from pre-ionized low-density foam for effective and robust direct laser acceleration of electrons. High Power Laser Sci. Eng. 13 , e3. https://doi.org/10.1017/hpl.2024.85 (2025). Borisenko, N. G. et al. Noizy low-density targets that worked as bright emitters under laser illumination. J. Phys. : Conf. Ser. 1692 , 012026. https://doi.org/10.1088/1742-6596/1692/1/012026 (2020). Rosmej, O. N. et al. Bright betatron radiation from direct laser-accelerated electrons at moderate relativistic laser intensity. Matter Radiat. Extremes . 6 , 048401. https://doi.org/10.1063/5.0042315 (2021). Cikhardt, J. et al. Characterization of bright betatron radiation generated by direct laser acceleration of electrons in plasma of near critical density. Matter Radiat. Extremes . 9 , 027201. https://doi.org/10.1063/5.0181119 (2024). Karoon, P., Kobda, C., Talabnin, C. & Fuss, M. C. Experimental study of radiolytic oxygen depletion from X-ray irradiation in water and liquid samples. RSU International Research Conference. (2023). https://doi.org/10.14458/RSU.res.2023.46 Abolfath, R., Grosshans, D. & Mohan, R. Oxygen depletion in FLASH ultra-high-dose-rate radiotherapy: A molecular dynamics simulation. Med. Phys. 47 (12), 6551–6561. https://doi.org/10.1002/mp.14548 (2020). GSI Helmholtzzentrum für Schwerionenforschung. Proton and, Carbon Ion, F. L. A. S. H. & Radiotherapy Online: https://www.gsi.de/work/forschung/biophysik/forschungsfelder/particle-therapie-physics/proton-and-carbon-ion-flash#:~:text=FLASH%20radiotherapy%20is%20considered%20a,and%20quantify%20the%20FLASH%20for [Accessed: July 7, 2025]. Berger, M. J., Coursey, J. S., Zucker, M. A., Chang, J. & Stopping-Power & Range Tables for Electrons, Protons, and Helium Ions. (2017). https://dx.doi.org/10.18434/T4NC7P/ Hubbell, J. H. & Seltzer, S. M. X-Ray Mass Attenuation Coefficients (NIST Standard Reference Database 126). (1996). https://www.nist.gov/pml/x-ray-mass-attenuation-coefficients Ast, C., Schmälzlin, E., Löhmannsröben, H. G. & Van Dongen, J. T. Optical Oxygen Micro- and Nanosensors for Plant Applications. Sensors 12 (6), 7015–7032. https://doi.org/10.3390/s120607015 (2012). Additional Declarations No competing interests reported. Supplementary Files Sci.Rep.SupplementaryInformation17.08.2025.docx Cite Share Download PDF Status: Published Journal Publication published 17 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 06 Oct, 2025 Reviews received at journal 02 Oct, 2025 Reviews received at journal 30 Sep, 2025 Reviewers agreed at journal 17 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers agreed at journal 12 Sep, 2025 Reviewers agreed at journal 11 Sep, 2025 Reviewers invited by journal 10 Sep, 2025 Editor assigned by journal 01 Sep, 2025 Editor invited by journal 01 Sep, 2025 Submission checks completed at journal 20 Aug, 2025 First submitted to journal 20 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7391364","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":516733042,"identity":"b9bf0821-137b-42d2-aa68-621703e4db83","order_by":0,"name":"Mikhail Gyrdymov","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYBACCXYgkcAgUd8P4iUUEKOFGazFhnFmA4hhQKwWBoY0xg0HQDQxWiSb2a9ueNh2mNn4/OrEDw8MGOT5xQ7g1yLNzFN2I7HtMJvZjbebJYAOM5w5OwG/FjlmnrQbCWcO85jdOLsBpCXB4DaRWiSMZ5zd/IMoLdLM7MduJFSkGRjw924jzhbJZh42oBabBIkbvNssEgwkCPtF4nj7s5s/DCQS+PvPbr75o8JGnl+agBYGBh5oXEiAVUoQUg4C7A8gNP8BYlSPglEwCkbBSAQAwFpFIm+bsAQAAAAASUVORK5CYII=","orcid":"","institution":"Goethe University Frankfurt","correspondingAuthor":true,"prefix":"","firstName":"Mikhail","middleName":"","lastName":"Gyrdymov","suffix":""},{"id":516733043,"identity":"2bec8fae-dbc5-44e8-9a75-8306677feae5","order_by":1,"name":"Vratislav Fabian","email":"","orcid":"","institution":"Czech Technical University in Prague","correspondingAuthor":false,"prefix":"","firstName":"Vratislav","middleName":"","lastName":"Fabian","suffix":""},{"id":516733044,"identity":"db9b2265-1d26-4c04-a384-1262c2ccc106","order_by":2,"name":"Nikolai Bukharskii","email":"","orcid":"","institution":"P. N. Lebedev Physical Institute (LPI), Russian Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nikolai","middleName":"","lastName":"Bukharskii","suffix":""},{"id":516733045,"identity":"01faeef8-6417-4364-ac37-6e905e9ef0ec","order_by":3,"name":"Michael Häfner","email":"","orcid":"","institution":"Goethe University Frankfurt","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Häfner","suffix":""},{"id":516733046,"identity":"3333765d-ed6c-4dcf-a8b3-db7657456c83","order_by":4,"name":"Pharewa Karoon","email":"","orcid":"","institution":"Suranaree University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Pharewa","middleName":"","lastName":"Karoon","suffix":""},{"id":516733049,"identity":"427e0e74-2f21-4be7-a8e7-c9419026b4c7","order_by":5,"name":"Nataliya G. Borisenko","email":"","orcid":"","institution":"P. N. Lebedev Physical Institute (LPI), Russian Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nataliya","middleName":"G.","lastName":"Borisenko","suffix":""},{"id":516733050,"identity":"7746d2cf-9743-4cf1-b316-61b82dd92fd7","order_by":6,"name":"Jakub Cikhardt","email":"","orcid":"","institution":"Czech Technical University in Prague","correspondingAuthor":false,"prefix":"","firstName":"Jakub","middleName":"","lastName":"Cikhardt","suffix":""},{"id":516733051,"identity":"183a442c-79fb-4f0b-9230-d70f5eb79c8d","order_by":7,"name":"Sero Zähter","email":"","orcid":"","institution":"Focused Energy GmbH","correspondingAuthor":false,"prefix":"","firstName":"Sero","middleName":"","lastName":"Zähter","suffix":""},{"id":516733052,"identity":"b7639ea4-38d4-4f87-9989-347845dc0fcc","order_by":8,"name":"Philipp Korneev","email":"","orcid":"","institution":"P. N. Lebedev Physical Institute (LPI), Russian Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Philipp","middleName":"","lastName":"Korneev","suffix":""},{"id":516733053,"identity":"e8292388-a60b-46b4-af00-83bf652fafc8","order_by":9,"name":"Joachim Jacoby","email":"","orcid":"","institution":"Goethe University Frankfurt","correspondingAuthor":false,"prefix":"","firstName":"Joachim","middleName":"","lastName":"Jacoby","suffix":""},{"id":516733054,"identity":"c5c21d12-2f66-4b9e-8285-8abab0783613","order_by":10,"name":"Nikolay E. Andreev","email":"","orcid":"","institution":"Russian Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nikolay","middleName":"E.","lastName":"Andreev","suffix":""},{"id":516733055,"identity":"280cb50e-3afd-4bdb-969a-cbef3f8a7c17","order_by":11,"name":"Olga N. Rosmej","email":"","orcid":"","institution":"GSI Helmholtzzentrum für Schwerionenforschung","correspondingAuthor":false,"prefix":"","firstName":"Olga","middleName":"N.","lastName":"Rosmej","suffix":""}],"badges":[],"createdAt":"2025-08-17 08:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7391364/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7391364/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-026-40281-4","type":"published","date":"2026-02-17T15:58:11+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91654123,"identity":"aa26d8bd-c0af-4c07-9d3c-04ae2abe01c8","added_by":"auto","created_at":"2025-09-18 17:42:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":188100,"visible":true,"origin":"","legend":"\u003cp\u003eStages dominated by key processes in biological media or aqueous solutions following radiation exposure. Upon irradiation of aqueous systems, ionization and electronic excitation initiate molecular dissociations, resulting in the formation of primary radiolytic species such as radicals and hydrated electrons. These reactive species subsequently diffuse and interact with each other, with the surrounding water, and with dissolved molecular oxygen or biomolecules during the expansion of the chemical track. (Adapted from Figure 2 in Ref. [15]).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/63983fc78e200e8052c6e71b.png"},{"id":91652228,"identity":"35bab213-e2c3-4627-81a5-b6929fd64fee","added_by":"auto","created_at":"2025-09-18 17:34:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":233072,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Experimental setup for measurements of the angular-dependent electron spectra. (b) Electron spectra measured for a laser shot on an 800 ± 50 µm thick polymer foam target with a mean density of 2 mg/cm³ (shot #25 P207). (c) Angular distribution of electrons with energy Eₑ \u0026gt; 7.5 MeV recorded using a cylindrical diagnostic consisting of a steel stack with imaging plates (IP) inserted between the sheets.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/bfedad1ad2a129f5dbe6e40c.png"},{"id":91652234,"identity":"55586f00-e0ae-4459-b55b-e6106e303b9a","added_by":"auto","created_at":"2025-09-18 17:34:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":333605,"visible":true,"origin":"","legend":"\u003cp\u003eTwo-dimensional distribution of the dose recorded on radiochromic films (RCFs): in front of the tank (RCF#1), behind the tank (RCF#2), and after the magnets (RCF#3). The example corresponds to shot #9 with a 1000 µm CHO-foam target of 2 mg/cm³ density. Laser parameters: 3 ns pre-pulse containing 1% of the total laser energy; 3 ns delay before the sub-ps pulse; peak intensity of the sub-ps pulse of ~10¹⁹ W/cm². The distances from the target chamber center (TCC) to RCF#1 and RCF#2 were 40 mm and 56 mm, respectively.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/d95fbb4f20223a15dd039fe1.png"},{"id":91654801,"identity":"daf044ce-7c42-483d-a442-bbc5e4e82d18","added_by":"auto","created_at":"2025-09-18 17:50:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":337713,"visible":true,"origin":"","legend":"\u003cp\u003eMean RCF dose in the 5 × 5 mm² interaction area in front of the tank (RCF#1) and behind the tank (RCF#2), corresponding to the blue box in Fig. 3. By keeping the laser pulse parameters constant, different dose levels were obtained by varying the foam target density and thickness.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/7b248434c5b6e0764c4fee8b.png"},{"id":91654805,"identity":"b2dc9dd8-2be4-46e8-9502-e0179ae07b61","added_by":"auto","created_at":"2025-09-18 17:50:51","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":211150,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Measurement of the O₂ concentration in the tank using an optical fiber probe, shot #12 P213. (b)\u0026nbsp;Dependence of the O\u003csub\u003e2\u003c/sub\u003e concentration drop on the dose deposited by DLA electrons.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/269395a6d09013814286e6d7.png"},{"id":91652236,"identity":"e96fbaa0-8cab-4d2f-8574-7e65bd8c20f4","added_by":"auto","created_at":"2025-09-18 17:34:51","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":420816,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Experimental setup for the “FLASH effect” study at the PHELIX facility. (b) RCF shielding for protons and ions after 150 µm Al foil. (c) Water tank setup. (d) Electron stopping power in different media used (data from ESTAR [29]).\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/897be716c267461fb73f8a59.png"},{"id":91652249,"identity":"fb1f494b-8bcd-43f5-9b4f-a75d6ddb4c6b","added_by":"auto","created_at":"2025-09-18 17:34:51","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":243190,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Concept of the target setup. (b) Electron spectra “measured” after: foam; foam + 2 mm PEEK; foam + 80 µm Au + 2 mm PEEK, with a zoomed view of the low-energy region.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/3a9e72262913542d52ba33e6.png"},{"id":103251128,"identity":"293283ea-78a2-4bc8-98cc-c46fb6a8b645","added_by":"auto","created_at":"2026-02-23 16:04:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2712772,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/272aadf8-cc38-44d8-8da0-7056e8d52c16.pdf"},{"id":91654125,"identity":"ec396375-baa4-4cd3-9cc8-af78c4b36fd1","added_by":"auto","created_at":"2025-09-18 17:42:51","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":992201,"visible":true,"origin":"","legend":"","description":"","filename":"Sci.Rep.SupplementaryInformation17.08.2025.docx","url":"https://assets-eu.researchsquare.com/files/rs-7391364/v1/7860d34c8a611ca65294a7ec.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ultra-short pulse source of ionizing radiation with a dose rate of Gy/ps based on direct laser acceleration of electrons for studying the FLASH effect","fulltext":[{"header":"Introduction","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eFLASH radiotherapy\u003c/h2\u003e\u003cp\u003eModern radiotherapy employs high-energy photons, protons, and electrons to treat cancer, but collateral damage to healthy tissue remains a major clinical limitation. Low linear energy transfer (LET) radiation such as X-rays and electrons induces DNA damage predominantly through the radiolysis of water, leading to the formation of reactive oxygen species (ROS). The presence of oxygen in normal tissues amplifies this effect \u0026mdash; a phenomenon known as the oxygen effect \u0026mdash; which contributes to radiation-induced toxicities such as inflammation and fibrosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. To improve the therapeutic ratio, innovative approaches are being pursued to reduce normal tissue injury without compromising tumor control.\u003c/p\u003e\u003cp\u003eOne promising strategy is ultra-high dose-rate irradiation, known as FLASH radiotherapy, which delivers a therapeutic dose within a fraction of a second (typically\u0026thinsp;\u0026gt;\u0026thinsp;40 Gy/s). Preclinical studies have shown that FLASH can significantly spare normal tissue while maintaining tumor control \u0026mdash; a phenomenon referred to as the FLASH effect [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Although the underlying mechanisms are not fully understood, it is hypothesized that rapid radiolytic depletion of oxygen and altered ROS dynamics contribute to this transient radioresistance. Achieving FLASH-compatible dose rates remains a technical challenge with conventional accelerators, prompting interest in alternative delivery systems such as high-intensity laser-driven particle sources. The PHELIX laser (\u003cb\u003eP\u003c/b\u003eetawatt \u003cb\u003eH\u003c/b\u003eigh \u003cb\u003eE\u003c/b\u003energy \u003cb\u003eL\u003c/b\u003easer for Heavy \u003cb\u003eI\u003c/b\u003eon E\u003cb\u003ex\u003c/b\u003eperiments), for example, can generate ultra-short, high-dose electron of bursts, achieving instantaneous dose rates over 10 Gy/ps (10\u0026sup1;\u0026sup3; Gy/s) and absolute dose values of several tens of Gy, offering a unique platform to investigate FLASH effects under controlled conditions [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSince biological tissues consist primarily of water, radiation-induced chemical processes in vivo are largely mediated by water radiolysis and the subsequent formation of ROS, such as hydroxyl radicals (\u0026middot;OH), superoxide anions (O₂\u0026middot;⁻), and hydrogen peroxide (H₂O₂) [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These reactive species account for the majority of indirect radiation damage to DNA and other biomolecules. Importantly, aqueous solutions saturated with oxygen undergo similar radical chemistry and oxygen consumption dynamics as biological tissues during irradiation, making them a robust first approximation for studying oxygen-dependent radiochemical processes. This includes key phenomena relevant to FLASH, such as radiolytic oxygen depletion and transient shifts in ROS balance. Accordingly, the PHELIX experiments employ water and aqueous media as model systems to probe the fundamental chemistry underlying the FLASH effect and its potential biological implications.\u003c/p\u003e\u003cp\u003eThe results of this study \u0026mdash; assuming further improvements in dosimetric accuracy \u0026mdash; pave the way for benchmarking the chemical-stage predictions of Monte Carlo track-structure codes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], which simulate intricate reaction dynamics and offer valuable insights into the radiochemistry underlying the FLASH effect. Of particular interest is the role of inter-track radical recombination under ultra-high radiation intensities, a phenomenon that has been theoretically anticipated but remains experimentally unverified.\u003c/p\u003e\u003cp\u003eTypical benchmarking scenarios involve ultra-short irradiations in aqueous systems or solutions containing homogeneously distributed target molecules. However, experimental data under such conditions are scarce, especially in oxygenated environments, which are representative of biological systems. A major challenge lies in detecting measurable radical concentrations on sub-microsecond timescales \u0026mdash; the critical window for radiation-induced chemical transformations, see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eThe use of laser-accelerated electron bunches with durations on the order of 1 picosecond enables separation between the ultrafast ionization of oxygen \u0026mdash; occurring at the end of the physical stage and onset of the pre-chemical stage \u0026mdash; and the ensuing chemical reactions. This temporal decoupling presents a significant advantage for Monte Carlo simulations, such as those performed with the TRAX-CHEM code, which can model these conditions with high fidelity [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn this study, the depletion of dissolved oxygen during irradiation with a laser-driven electron beam (mean kinetic energy: 10 MeV) is quantitatively compared to TRAX-CHEM simulations as a function of delivered dose. Electron acceleration in low-density polymer foam targets, enabled by the 200 TW short-pulse PHELIX laser system [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], provides a unique platform for generating highly charged, collimated MeV-range electron beams capable of depositing several tens of Gy in biological targets within a single picosecond-scale laser shot.\u003c/p\u003e\u003cp\u003eThe amount of oxygen consumed during irradiation is directly linked to the yield of radiation-induced radical species and can therefore serve as a benchmark for Monte Carlo-based simulation tools. This approach contributes to a deeper understanding of the spatiotemporal complexity of radiation chemistry under ultra-high dose rate conditions.\u003c/p\u003e\u003cp\u003eHere, we demonstrate \u0026ndash; for the first time \u0026mdash; the applicability of this novel ionizing radiation source for radiochemical investigations. Specifically, we quantified the rate of oxygen consumption via the key reaction channels e\u003csub\u003eaq\u003c/sub\u003e⁻ + O\u003csub\u003e2\u003c/sub\u003e \u0026rarr; O\u003csub\u003e2\u003c/sub\u003e⁻ and H\u003cb\u003e\u0026middot;\u003c/b\u003e + O\u003csub\u003e2\u003c/sub\u003e \u0026rarr; HO\u003csub\u003e2\u003c/sub\u003e in both pure water and biologically relevant aqueous media at instantaneous dose rates of 50\u0026ndash;70 Gy/ps and per-shot doses of up to 50 Gy \u0026mdash; a uniquely high-value achievement in this context.\u003c/p\u003e\u003cp\u003e\u003cem\u003eDirect laser accelerated electrons as an ultra-high dose rate source of ionizing radiation.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eMultiple types of ionizing radiation, including particle and X-ray beams generated by conventional high-frequency (RF) accelerators, have been employed to investigate and demonstrate the FLASH effect, see Table\u0026nbsp;1 in [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Reported dose rates from these conventional sources \u0026mdash; including electron, proton, X-ray, and ion beams \u0026mdash; range from 40 Gy/s [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] to as high as 10⁹ Gy/s [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], with total doses of 10\u0026ndash;20 Gy being delivered over time spans from 10 nanoseconds to several hundred milliseconds.\u003c/p\u003e\u003cp\u003eAmong these different ionization sources, relativistic electron beams offer advantageous characteristics: higher energy deposition per unit path length compared to X-rays, while achieving more uniform volumetric energy deposition compared to protons and ions. Unlike conventional accelerator-based beams, which operate with pulse durations in the nanosecond to sub-second range, laser-driven sources are capable of producing particle and X-ray bursts on sub-picosecond timescales. This enables instantaneous dose rates that far exceed those achievable with standard technologies, thus offering new opportunities for exploring the biological and chemical underpinnings of the FLASH effect [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDirect laser acceleration (DLA) of electrons interacting with plasmas at near-critical electron densities (NCD) offers a promising mechanism for generating ultra-high dose rate ionizing radiation. When sub-picosecond laser pulses interact with NCD plasmas, DLA electrons with kinetic energies exceeding 7.5 MeV (approximately five times the ponderomotive potential) can be produced, exhibiting beam charges of several tens of nC, sub-picosecond pulse durations, and high directional stability [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These properties enable localized delivery of both high radiation doses and ultra-high dose rates within target materials.\u003c/p\u003e\u003cp\u003eAt the PHELIX facility, experiments conducted at moderate relativistic intensities (10\u0026sup1;⁹ W/cm\u0026sup2;) demonstrated the generation of DLA electron beams through the interaction of sub-ps laser pulses with pre-ionized, low-density polymer foam targets. Pre-ionization was achieved using an auxiliary nanosecond laser pulse, which converted the foam into plasma with electron densities approaching 6\u0026times;10\u0026sup2;⁰ cm⁻\u0026sup3; \u0026ndash; conditions suitable for effective DLA electron generation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eExperimental measurements and numerical simulations confirm that the DLA-generated electron beam is collimated within a half angle of 13\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg; and its energy distribution follows an exponential energy distribution characterized by an effective temperature in the range of 10\u0026ndash;15 MeV, which is an order of magnitude higher than those achieved with conventional solid-foil targets irradiated under comparable laser conditions. The picosecond duration of the electron pulse closely matches the laser pulse length, enabling temporally confined dose delivery.\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the experimental setup, including up to four 0.99 T magnetic spectrometers positioned at various angles relative to the laser axis (a), the measured electron spectra for 800\u0026thinsp;\u0026plusmn;\u0026thinsp;50 \u0026micro;m thick polymer foam targets with a mean density of 2 mg/cm\u0026sup3; (b) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Additionally, the angular distribution of electrons with energies exceeding 7.5 MeV was recorded using a cylindrical detector composed of three 3 mm steel layers interleaved with imaging plates (IP) (c) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The electron beam displays an exponential spectral shape with effective temperatures of approximately 13 MeV at \u0026minus;\u0026thinsp;10\u0026deg; and up to 16 MeV along the laser axis, confined within a solid angle of 0.1 sr in case of electrons with energies\u0026thinsp;\u0026gt;\u0026thinsp;7.5 MeV.\u003c/p\u003e\u003cp\u003eThe experiments performed at the PHELIX facility demonstrate that such DLA electron beams are capable of delivering radiation doses of 20\u0026ndash;50 Gy to aqueous or cellular targets within a single picosecond pulse. This temporal confinement provides a unique opportunity to distinguish between the immediate physical ionization of oxygen and the subsequent chemical reaction cascades. The unprecedented combination of high absolute dose and ultra-high dose rates exceeding 70 Gy/ps renders the resulting data exceptionally valuable for benchmarking Monte Carlo simulations of radiation chemistry under extreme conditions.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Experimental setup","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003ePrimary target and laser parameters\u003c/h2\u003e\u003cp\u003eThe experiment was conducted in single-shot mode at the PHELIX laser facility, Helmholtzzentrum GSI Darmstadt. A well-controlled nanosecond (ns) pulse with an intensity of ~\u0026thinsp;10\u0026sup1;\u0026sup3; W/cm\u0026sup2; (corresponding to 0.3% of E\u003csub\u003etot\u003c/sub\u003e in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) was first used to transform a foam target into a plasma with near-critical electron density (NCD), n\u003csub\u003ecr\u003c/sub\u003e = 10\u0026sup2;\u0026sup1; cm⁻\u0026sup3; for λ\u0026thinsp;=\u0026thinsp;1.053 \u0026micro;m. After a delay of 3\u0026ndash;5 ns, the main laser pulse, with a duration of 750\u0026thinsp;\u0026plusmn;\u0026thinsp;250 fs and an energy of 70\u0026thinsp;\u0026plusmn;\u0026thinsp;10 J (measured before the compressor), interacted with the plasma target. The measured laser energy within the FWHM of the focal spot was 20\u0026thinsp;\u0026plusmn;\u0026thinsp;2 J, corresponding to an intensity of ~\u0026thinsp;10\u0026sup1;⁹ W/cm\u0026sup2;. Nanosecond and sub-picosecond pulses were focused onto the target by the same off-axis parabolic mirror with a focal length of 150 cm (f/5). The foam targets were CHO polymer aerogels with an initial average density of 2\u0026ndash;5 mg/cm\u0026sup3; and a thickness of 300\u0026ndash;1500 \u0026micro;m, grown inside a copper washer with an inner diameter of 2.5 mm. In the case of full ionization of CHO-atoms, the electron density of the resulting plasma corresponds to 0.65n\u003csub\u003ecr\u003c/sub\u003e [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eSecondary targets for FLASH irradiation\u003c/h3\u003e\n\u003cp\u003eSecondary targets included various liquids such as deionized water, phosphate-buffered saline (PBS), cell culture medium (F-12 Nutrient Medium, or Ham\u0026rsquo;s F12), and lysed cells, which were placed in airtight cylindrical tanks suitable for vacuum operation. All samples were fully oxygenated prior to irradiation.\u003c/p\u003e\n\u003ch3\u003eExperimental setup for irradiation of the secondary targets\u003c/h3\u003e\n\u003cp\u003eThe schematic arrangement is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, with additional details in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea. DLA electrons irradiated the tank containing a water-like medium, which was positioned between two magnets providing a 0.4 T magnetic field. This configuration deflected electrons with energies below 7 MeV and ensured homogeneous irradiation of the tank, where O₂ concentration measurements were performed. A carbon collimator was employed to improve quasi-uniform irradiation conditions by absorbing low-energy electrons propagating at larger angles. The tank, with an internal volume of 5 \u0026times; 5 \u0026times; 5 mm\u0026sup3;, was equipped with a 2 mm diameter optical fiber connected to an oxygen meter located outside the target chamber. Further details are provided in the \u0026ldquo;Methods\u0026rdquo; section.\u003c/p\u003e\n\u003ch3\u003eReconstruction of the radiation dose inside the tank\u003c/h3\u003e\n\u003cp\u003eThe objective of the experiment was to establish a correlation between the decrease in O₂ concentration in the tank, induced by ultra-high flux laser-driven relativistic electrons, and the corresponding deposited dose. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents an example of the dose generated by relativistic electron beams penetrating a radiochromic film (RCF) for shot #9. In this case, DLA electrons were produced via the interaction of a PHELIX laser pulse, with an intensity of 10\u0026sup1;⁹ W/cm\u0026sup2;, with a 1000 \u0026micro;m CHO-foam target of 2 mg/cm\u0026sup3; density, pre-ionized by a nanosecond pulse. As direct dose measurements within the tank were not feasible, the dose was reconstructed using RCF data recorded outside the tank, along the electron beam path.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents a diagram of doses recorded on RCF#1 and RCF#2, averaged over a 5 \u0026times; 5 mm\u0026sup2; area corresponding to the tank position (blue box in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), for laser shots using foam targets with volume densities of 2\u0026ndash;5 mg/cm\u0026sup3; and thicknesses of 400\u0026ndash;1500 \u0026micro;m. Comparison of RCF#1 and RCF#2 data indicates that protons with initial energies exceeding 10 MeV dominate the signal at RCF#1 after passing through the shielding. The proton-induced dose on RCF#1 increases from approximately 50 Gy to 150 Gy with increasing foam areal density. The relative dose variation due to inhomogeneous distribution on RCF#1 in front of the tank ranged from 10\u0026ndash;40% across different laser shots, with the primary contribution from MeV protons.\u003c/p\u003e\u003cp\u003eOn RCF#2, located behind the tank, the dose originates from MeV electrons and soft X-rays, with relative deviations between 5% and 18% across different shots. In Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, laser shots are grouped by similar foam and laser pulse parameters; the average dose values and variation intervals (for RCF#2) are shown for each group.\u003c/p\u003e\u003cp\u003eDose differences within each group can be attributed to several factors: the laser energy before the compressor varied from 60 to 80 J between shots, and the focusing quality changed significantly over the course of the day due to heating of the Nd:glass gain medium. Both the energy and intensity of the laser pulse influence the charge of the DLA electrons and, consequently, the ionizing radiation dose.\u003c/p\u003e\u003cp\u003eRCF#2 and RCF#3 represent doses from DLA electrons emerging from the tank and exhibit the same trend with increasing foam areal density as RCF#1. The lateral shift of the RCF signal relative to the laser axis (see marked areas 1, 2 on RCF#2 and areas 4, 5 on RCF#3 in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) confirms the predominant role of electrons deflected in the 0.4 T static magnetic field. Protons with energies above 10 MeV, detected via the Time-of-Flight method [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], are fully stopped by the 2 mm-thick tank wall. For this reason, only the RCF#2 and RCF#3 signals were used for dose evaluation. Absolute calibration of EBT-3 and EBT-XD films was performed using an X-ray source.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn the experiment, simultaneous measurements of the O₂ concentration, the dose inside the tank, and the energy and angular distribution of the DLA electrons were not possible. Therefore, a reconstruction method was developed to estimate the dose at six selected positions on RCF#2 and RCF#3 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) by optimizing the assumed energy and angular distribution of the electrons.\u003c/p\u003e\u003cp\u003eFrom previous measurements (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]), the energy distribution of the DLA electrons can be approximated by an exponential function with two effective temperatures:\u003cdiv id=\"Equ1\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equ1\" name=\"EquationSource\"\u003e\n$$\\:f={\\frac{{d}^{2}N}{dE\\bullet\\:d\\varOmega\\:}|}_{\\alpha\\:}={N}_{0}\\left(\\lambda\\:\\bullet\\:exp\\left(-\\frac{E}{{T}_{1}}\\right)\\:+(1-\\lambda\\:)\\bullet\\:exp\\left(-\\frac{E}{{T}_{2}}\\right)\\right)\\bullet\\:exp\\left(-{\\left(\\frac{\\alpha\\:-{\\alpha\\:}_{0}}{\\varDelta\\:\\alpha\\:}\\right)}^{2}\\right)$$\u003c/div\u003e\u003cdiv class=\"EquationNumber\"\u003e1\u003c/div\u003e\u003c/div\u003e,\u003c/p\u003e\u003cp\u003ewhere \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{N}_{0}\\)\u003c/span\u003e\u003c/span\u003e (for E\u0026thinsp;\u0026gt;\u0026thinsp;2 MeV) is the total number of the DLA electrons, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\lambda\\:\\)\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\left(1-\\lambda\\:\\right)\\)\u003c/span\u003e\u003c/span\u003e are the fractions of electrons with effective temperatures \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{T}_{1}\\)\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{T}_{2}\\)\u003c/span\u003e\u003c/span\u003e, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}_{0}\\:\\)\u003c/span\u003e\u003c/span\u003eis the angle between the laser axis and the electron beam, and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\varDelta\\:\\alpha\\:\\)\u003c/span\u003e\u003c/span\u003e is the divergence parameter related to the half-angle of FWHM: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\varDelta\\:\\alpha\\:}_{1/2FWHM}=\\varDelta\\:\\alpha\\:\\bullet\\:\\sqrt{ln\\left(2\\right)}\\)\u003c/span\u003e\u003c/span\u003e (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e\u003cp\u003eAs a first step in dose evaluation for the secondary target, the parameters of Eq.\u0026nbsp;(\u003cspan refid=\"Equ1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) were taken from the reference shot in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Iterative optimization was then performed to determine the six parameters in Eq.\u0026nbsp;(\u003cspan refid=\"Equ1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) that yielded the best match between the calculated and measured doses at all six positions on RCF#2 and RCF#3 for each laser shot.\u003c/p\u003e\u003cp\u003eIt is important to note that the stopping powers for water (or water-like media), the RCF material (active and protective layers), and PEEK (tank wall material) are very similar, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ed in Methods. This similarity implies comparable doses inside the tank for different aqueous media, provided that the experimental conditions \u0026ndash; such as target-laser parameters and relative positioning of the primary and secondary targets \u0026ndash; remain unchanged.\u003c/p\u003e\u003cp\u003eThe irradiation dose was calculated based on the optimized electron energy distribution, ensuring the best agreement between measured RCF doses and the corresponding stopping power of the biological medium. Details of the reconstruction method are provided in \u0026ldquo;Supplementary Information\u0026rdquo;.\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eMeasurement of the O\u003csub\u003e2\u003c/sub\u003e concentration\u003c/h2\u003e\u003cp\u003eDuring the laser shots, a prompt decrease in the O₂ concentration was observed. An example of the recorded O₂ concentration drop is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea for irradiation of water with a beam of DLA electrons. This rapid oxygen depletion, induced by ultra-high dose rates, contrasts with the behavior at low dose rates, where a gradual decline is typically observed, as in the case of X-ray sources [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] The measurements were conducted with a time resolution of 1 s, as determined by the detector [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb presents the dependence of the O₂ concentration drop on the dose deposited by the DLA electrons. This dependence can be approximated by a linear fit with a slope of 0.33 \u0026micro;M/Gy (red line in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb), while the experimentally determined values are 0.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 \u0026micro;M/Gy for water and 0.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 \u0026micro;M/Gy for the culture medium. For these approximations, the point with coordinates (0, 0) was fixed.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eMonte Carlo track structure simulations, which can model the physical-chemical stage of electron and ion tracks in water, are useful for estimating radiochemical yields in the early stages of radiation-induced chemical evolution. In this work, the experimental results are compared with predictions of the TRAX-CHEM code [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This code calculates the yields of molecular species and radicals in oxygenated aqueous solutions and has been used to estimate molecular oxygen removal as a function of the dose delivered by 1 MeV electrons in sealed oxygenated solutions [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHowever, both the complexity of the underlying processes and technological limitations necessitate several assumptions and approximations when comparing simulations with experimental results. Most Monte Carlo codes assume that the dose is delivered instantaneously and that the entire track evolution is completed within the first microsecond. In contrast, irradiation times typically required in medical or FLASH accelerator facilities to achieve the high doses needed for measurable oxygen depletion are on the same order of magnitude \u0026ndash; or even longer \u0026ndash; than the simulated chemical stage timescale.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eOxygen depletion and tissue-sparing effects\u003c/h2\u003e\u003cp\u003eA leading hypothesis for the normal tissue-sparing effect observed at ultra-high dose rates is rapid oxygen depletion during the radiation pulse, which in turn reduces oxidative damage. When a FLASH dose is delivered almost instantaneously, local oxygen in tissues is consumed by radiation-induced radical reactions faster than it can be replenished by diffusion or blood flow [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This transient drop in oxygen tension is critical because oxygen is a potent radiosensitizer: under conventional dose rates, oxygen \u0026ldquo;fixes\u0026rdquo; DNA damage by forming peroxyl radicals, making oxygen-rich normal tissues highly susceptible to radiation injury [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In FLASH irradiation, the sudden hypoxia renders normal cells more radioresistant during the pulse, curtailing the yield of harmful ROS.\u003c/p\u003e\u003cp\u003eExperimental evidence strongly supports this mechanism. For example, FLASH-irradiated mouse brains were found to have significantly lower levels of ROS and hydrogen peroxide, with correspondingly less DNA damage in neurons and glia compared to brains irradiated at conventional dose rates [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In cell culture studies, human normal lung fibroblasts exposed to proton FLASH showed fewer senescent cells and lower TGF-β1 expression \u0026mdash; a marker of fibrosis and oxidative stress \u0026mdash; than cells exposed to the same dose at a standard dose rate [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Likewise, in mouse models, FLASH dramatically reduces classic radiation toxicity: Favaudon et al. reported that a 15\u0026ndash;20 Gy dose to the lungs caused severe fibrosis and activation of TGF-β pathways when delivered conventionally, but no lung fibrosis or complications when administered as a\u0026thinsp;\u0026lt;\u0026thinsp;1 s FLASH pulse [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSuch findings indicate that ultra-rapid dosing spares normal tissue by minimizing ongoing radical generation and damage fixation \u0026mdash; essentially outpacing the biological processes that normally amplify radiation injury. The implications for therapy are profound \u0026mdash; by blunting oxygen-dependent damage in healthy tissues, FLASH could allow for higher tumor doses or enable the treatment of tumors located near sensitive organs with far fewer side effects [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In other words, rapid oxygen depletion widens the therapeutic window of radiotherapy, as normal tissues tolerate ultra-high dose-rate exposure markedly better than conventional irradiation. The PHELIX study exemplifies these advantages: using a laser-driven beam, it achieves FLASH doses that spare normal cells via the oxygen depletion effect while still effectively ablating tumor cells. Going forward, this approach could transform clinical practice by enabling aggressive radiation treatments that maximize tumor kill while minimizing long-term damage to healthy tissue \u0026mdash; leveraging the unique radiobiology of FLASH to improve patient outcomes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, we propose the use of high-current directed beams of DLA electrons generated by the interaction of relativistic intense laser pulses with pre-ionized low-density polymer foams for studying the FLASH effect and its potential application in FLASH therapy.\u003c/p\u003e\u003cp\u003eRelativistic electron bursts provide higher energy deposition in matter compared to X-rays, are easier to transport and handle than protons, and maintain short pulse durations over long distances due to their relativistic energies.\u003c/p\u003e\u003cp\u003eHigh-current MeV electron beams, accelerated via direct laser acceleration, can deliver doses up to 1\u0026ndash;2 Gy per joule of focused laser energy per shot (20\u0026ndash;50 Gy for the PHELIX laser) at an unprecedented dose rate. The picosecond pulse duration allows separation of instantaneous oxygen ionization from subsequent chemical reactions. A sudden drop in oxygen saturation was observed in water and culture media during each laser shot, correlating with the delivered dose.\u003c/p\u003e\u003cp\u003eTherefore, this approach is unique and offers promising opportunities for benchmarking Monte Carlo track structure codes and for application in FLASH therapy, provided the accuracy of dose measurements is improved.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003cp\u003eA detailed schematic of the experimental setup is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea. To ensure uniform irradiation of the 5 mm diameter tank by DLA electrons, electrons with energies below 7 MeV were deflected using a static magnetic field of 0.4 T. This measure was crucial for performing O₂ concentration measurements under quasi-uniform irradiation conditions. Additionally, a carbon collimator was employed to attenuate low-energy electrons propagating at angles greater than 5\u0026deg; relative to the laser axis (see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe tank was shielded by three layers of EBT-3 radiochromic films (RCFs) to stop ions and protons (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eb). A 150 \u0026micro;m thick aluminum foil was used to attenuate soft X-rays. This shielding was sufficient to stop protons with energies up to 10 MeV and to reduce the X-ray signal at 6 keV to 10% of its initial intensity [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFor O₂ concentration measurements, an oxygen meter was used. It transmitted light at 505 nm through a 2 mm diameter optical fiber to a sensor spot (SP-Pst3-SA23-D5-OIW-US) containing luminophores [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The sensor spot was placed on the inner wall of the 5 \u0026times; 5 \u0026times; 5 mm\u0026sup3; tank filled with the medium, allowing light penetration (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ec). Due to photoluminescence quenching, oxygen molecules in the medium reduce luminescence from the sensor spot [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The resulting signal was sent back to the oxygen meter for analysis, which was connected to a PC for real-time data recording.\u003c/p\u003e\u003cp\u003eTo protect the PC and optical sensor from electromagnetic pulses during laser shots, both were housed inside a Faraday cage located adjacent to the target chamber. A remote connection to the PC was established via an internal network for control from the control room.\u003c/p\u003e\u003cp\u003eThe tank parts (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ec) were glued to ensure airtightness, allowing operation under vacuum conditions. The tank walls were made from polyetheretherketone (PEEK), a radiation- and chemically-resistant material that does not leach chemicals or oxygen when irradiated. Before sealing, the tank was completely filled with the sample, ensuring no air bubbles were trapped.\u003c/p\u003e\u003cp\u003eImportantly, the stopping powers of water (or water-like media), the active and protective layers of the RCFs, and PEEK are very similar, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ed. This similarity allows us to assume comparable doses within the tank for different contents, provided the experimental conditions \u0026ndash; such as target, laser parameters, and tank position \u0026ndash; are kept constant.\u003c/p\u003e\u003cp\u003e\u003cem\u003eGEANT4 simulation of dose distribution for the optimized experimental setup.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAn alternative design of the setup with the water tank, shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ea, allows avoiding complications caused by low-energy electrons (\u0026lt;\u0026thinsp;7 MeV), which carry the main beam charge, and protons with energies\u0026thinsp;\u0026le;\u0026thinsp;15 MeV in dose measurements inside and outside the tank \u0026ndash; eliminating the need for a magnetic deflection and enabling more precise dose determination within the irradiated medium.\u003c/p\u003e\u003cp\u003eIn this setup, one half of the tank contains the liquid samples, while the second, open part houses RCFs positioned on the left and right sides of the optical fiber. Both parts share common 2 mm thick PEEK walls and are separated by a sealed optical window (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ea).\u003c/p\u003e\u003cp\u003eDose distribution simulations induced by electrons in water were performed using the GEANT4 Monte Carlo code. The input parameters included electron energy and angular distributions measured during the interaction of a 10\u0026sup1;⁹ W/cm\u0026sup2; PHELIX laser pulse with pre-ionized, 2 mg/cm\u0026sup3;, 800 \u0026micro;m thick CHO-foam.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo achieve more homogeneous irradiation of the 5 mm diameter water tank by high-current DLA electrons, electrons were passed through 80 \u0026micro;m thick gold and 2 mm thick PEEK plates (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ea). These plates convert and scatter the low-energy electron fraction, reducing its dose contribution per solid angle and thus homogenizing the dose distribution within the water tank. The corresponding electron spectra are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eb.\u003c/p\u003e\u003cp\u003eRadiochromic films placed around the optical fiber recorded doses of 45 Gy (RCF#1) and 32 Gy (RCF#2), corresponding to an estimated dose of 39\u0026thinsp;\u0026plusmn;\u0026thinsp;3 Gy deposited in the water within the measurement area.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eAdditional information\u003c/h2\u003e\u003cp\u003e\u0026ldquo;Supplementary Information\u0026rdquo;. The online version contains supplementary material available at \u0026hellip;.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis work was funded by the German Ministry for Education and Research (BMBF) under contract No. 05P21SJFA2 and supported by the Czech Ministry of Education, Youth and Sports (Project No. CZ.02.2.69/0.0/0.0/18_053/0016980) and the Grant Agency of the Czech Republic (Grant No. GM23-05027M).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eO.N.R., S.Z., M.G. conceived and designed the experiment. Pha.K. developed the diagnostic for measurement of oxygen concentration. M.G. constructed and developed the construction for measurement of radiation dose from particles in a magnetic field. N.G.B. produced and prepared polymer foam targets. M.G., J.C., Pha.K., N.B., S.Z. and O.N.R. performed the experiment, M.G., Pha.K., M.H. and O.N.R. analyzed the data. M.H. and M.G. performed and guided python simulations, N.B. performed and guided simulations in GEANT4. M.G., O.N.R., V.F, M.F., D.B. wrote the manuscript with revisions by all co-authors. N.E.A. and O.N.R. provided overall supervision.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe results presented here are based on Experiment P213 performed at the PHELIX facility at the GSI Helmholtzzentrum f\u0026uuml;r Schwerionenforschung, Darmstadt, Germany, in the framework of FAIR Phase-0 in 2021. The authors are very grateful for the support provided by the PHELIX laser team. This work was funded by the German Ministry for Education and Research (BMBF) under contract No. 05P21SJFA2 and supported by the Czech Ministry of Education, Youth and Sports (Project No. CZ.02.2.69/0.0/0.0/18_053/0016980) and the Grant Agency of the Czech Republic (Grant No. GM23-05027M).The authors express their sincere gratitude to Martina K. Fuss and Daria Boscolo for their invaluable contributions to the development and realization of this project. Their expertise was instrumental to the success of this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting the plots of this article and other results of this study are available from the corresponding authors on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePrasanna, P. G. et al. Normal tissue injury induced by photon and proton therapies: Gaps and opportunities. \u003cem\u003eInt. J. Radiat. Oncol. Biol. Phys.\u003c/em\u003e \u003cb\u003e110\u003c/b\u003e (5), 1325\u0026ndash;1340. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ijrobp.2021.02.043\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2021.02.043\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGao, Y. et al. A potential revolution in cancer treatment: A topical review of FLASH radiotherapy. \u003cem\u003eJ. Appl. Clin. Med. Phys.\u003c/em\u003e \u003cb\u003e23\u003c/b\u003e (10), e13790. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/acm2.13790\u003c/span\u003e\u003cspan address=\"10.1002/acm2.13790\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFavaudon, V. et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. \u003cem\u003eSci. Translat Med.\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e, 245. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1126/scitranslmed.3008973\u003c/span\u003e\u003cspan address=\"10.1126/scitranslmed.3008973\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVozenin, M. C., Hendry, J. H. \u0026amp; Limoli, C. L. Biological benefits of ultrahigh dose rate FLASH radiother-apy: sleeping beauty awoken. \u003cem\u003eClin. Oncol.\u003c/em\u003e \u003cb\u003e31\u003c/b\u003e, 407\u0026ndash;415. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.clon.2019.04.001\u003c/span\u003e\u003cspan address=\"10.1016/j.clon.2019.04.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVozenin, M. C. et al. The advantage of FLASH confirmed in mini-pig and cat-cancer patientsю. \u003cem\u003eClin. Canc Res.\u003c/em\u003e \u003cb\u003e25\u003c/b\u003e, 35\u0026ndash;42. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1158/1078-0432.ccr-17-3375\u003c/span\u003e\u003cspan address=\"10.1158/1078-0432.ccr-17-3375\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMontay-Gruel, P. et al. Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species. \u003cem\u003eProc. Natl. Acad. Sci. USA\u003c/em\u003e 116, 10943\u0026ndash;10951. (2019). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1073/pnas.1901777116\u003c/span\u003e\u003cspan address=\"10.1073/pnas.1901777116\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAdrian, G. et al. The FLASH effect depends on oxygen concentration. \u003cem\u003eBrit J. Radiol.\u003c/em\u003e \u003cb\u003e93\u003c/b\u003e, 20190702. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1259/bjr.20190702\u003c/span\u003e\u003cspan address=\"10.1259/bjr.20190702\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBourhis, J. et al. Treatment of a first patient with FLASH-radiotherapy. \u003cem\u003eRadiother Oncol.\u003c/em\u003e \u003cb\u003e139\u003c/b\u003e, 18\u0026ndash;22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.radonc.2019.06.019\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2019.06.019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOrobeti, S. et al. First in vitro cell co-culture experiments using laser-induced high-energy electron FLASH irradiation for the development of anti-cancer therapeutic strategies. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e, 14866. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41598-024-65137-7\u003c/span\u003e\u003cspan address=\"10.1038/s41598-024-65137-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosmej, O. N. et al. High-current laser-driven beams of relativistic electrons for high energy density research. \u003cem\u003ePlasma Phys. Control Fusion\u003c/em\u003e. \u003cb\u003e62\u003c/b\u003e, 115024. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1088/1361-6587/abb24e\u003c/span\u003e\u003cspan address=\"10.1088/1361-6587/abb24e\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBoscolo, D., Kr\u0026auml;mer, M., Fuss, M. C., Durante, M. \u0026amp; Scifoni, E. Impact of Target Oxygenation on the Chemical Track Evolution of Ion and Electron Radiation. \u003cem\u003eInt. J. Mol. Sci.\u003c/em\u003e \u003cb\u003e21\u003c/b\u003e, 424. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/ijms21020424\u003c/span\u003e\u003cspan address=\"10.3390/ijms21020424\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBoscolo, D., Scifoni, E., Durante, M., Kr\u0026auml;mer, M. \u0026amp; Fuss, M. C. May oxygen depletion explain the FLASH effect? A chemical track structure analysis. \u003cem\u003eRadiother. Oncol.\u003c/em\u003e \u003cb\u003e162\u003c/b\u003e, 68\u0026ndash;75. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.radonc.2021.06.031\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2021.06.031\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosini, G., Ciarrocchi, E., Ciarrocchi, E. \u0026amp; D\u0026rsquo;Orsi, B. Mechanisms of the FLASH effect: current insights and advances. \u003cem\u003eFront Cell. Dev. Biol. : Sec Cancer Cell. Biology\u003c/em\u003e. \u003cb\u003e13\u003c/b\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fcell.2025.1575678\u003c/span\u003e\u003cspan address=\"10.3389/fcell.2025.1575678\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarshall, K. L., Velayutham, M., Khramtsov, V. V., Mizener, A. \u0026amp; Cifarelli, C. P. Enhancing radiation-induced reactive oxygen species generation through mitochondrial transplantation in human glioblastoma. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 7618. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41598-025-91331-2\u003c/span\u003e\u003cspan address=\"10.1038/s41598-025-91331-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWeber, U. A., Scifoni, E. \u0026amp; Durante, M. FLASH radiotherapy with carbon ion beams. \u003cem\u003eMed. Phys.\u003c/em\u003e \u003cb\u003e49\u003c/b\u003e, 1974\u0026ndash;1992. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/mp.15135\u003c/span\u003e\u003cspan address=\"10.1002/mp.15135\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosmej, O. N. et al. Interaction of relativistically intense laser pulses with long-scale near critical plasmas for optimization of laser based sources of MeV electrons and gamma-rays. \u003cem\u003eNew. J. Phys.\u003c/em\u003e \u003cb\u003e21\u003c/b\u003e, 043044. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1088/1367-2630/ab1047\u003c/span\u003e\u003cspan address=\"10.1088/1367-2630/ab1047\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eG\u0026uuml;nther, M. M. et al. Forward-looking insights in laser-generated ultra-intense γ-ray and neutron sources for nuclear application and science. \u003cem\u003eNat. Commun.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 170. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41467-021-27694-7\u003c/span\u003e\u003cspan address=\"10.1038/s41467-021-27694-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin, B. et al. Mechanisms of FLASH effect. \u003cem\u003eFront. Oncol.\u003c/em\u003e \u003cb\u003e12\u003c/b\u003e, 995612. https://doi.org/10.3389%2Ffonc.2022.995612 (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFouillade, C. et al. FLASH irradiation spares lung progenitor cells and limits the incidence of radio-induced senescence. \u003cem\u003eClin. Cancer Res.\u003c/em\u003e \u003cb\u003e26\u003c/b\u003e (6), 1497\u0026ndash;1506. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1158/1078-0432.ccr-19-1440\u003c/span\u003e\u003cspan address=\"10.1158/1078-0432.ccr-19-1440\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang, G. et al. Association of cancer stem cell radio-resistance under ultra-high dose rate FLASH irradiation with lysosome-mediated autophagy. \u003cem\u003eFront. Cell. Dev. Biol.\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e, 672693. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fcell.2021.672693\u003c/span\u003e\u003cspan address=\"10.3389/fcell.2021.672693\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKacem, H., Almeida, A., Cherbuin, N. \u0026amp; Vozenin, M. C. Understanding the FLASH effect to unravel the potential of ultra-high dose rate irradiation. \u003cem\u003eInt. J. Radiat. Biol.\u003c/em\u003e \u003cb\u003e98\u003c/b\u003e (3), 506\u0026ndash;516. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/09553002.2021.2004328\u003c/span\u003e\u003cspan address=\"10.1080/09553002.2021.2004328\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosmej, O. N. et al. Advanced plasma target from pre-ionized low-density foam for effective and robust direct laser acceleration of electrons. \u003cem\u003eHigh Power Laser Sci. Eng.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, e3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1017/hpl.2024.85\u003c/span\u003e\u003cspan address=\"10.1017/hpl.2024.85\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBorisenko, N. G. et al. Noizy low-density targets that worked as bright emitters under laser illumination. \u003cem\u003eJ. Phys. : Conf. Ser.\u003c/em\u003e \u003cb\u003e1692\u003c/b\u003e, 012026. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1088/1742-6596/1692/1/012026\u003c/span\u003e\u003cspan address=\"10.1088/1742-6596/1692/1/012026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosmej, O. N. et al. Bright betatron radiation from direct laser-accelerated electrons at moderate relativistic laser intensity. \u003cem\u003eMatter Radiat. Extremes\u003c/em\u003e. \u003cb\u003e6\u003c/b\u003e, 048401. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1063/5.0042315\u003c/span\u003e\u003cspan address=\"10.1063/5.0042315\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCikhardt, J. et al. Characterization of bright betatron radiation generated by direct laser acceleration of electrons in plasma of near critical density. \u003cem\u003eMatter Radiat. Extremes\u003c/em\u003e. \u003cb\u003e9\u003c/b\u003e, 027201. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1063/5.0181119\u003c/span\u003e\u003cspan address=\"10.1063/5.0181119\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaroon, P., Kobda, C., Talabnin, C. \u0026amp; Fuss, M. C. Experimental study of radiolytic oxygen depletion from X-ray irradiation in water and liquid samples. \u003cem\u003eRSU International Research Conference.\u003c/em\u003e (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.14458/RSU.res.2023.46\u003c/span\u003e\u003cspan address=\"10.14458/RSU.res.2023.46\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbolfath, R., Grosshans, D. \u0026amp; Mohan, R. Oxygen depletion in FLASH ultra-high-dose-rate radiotherapy: A molecular dynamics simulation. \u003cem\u003eMed. Phys.\u003c/em\u003e \u003cb\u003e47\u003c/b\u003e (12), 6551\u0026ndash;6561. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/mp.14548\u003c/span\u003e\u003cspan address=\"10.1002/mp.14548\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGSI Helmholtzzentrum f\u0026uuml;r Schwerionenforschung. Proton and, Carbon Ion, F. L. A. S. H. \u0026amp; Radiotherapy Online: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.gsi.de/work/forschung/biophysik/forschungsfelder/particle-therapie-physics/proton-and-carbon-ion-flash#:~:text=FLASH%20radiotherapy%20is%20considered%20a,and%20quantify%20the%20FLASH%20for\u003c/span\u003e\u003cspan address=\"https://www.gsi.de/work/forschung/biophysik/forschungsfelder/particle-therapie-physics/proton-and-carbon-ion-flash#:~:text=FLASH%20radiotherapy%20is%20considered%20a,and%20quantify%20the%20FLASH%20for\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed: July 7, 2025].\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBerger, M. J., Coursey, J. S., Zucker, M. A., Chang, J. \u0026amp; Stopping-Power \u0026amp; Range Tables for Electrons, Protons, and Helium Ions. (2017). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://dx.doi.org/10.18434/T4NC7P/\u003c/span\u003e\u003cspan address=\"10.18434/T4NC7P/\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHubbell, J. H. \u0026amp; Seltzer, S. M. X-Ray Mass Attenuation Coefficients (NIST Standard Reference Database 126). (1996). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nist.gov/pml/x-ray-mass-attenuation-coefficients\u003c/span\u003e\u003cspan address=\"https://www.nist.gov/pml/x-ray-mass-attenuation-coefficients\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAst, C., Schm\u0026auml;lzlin, E., L\u0026ouml;hmannsr\u0026ouml;ben, H. G. \u0026amp; Van Dongen, J. T. Optical Oxygen Micro- and Nanosensors for Plant Applications. \u003cem\u003eSensors\u003c/em\u003e \u003cb\u003e12\u003c/b\u003e (6), 7015\u0026ndash;7032. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/s120607015\u003c/span\u003e\u003cspan address=\"10.3390/s120607015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7391364/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7391364/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Results of the pilot experiment on the ultra-intense irradiation of the water phantom and various biological media with laser-driven beams of relativistic electrons in context of the FLASH effect are presented. Directed high-current beams of MeV electrons were generated by the interaction of sub-ps high-energy PHELIX laser pulses with low-density polymer foam, which was converted into a plasma of near-critical density by an additional nanosecond laser pulse. The combination of 20–50 Gy of ionizing radiation delivered by the relativistic electron beam in a single laser shot and the world's highest dose rate of 70 Gy/ps makes this source unique for studying the FLASH effect and for applications. The picosecond duration of the electron beam allows the separation of the process of ultrafast (instantaneous) oxygen ionization and the subsequent chemical reactions. In each laser shot, a sudden drop in oxygen saturation as a function of the delivered dose was measured in water and biological media. The dependence obtained is consistent with the results of the Monte Carlo simulation.","manuscriptTitle":"Ultra-short pulse source of ionizing radiation with a dose rate of Gy/ps based on direct laser acceleration of electrons for studying the FLASH effect","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-18 17:34:46","doi":"10.21203/rs.3.rs-7391364/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-06T11:56:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-02T05:54:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-30T08:27:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"24063615667264826456325437680047693599","date":"2025-09-17T21:16:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"12028193179857612355592113621279489510","date":"2025-09-15T08:47:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"200111308055504206435565668444096821186","date":"2025-09-12T06:54:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"171388524948271344139207373697411104125","date":"2025-09-11T07:34:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-10T06:33:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-01T05:47:40+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-01T05:10:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-20T16:55:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-08-20T16:53:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6a9d4a86-7919-407a-af33-1bbcd03a2a2c","owner":[],"postedDate":"September 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54904517,"name":"Physical sciences/Optics and photonics"},{"id":54904518,"name":"Physical sciences/Physics"}],"tags":[],"updatedAt":"2026-02-23T16:01:40+00:00","versionOfRecord":{"articleIdentity":"rs-7391364","link":"https://doi.org/10.1038/s41598-026-40281-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-02-17 15:58:11","publishedOnDateReadable":"February 17th, 2026"},"versionCreatedAt":"2025-09-18 17:34:46","video":"","vorDoi":"10.1038/s41598-026-40281-4","vorDoiUrl":"https://doi.org/10.1038/s41598-026-40281-4","workflowStages":[]},"version":"v1","identity":"rs-7391364","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7391364","identity":"rs-7391364","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}