A new platform for ultra-high dose rate radiobiological research using the BELLA PW laser proton beamline.
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ABSTRACT:
SUBMITTER: Bin J
PROVIDER: S-EPMC8795353 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThere is currently significant interest in assessing the role of oxygen in the radiobiological effects at ultra-high dose rates. Oxygen modulation is postulated to play a role in the enhanced sparing effect observed in FLASH radiotherapy, where particles are delivered at 40-1000 Gy/s. Furthermore, the development of laser-driven accelerators now enables radiobiology experiments in extreme regimes where dose rates can exceed 109 Gy/s, and predicted oxygen depletion effects on cellular response can be tested. Access to appropriate experimental enviroments, allowing measurements under controlled oxygenation conditions, is a key requirement for these studies. We report on the development and application of a bespoke portable hypoxia chamber specifically designed for experiments employing laser-driven sources, but also suitable for comparator studies under FLASH and conventional irradiation conditions.Materials and methodsWe used oxygen concentration measurements to test the induction of hypoxia and the maintenance capacity of the chambers. Cellular hypoxia induction was verified using hypoxia inducible factor-1α immunostaining. Calibrated radiochromic films and GEANT-4 simulations verified the dosimetry variations inside and outside the chambers. We irradiated hypoxic human skin fibroblasts (AG01522B) cells with laser-driven protons, conventional protons and reference 225 kVp X-rays to quantify DNA DSB damage and repair under hypoxia. We further measured the oxygen enhancement ratio for cell survival after X-ray exposure in normal fibroblast and radioresistant patient- derived GBM stem cells.ResultsOxygen measurements showed that our chambers maintained a radiobiological hypoxic environment for at least 45 min and pathological hypoxia for up to 24 h after disconnecting the chambers from the gas supply. We observed a significant reduction in the 53BP1 foci induced by laser-driven protons, conventional protons and X-rays in the hypoxic cells compared to normoxic cells at 30 min post-irradiation. Under hypoxic irradiations, the Laser-driven protons induced significant residual DNA DSB damage in hypoxic AG01522B cells compared to the conventional dose rate protons suggesting an important impact of these extremely high dose-rate exposures. We obtained an oxygen enhancement ratio (OER) of 2.1 ± 0.1 and 2.5 ± 0.1 respectively for the AG01522B and patient-derived GBM stem cells for X-ray irradiation using our hypoxia chambers.ConclusionWe demonstrated the design and application of portable hypoxia chambers for studying cellular radiobiological endpoints after exposure to laser-driven protons at ultra-high dose, conventional protons and X-rays. Suitable levels of reduced oxygen concentration could be maintained in the absence of external gassing to quantify hypoxic effects. The data obtained provided indication of an enhanced residual DNA DSB damage under hypoxic conditions at ultra-high dose rate compared to the conventional protons or X-rays.
| S-EPMC9013042 | biostudies-literature
Project description:Transmission beam (TB) proton therapy (PT) uses single, high energy beams with Bragg-peak behind the target, sharp penumbras and simplified planning/delivery. TB facilitates ultra-high dose-rates (UHDRs, e.g., ≥40 Gy/s), which is a requirement for the FLASH-effect. We investigated (1) plan quality for conventionally-fractionated head-and-neck cancer treatment using spot-scanning proton TBs, intensity-modulated PT (IMPT) and photon volumetric-modulated arc therapy (VMAT); (2) UHDR-metrics. VMAT, 3-field IMPT and 10-field TB-plans, delivering 70/54.25 Gy in 35 fractions to boost/elective volumes, were compared (n = 10 patients). To increase spot peak dose-rates (SPDRs), TB-plans were split into three subplans, with varying spot monitor units and different gantry currents. Average TB-plan organs-at-risk (OAR) sparing was comparable to IMPT: mean oral cavity/body dose were 4.1/2.5 Gy higher (9.3/2.0 Gy lower than VMAT); most other OAR mean doses differed by <2 Gy. Average percentage of dose delivered at UHDRs was 46%/12% for split/non-split TB-plans and mean dose-averaged dose-rate 46/21 Gy/s. Average total beam-on irradiation time was 1.9/3.8 s for split/non-split plans and overall time including scanning 8.9/7.6 s. Conventionally-fractionated proton TB-plans achieved comparable OAR-sparing to IMPT and better than VMAT, with total beam-on irradiation times <10s. If a FLASH-effect can be demonstrated at conventional dose/fraction, this would further improve plan quality and TB-protons would be a suitable delivery system.
| S-EPMC8070061 | biostudies-literature
Project description:FLASH-radiotherapy may provide significant sparing of healthy tissue through ultra-high dose rates in protons, electrons, and x-rays while maintaining the tumor control. Key factors for the FLASH effect might be oxygen depletion, the immune system, and the irradiated blood volume, but none could be fully confirmed yet. Therefore, further investigations are necessary. We investigated the protective (tissue sparing) effect of FLASH in proton treatment using an in-vivo mouse ear model. The right ears of Balb/c mice were irradiated with 20 MeV protons at the ion microprobe SNAKE in Garching near Munich by using three dose rates (Conv = 0.06 Gy/s, Flash9 = 9.3 Gy/s and Flash930 = 930 Gy/s) at a total dose of 23 Gy or 33 Gy. The ear thickness, desquamation, and erythema combined in an inflammation score were measured for 180 days. The cytokines TGF-β1, TNF-α, IL1α, and IL1β were analyzed in the blood sampled in the first 4 weeks and at termination day. No differences in inflammation reactions were visible in the 23 Gy group for the different dose rates. In the 33 Gy group, the ear swelling and the inflammation score for Flash9 was reduced by (57 ± 12) % and (67 ± 17) % and for Flash930 by (40 ± 13) % and (50 ± 17) % compared to the Conv dose rate. No changes in the cytokines in the blood could be measured. However, an estimation of the irradiated blood volume demonstrates, that 100-times more blood is irradiated when using Conv compared to using Flash9 or Flash930. This indicates that blood might play a role in the underlying mechanisms in the protective effect of FLASH.
| S-EPMC10791610 | biostudies-literature
Project description:Intense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. Here we experimentally show the successful implementation of a highly efficient (50% transmission) and tuneable dual pulsed solenoid setup to generate a homogeneous (laterally and in depth) volumetric dose distribution (cylindrical volume of 5 mm diameter and depth) at a single pulse dose of 0.7 Gy via multi-energy slice selection from the broad input spectrum. The experiments were conducted at the Petawatt beam of the Dresden Laser Acceleration Source Draco and were aided by a predictive simulation model verified by proton transport studies. With the characterised beamline we investigated manipulation and matching of lateral and depth dose profiles to various desired applications and targets. Using an adapted dose profile, we performed a first proof-of-technical-concept laser-driven proton irradiation of volumetric in-vitro tumour tissue (SAS spheroids) to demonstrate concurrent operation of laser accelerator, beam shaping, dosimetry and irradiation procedure of volumetric biological samples.
| S-EPMC7272427 | biostudies-literature
Project description:Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4-8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is often a lot of normal tissue within the planning target volume (PTV). We investigated WBI plan quality and determined FLASH-dose for various machine settings using ultra-high dose rate (UHDR) proton transmission beams (TBs). While five-fraction WBI is commonplace, a potential FLASH-effect might facilitate shorter treatments, so hypothetical 2- and 1-fraction schedules were also analyzed. Using one tangential 250 MeV TB delivering 5 × 5.7 Gy, 2 × 9.74 Gy or 1 × 14.32 Gy, we evaluated: (1) spots with equal monitor units (MUs) in a uniform square grid with variable spacing; (2) spot MUs optimized with a minimum MU-threshold; and (3) splitting the optimized TB into two sub-beams: one delivering spots above an MU-threshold, i.e., at UHDRs; the other delivering the remaining spots necessary to improve plan quality. Scenarios 1-3 were planned for a test case, and scenario 3 was also planned for three other patients. Dose rates were calculated using the pencil beam scanning dose rate and the sliding-window dose rate. Various machine parameters were considered: minimum spot irradiation time (minST): 2 ms/1 ms/0.5 ms; maximum nozzle current (maxN): 200 nA/400 nA/800 nA; two gantry-current (GC) techniques: energy-layer and spot-based. For the test case (PTV = 819 cc) we found: (1) a 7 mm grid achieved the best balance between plan quality and FLASH-dose for equal-MU spots; (2) near the target boundary, lower-MU spots are necessary for homogeneity but decrease FLASH-dose; (3) the non-split beam achieved >95% FLASH for favorable (not clinically available) machine parameters (SB GC, low minST, high maxN), but <5% for clinically available settings (EB GC, minST = 2 ms, maxN = 200 nA); and (4) splitting gave better plan quality and higher FLASH-dose (~50%) for available settings. The clinical cases achieved ~50% (PTV = 1047 cc) or >95% (PTV = 477/677 cc) FLASH after splitting. A single UHDR-TB for WBI can achieve acceptable plan quality. Current machine parameters limit FLASH-dose, which can be partially overcome using beam-splitting. WBI FLASH-RT is technically feasible.
| S-EPMC10177419 | biostudies-literature
Project description:The increasing use of proton radiotherapy during the last decade and the rising number of long-term survivors has given rise to a vital discussion on potential effects on normal tissue. So far, deviations from clinically applied generic RBE (relative biological effectiveness) of 1.1 were only obtained by in vitro studies, whereas indications from in vivo trials and clinical studies are rare. In the present work, wildtype zebrafish embryos (Danio rerio) were used to characterize the effects of plateau and mid-SOBP (spread-out Bragg peak) proton radiation relative to that induced by clinical MV photon beam reference. Based on embryonic survival data, RBE values of 1.13 ± 0.08 and of 1.20 ± 0.04 were determined four days after irradiations with 20 Gy plateau and SOBP protons relative to 6 MV photon beams. These RBE values were confirmed by relating the rates of embryos with morphological abnormalities for the respective radiation qualities and doses. Besides survival, the rate of spine bending, as one type of developmental abnormality, and of pericardial edema, as an example for acute radiation effects, were assessed. The results revealed that independent on radiation quality both rates increased with time approaching almost 100% at the 4th day post irradiation with doses higher than 15 Gy. To sum up, the applicability of the zebrafish embryo as a robust and simple alternative model for in vivo characterization of radiobiological effects in normal tissue was validated and the obtained RBE values are comparable to previous finding in animal trials.
| S-EPMC6224071 | biostudies-literature
Project description:BackgroundLaser acceleration of protons and heavy ions may in the future be used in radiation therapy. Laser-driven particle beams are pulsed and ultra high dose rates of >10⁹ Gy s⁻¹ may be achieved. Here we compare the radiobiological effects of pulsed and continuous proton beams.MethodsThe ion microbeam SNAKE at the Munich tandem accelerator was used to directly compare a pulsed and a continuous 20 MeV proton beam, which delivered a dose of 3 Gy to a HeLa cell monolayer within < 1 ns or 100 ms, respectively. Investigated endpoints were G2 phase cell cycle arrest, apoptosis, and colony formation.ResultsAt 10 h after pulsed irradiation, the fraction of G2 cells was significantly lower than after irradiation with the continuous beam, while all other endpoints including colony formation were not significantly different. We determined the relative biological effectiveness (RBE) for pulsed and continuous proton beams relative to x-irradiation as 0.91 ± 0.26 and 0.86 ± 0.33 (mean and SD), respectively.ConclusionsAt the dose rates investigated here, which are expected to correspond to those in radiation therapy using laser-driven particles, the RBE of the pulsed and the (conventional) continuous irradiation mode do not differ significantly.
| S-EPMC3215966 | biostudies-literature
Project description:Radiation therapy, one of the most effective therapies to treat cancer, is highly toxic to healthy tissue. The delivery of radiation at ultra-high dose rates, FLASH radiation therapy (FLASH), has been shown to maintain therapeutic anti-tumor efficacy while sparing normal tissues compared to conventional dose rate irradiation (CONV). Though promising, these studies have been limited mainly to murine models. Here, we leveraged enteroids, three-dimensional cell clusters that mimic the intestine, to study human-specific tissue response to radiation. We observed enteroids have a greater colony growth potential following FLASH compared with CONV. In addition, the enteroids that reformed following FLASH more frequently exhibited proper intestinal polarity. While we did not observe differences in enteroid damage across groups, we did see distinct transcriptomic changes. Specifically, the FLASH enteroids upregulated the expression of genes associated with the WNT-family, cell-cell adhesion, and hypoxia response. These studies validate human enteroids as a model to investigate FLASH and provide further evidence supporting clinical study of this therapy. Insight Box Promising work has been done to demonstrate the potential of ultra-high dose rate radiation (FLASH) to ablate cancerous tissue, while preserving healthy tissue. While encouraging, these findings have been primarily observed using pre-clinical murine and traditional two-dimensional cell culture. This study validates the use of human enteroids as a tool to investigate human-specific tissue response to FLASH. Specifically, the work described demonstrates the ability of enteroids to recapitulate previous in vivo findings, while also providing a lens through which to probe cellular and molecular-level responses to FLASH. The human enteroids described herein offer a powerful model that can be used to probe the underlying mechanisms of FLASH in future studies.
2024-09-16 | GSE275276 | GEO
Project description:The achievable energy and the stability of accelerated electron beams have been the most critical issues in laser wakefield acceleration. As laser propagation, plasma wave formation and electron acceleration are highly nonlinear processes, the laser wakefield acceleration (LWFA) is extremely sensitive to initial experimental conditions. We propose a simple and elegant waveform control method for the LWFA process to enhance the performance of a laser electron accelerator by applying a fully optical and programmable technique to control the chirp of PW laser pulses. We found sensitive dependence of energy and stability of electron beams on the spectral phase of laser pulses and obtained stable 2-GeV electron beams from a 1-cm gas cell of helium. The waveform control technique for LWFA would prompt practical applications of centimeter-scale GeV-electron accelerators to a compact radiation sources in the x-ray and ?-ray regions.
| S-EPMC5579019 | biostudies-literature
Project description:IntroductionCell repair dynamics are crucial in optimizing anti-cancer therapies. Various assays (eg, comet assay and γ-H2AX) assess post-radiation repair kinetics, but interpreting such data is challenging and model-based data analyses are required. However, ambiguities in parameter calibration remain an unsolved challenge. To address this, we propose combining survival dose-rate effects with computer simulations to gain knowledge about repair kinetics.MethodsAfter a literature review, theoretical discriminators based on common fractionation/dose-rate-related effects were defined to discard unrealistic model dynamics. The Multi-Hit Repair (MHR) model was calibrated with canine osteosarcoma Abrams cell line data to study the discriminators' efficacy in scenarios with limited survival data. Additionally, survival dose-rate-dependent data from the human SiHa cervical cancer cell line were used to illustrate the survival behavior at diverse dose-rates and the capability of the MHR to model these data.ResultsSiHa data confirmed the validity of the proposed discriminators. The discriminators filtered 99% of parameter sets, improving the calibration of Abrams cells data. Furthermore, results from both cell lines may hint universal aspects of cellular repair.ConclusionsDose-rate theoretical discrimination criteria are an effective method to understand repair kinetics and improve radiobiological model calibration. Moreover, this methodology may be used to analyze diverse biological data using dynamic models in-silico.
| S-EPMC11367615 | biostudies-literature