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After the rediscovery of the normal tissue sparing effect of high dose rate radiation, i.e. the so-called FLASH effect, by Favaudon et al. in 2014, research activities on this topic have been revived and are flourishing ever since. Yet, the exact biological mechanism as well as the required boundary conditions and radiation qualities to reach said sparing remain mostly unclear. We present a laser-based irradiation platform at the Draco PW facility that enables systematic studies into the FLASH regime using proton peak dose rates of up to 10^9 Gy/s. Besides the PW class laser acceleration source, a key component is a pulsed high-field beamline to transport and shape the laser driven proton bunches spectrally and spatially in order to generate homogeneous dose distributions tailored to match the irradiation sample. Making use of the diverse capabilities of the laser driven irradiation platform a pilot experiment of highest complexity has been conducted – a systematic in-vivo tumor irradiation in a specifically developed mouse model. A plethora of online particle diagnostics, including Time-of-Flight, bulk scintillators and screens as well as ionization chambers, in conjunction with diagnostics for retrospective absolute dosimetry (radiochromic films) allowed for an unprecedented level of precision in mean dose delivery (±10 %) and dose homogeneity (±5 %) for the challenging beam qualities of a laser accelerator. The tailored detector suite is complemented by predictive simulations. The talk addresses how our interdisciplinary team overcame all hurdles from animal model development, over enhancing the laser and laser acceleration stability, to dose delivery and online dose monitoring. Results on radiation induced tumor growth delay by laser driven as well as conventionally accelerated proton beams are critically discussed.

Laser-driven proton pulse provide unique properties in terms of pulse structure (ns) and instantaneous dose rate (10^9 Gy/s) but - inherently broadband and highly divergent - pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for three-dimensional cases. We present the successful implementation and characterisation of a highly efficient and tuneable dual pulsed solenoid beamline at the Draco PW facility[1] to generate volumetric dose distribution tailored to specific applications[2]. The vast experimental scope and already successfully performed studies range from systematic volumetric in-vivo tumour irradiations in a dedicated mouse model (with a stable mean dose delivery of ±10 % and a spatial dose homogeneity of ±5 % over a cylindrical volume of 5 mm diameter and height) to high-dose-rate irradiations in the FLASH regime (using proton peak dose rates of up to 10^9 Gy/s with about 20 Gy/shot homogeneously over a cylindrical sample volume of 4.5 mm diameter and 3 mm height) as well as particle diagnostics commissioning (with a multitude of spatial and spectral dose distributions). The beamline setup is complemented by a complex beam monitoring and dosimetry detector suite adapted to the ultra-high dose rate pulses and is in its unique synergy and redundancy capable of %-level precision dose delivery to samples as required for systematic irradiation studies. In addition to established radiochromic film dosimetry, the detector suite includes saturation-corrected (transmission) ionisation chambers [3] as well as screen and bulk scintillator setups, partly with tomographic reconstruction capabilities for 3D dose distribution retrieval. Moreover, non-invasive, single-shot-capable online time-of-flight-based spectral characterisation of filtered proton pulses has proven a powerful tool for beam monitoring as well as dosimetric purposes. In this presentation the complex and versatile dose delivery system of laser-driven protons at the Draco PW using pulsed solenoids will be discussed. Its characterisation, technological development and improvement as well as the dosimetry suite as a vital part of the precise dose delivery will be addressed, while the presentation by U. Schramm covers recent experimental activities in detail. [1] T. Ziegler, et al., Proton beam quality enhancement by spectral phase control of a PW-class laser system, https://arxiv.org/abs/2007.11499 (2020) [2] Brack, et al., Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline, SciRep, 10:9118, (2020) [3] Gotz M, et al., A new model for volume recombination in plane‐parallel chambers in pulsed fields of high dose‐per‐pulse. Phys Med Biol., 62: 8634, (2017)

In many species, social communication and mate choice are influenced by olfactory cues associated with the major histocompatibility complex (MHC). It has been reported that humans also respond to olfactory signals related to the human MHC-equivalent, the Human Leucocyte Antigen (HLA)-System, and exhibit an olfactory-mediated preference for potential mating partners with a dissimilar, disassortative, HLA-type compared to their own. The aim of this study was to investigate whether HLA-associated peptides, presented as volatile cues, elicit neuronal responses at the receptors in the human olfactory epithelium and can be consciously perceived. To this end the discrimination ability for peptides was tested in a 3-alternative forced choice model. Furthermore electro-olfactograms of the olfactory epithelium and EEG-derived chemosensory event related potentials were recorded using precisely controlled olfactometric stimulation with peptides and control odors. Based on responses from 52 young, healthy participants the peptides could not be discriminated and the electrophysiological signals provided no evidence for a specific response to the peptides which was in contrast to the control odors. In conclusion, within the current setup the results suggest that HLA-associated peptides do not produce specific olfactory activation in humans. (C) 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

Background and purpose In consequence of a previous study, where no protecting proton Flash effect was found for zebrafish embryos, potential reasons and requirements for inducing a Flash effect should be investigated with higher pulse dose rate and partial oxygen pressure (pO2) as relevant parameters. Materials and methods The experiments were performed at the research electron accelerator ELBE, whose variable pulse structure enables dose delivery as electron Flash and quasi-continuously (reference irradiation). Zebrafish embryos were irradiated with ~26 Gy either continuously at a dose rate of ~6.7 Gy/min (reference) or by 1441 electron pulses within 111 µs at a pulse dose rate of 109 Gy/s and a mean dose rate of 105Gy/s, respectively. Using the OxyLite system to measure the pO2 a low- (pO2 ≤ 5 mmHg) and a high-pO2 group were defined on basis of the oxygen depletion kinetics in sealed embryo samples. Results A protective Flash effect was seen for most endpoints ranging from 4 % less reduction in embryo length to about 20–25% less embryos with spinal curvature and pericardial edema, relative to reference irradiation. The reduction of pO2 below atmospheric levels (148 mmHg) resulted in higher protection, which was however more pronounced in the low-pO2 group. Conclusion The Flash experiment at ELBE showed that the zebrafish embryo model is appropriate for studying the radiobiological response of high dose rate irradiation. The applied high pulse dose rate was confirmed as important beam parameter as well as the pivotal role of pO2 during irradiation.

Background and purpose Motivated by first animal trials showing the normal tissue protecting effect of electron and photon Flash irradiation relative to conventional continuous beam delivery, the feasibility of proton Flash should be assessed. Materials and methods A setup and beam parameter settings for the treatment of zebrafish embryo with proton Flash and proton beam of conventional dose rate were established at the University Proton Therapy Dresden. Zebrafish embryos were treated with graded doses and the differential effect on embryonic survival and the induction of morphological malformations was followed for up to four days after irradiation. Results Beam parameters for the realization of proton Flash were set and tested with respect to controlled dose delivery to biological samples. The dose dependent embryonic survival data obtained for protons delivered as Flash and with a beam of conventional dose rate of 5 Gy/min show not significant influence of proton dose rate. Similarly, just a trend towards a protective effect of proton Flash was revealed for the induction of pericardial oedema as one type of acute radiation effect and spinal curvature as a developmental abnormality. Conclusion The feasibility of Flash proton irradiation was successfully shown, whereas more experiments are required to understand the absence of a clear protecting effect and therefore to figure out the limits and requirements for the Flash effect.

Regarding the long-term goal to develop and establish laser-based particle accelerators for a future radiotherapeutic treatment of cancer, the radiobiological consequences of the characteristic short intense particle pulses with ultra-high peak dose rate, but low repetition rate of laser-driven beams have to be investigated. This work presents in vitro experiments performed at the radiation source ELBE (Electron Linac for beams with high Brilliance and low Emittance). This accelerator delivered 20-MeV electron pulses with ultra-high pulse dose rate of 10(10) Gy/min either at the low pulse frequency analogue to previous cell experiments with laser-driven electrons or at high frequency for minimizing the prolonged dose delivery and to perform comparison irradiation with a quasi-continuous electron beam analogue to a clinically used linear accelerator. The influence of the different electron beam pulse structures on the radiobiological response of the normal tissue cell line 184A1 and two primary fibroblasts was investigated regarding clonogenic survival and the number of DNA double-strand breaks that remain 24 h after irradiation. Thereby, no considerable differences in radiation response were revealed both for biological endpoints and for all probed cell cultures. These results provide evidence that the radiobiological effectiveness of the pulsed electron beams is not affected by the ultra-high pulse dose rates alone.

Author(s): Brack, Florian-Emanuel; Kroll, Florian; Gaus, Lennart; Bernert, Constantin; Beyreuther, Elke; Cowan, Thomas E; Karsch, Leonhard; Kraft, Stephan; Kunz-Schughart, Leoni A; Lessmann, Elisabeth; Metzkes-Ng, Josefine; Obst-Huebl, Lieselotte; Pawelke, Jorg; Rehwald, Martin; Schlenvoigt, Hans-Peter; Schramm, Ulrich; Sobiella, Manfred; Szabo, Emilia Rita; Ziegler, Tim; Zeil, Karl | Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In line with the long-term aim of establishing the laser-based particle acceleration for future medical application, the radiobiological consequences of the typical ultra-short pulses and ultra-high pulse dose rate can be investigated with electron delivery.The radiation source ELBE (Electron Linac for beams with high Brilliance and low Emittance) was used to mimic the quasi-continuous electron beam of a clinical linear accelerator (LINAC) for comparison with electron pulses at the ultra-high pulse dose rate of 10(10) Gy min(-1) either at the low frequency of a laser accelerator or at 13 MHz avoiding effects of prolonged dose delivery. The impact of pulse structure was analyzed by clonogenic survival assay and by the number of residual DNA double-strand breaks remaining 24 h after irradiation of two human squamous cell carcinoma lines of differing radiosensitivity.The radiation response of both cell lines was found to be independent from electron pulse structure for the two endpoints under investigation.The results reveal, that ultra-high pulse dose rates of 10(10) Gy min(-1) and the low repetition rate of laser accelerated electrons have no statistically significant influence (within the 95% confidence intervals) on the radiobiological effectiveness of megavoltage electrons.

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Laser particle acceleration/Laser radiotherapy/Cell response to electrons/Pulsed irradiation. The notable progress in laser particle acceleration techn ology promises potential medical application in cancer therapy through compact and cost effective laser devices that are suitable for already existing clinics. Previously, consequences on the radiobiological response by laser driven particle beams characterised by an ultra high peak dose rate have to be inves tigated. Therefore, tumour and non-malignant cells were irradiated with pulsed laser accelerated electrons at the JETI facility for the comparison with continuous electrons of a conventional therapy LINAC. Dose res ponse curves were measured for the biological endpoints clonogenic survival and residual DNA double strand breaks. The overall results show no significant differences in radiobiological response for in vitro cell experiments between laser accelerated pulsed and clinical used electron beams. These first systematic in vitro cell response studies with precise dosimetry to laser driven electron beams represent a first s tep toward the long term aim of the application of laser accelerated particles in radiotherapy.

Purpose: In recent years, laser-based acceleration of charged particles has rapidly progressed and medical applications, e.g., in radiotherapy, might become feasible in the coming decade. Requirements are monoenergetic particle beams with long-term stable and reproducible properties as well as sufficient particle intensities and a controlled delivery of prescribed doses at the treatment site. Although conventional and laser-based particle accelerators will administer the same dose to the patient, their different time structures could result in different radiobiological properties. Therefore, the biological response to the ultrashort pulse durations and the resulting high peak dose rates of these particle beams have to be investigated. The technical prerequisites, i.e., a suitable cellirradiation setup and the precise dosimetric characterization of a laser-based particle accelerator, have to be realized in order to prepare systematic cellirradiation experiments. Methods: The Jena titanium:sapphire laser system (JETI) was customized in preparation for cellirradiation experiments with laser-accelerated electrons. The delivered electron beam was optimized with regard to its spectrum, diameter, dose rate, and dose homogeneity. A custom-designed beam and dose monitoring system, consisting of a Roos ionization chamber, a Faraday cup, and EBT-1 dosimetry films, enables real-time monitoring of irradiation experiments and precise determination of the dose delivered to the cells. Finally, as proof-of-principle experiment cell samples were irradiated using this setup. Results: Laser-accelerated electron beams, appropriate forin vitro radiobiological experiments, were generated with a laser shot frequency of 2.5 Hz and a pulse length of 80 fs. After laser acceleration in the helium gas jet, the electrons were filtered by a magnet, released from the vacuum target chamber, and propagated in air for a distance of 220 mm. Within this distance a lead collimator (aperture of 35 mm) was introduced, leading, along with the optimized setup, to a beam diameter of 35 mm, sufficient for the irradiation of common cell culture vessels. The corresponding maximum dose inhomogeneity over the beam spot was less than 10% for all irradiated samples. At cell position, the electrons posses a mean kinetic energy of 13.6 MeV, a bunch length of about 5 ps (FWHM), and a mean pulse dose of 1.6 mGy/bunch. Cross correlations show clear linear dependencies for the online recorded accumulated bunch charges, pulse doses, and pulse numbers on absolute doses determined with EBT-1 films. Hence, the established monitoring system is suitable for beam control and a dedicated dose delivery. Additionally, reasonable day-to-day stable and reproducible properties of the electron beam were achieved. Conclusions: Basic technical prerequisites for future cellirradiation experiments with ultrashort pulsed laser-accelerated electrons were established at the JETI laser system. The implemented online control system is suitable to compensate beam intensity fluctuations and the achieved accuracy of dose delivery to the cells is sufficient for radiobiological cell experiments. Hence, systematicin vitrocellirradiation experiments can be performed, being the first step toward clinical application of laser-accelerated particles. Further steps, including the transfer of the established methods to experiments on higher biological systems or to other laser-based particle accelerators, will be prepared.

The application of ionising radiation for medical purposes requires the investigation of induced and persistent DNA damages, especially for soft X-rays that are assumed to be more effective than higher energy photons. Therefore, we examined the energy dependent time and dose response of residual DNA damage foci for soft X-rays in comparison to 200 kV photons.DNA damage present in cell line 184A1 within 48 h after irradiations with 10 kV, 25 kV and 200 kV photons was analysed by immunochemical detection of co-localised gamma-H2AX (phosphorylated histone H2AX) and 53BP1 (tumour protein 53 binding protein) foci.The dose dependencies of the colocated foci revealed significant energy dependent differences with increasing amounts of residual foci at decreasing X-ray energy independent on postirradiation time. Dose-dependent RBE (relative biological effectiveness) values ranging from 4 to 7 were determined for 10 kV relative to 200 kV X-rays based on the 24 hour dose responses. For 25 kV photons, ratios considerably higher than one were obtained only for doses above 2 Gy.The expected energy dependence with increasing DNA damage at decreasing photon energy was confirmed for the residual co-localised foci measured at different time points after irradiation.

The dependence of relative biological effectiveness (RBE) on photon energy is a topic of extensive discussions. The increasing amount of in vitro data in the low-energy region indicates this to be a complex dependence that is influenced by the end point and cell line studied. In the present investigation, the RBE of 10 kV X rays (W anode) was determined relative to 200 kV X rays (W anode, 0.5 mm copper filter) for cell survival in the dose range 1-10 Gy and for induction of micronuclei in the range 0.5-3.6 Gy for MCF-12A human mammary epithelial cells. The RBE for cell survival was found to increase with decreasing dose, being 1.21+/-0.03 at 10% survival. Considerably higher values were obtained for micronucleus induction, where the RBE(M) obtained from the ratio of the linear coefficients of the dose-effect curves was 2.6+/-0.4 for the fraction of binucleated cells with micronuclei and 4.1+/-1.0 for the number of micronuclei per binucleated cell. These values, together with our previous data, support a monotonic increase in RBE with decreasing photon energy down to the mean energy of 7.3 keV used in the present study.

The long-term goal to integrate laser-based particle accelerators into radiotherapy clinics not only requires technological development of high-intensity lasers and new techniques for beam detection and dose delivery, but also characterization of the biological consequences of this new particle beam quality, i.e. ultra-short, ultra-intense pulses. In the present work, we describe successful in vivo experiments with laser-driven electron pulses by utilization of a small tumour model on the mouse ear for the human squamous cell carcinoma model FaDu. The already established in vitro irradiation technology at the laser system JETI was further enhanced for 3D tumour irradiation in vivo in terms of beam transport, beam monitoring, dose delivery and dosimetry in order to precisely apply a prescribed dose to each tumour in full-scale radiobiological experiments. Tumour growth delay was determined after irradiation with doses of 3 and 6 Gy by laser-accelerated electrons. Reference irradiation was performed with continuous electron beams at a clinical linear accelerator in order to both validate the dedicated dosimetry employed for laser-accelerated JETI electrons and above all review the biological results. No significant difference in radiation-induced tumour growth delay was revealed for the two investigated electron beams. These data provide evidence that the ultra-high dose rate generated by laser acceleration does not impact the biological effectiveness of the particles.

In recent years, the new technology of laser based particle acceleration was developed at such a rate that medical application for cancer therapy could become feasible. Promising more compact and economic proton and ion accelerators the laser technology however results in specific properties, like ultra-short (~ps) and ultra-intensive particle beam pulses. The clinical applicability of such new beam qualities requires comprehensive translational research from basic investigations to cell and animal experiments, finally followed by clinical trials. For the first time, the new laser based irradiation technology was established for animal experiments by the German joint research project “onCOOPtics”. A complete irradiation facility for laser accelerated electrons was developed, set up, commissioned, tested and applied for radiobiological tumour irradiation experiments under usage of a mouse model at the high intensity laser system JETI. The integration of a magnet and a collimator system resulted in an optimized beam transport and efficient electron energy filtration. Moreover, a specific irradiation and dosimetry setup was integrated allowing for the formation of irradiation fields, the real-time control of beam parameters and dose delivery to the tumour. For an accurate and reproducible positioning of the tumour in the irradiation field the mice were fixed in a movable box and the tumour position was online verified by means of a CCD camera system. The combination of both, the advanced laser accelerator system and the newly implemented irradiation and dosimetry setup allowed the successful performance of systematic radiobiological studies over months. Moreover, the practicability and easy handling of the system results in a reasonable duration of about 15 min for the whole procedure of mouse preparation, positioning and irradiation. In conclusion, the successful establishment of all technical requirements for and the performance of systematic animal studies with laser accelerated electrons mark an important step towards the clinical application of laser accelerated particle beams.

Over the past years, several in vitro studies have been performed on DNA damage induced by soft X-rays, especially in the energy range below 50 keV. Radiation effects originating from such low-energy photons are relevant in the context of medical diagnostics, for example, mammography, or of accidental exposure to scattered radiation. The present study was initiated to investigate the X-ray energy-dependent induction of stable and unstable chromosomal aberrations in the human mammary epithelial cell line 184A1. Three colour fluorescence in situ hybridisation was applied to identify chromosomal damage in chromosomes 1, 8 and 17, induced by 10-kV or 25-kV soft X-rays as well as by 200-kV X-rays as a reference quality. The overall results confirm the X-ray energy dependencies published for human lymphocytes showing increasing chromosomal aberration frequencies and higher aberration complexity with decreasing X-ray energy and increasing dose. Comparing the obtained dose dependencies, ratios of 0.84 ± 0.09 and 1.22 ± 0.18 were revealed for stable translocations induced by 25- and 10-kV X-rays, respectively, using 200-kV X-rays as reference. Moreover, the analysis of the minimum number of breaks required to form the visible chromosomal damage resulted in similar ratios of 0.93 ± 0.07 for 25-kV X-rays and 1.25 ± 0.10 for 10-kV X-rays relative to 200-kV X-rays. In addition, non-DNA-proportional contributions of chromosomes 8 and 17 to the whole DNA damage and deviations from the expected 1:1 ratio of translocations and dicentrics were observed for cell line 184A1.

In recent years, the technology of laser-based particle acceleration has developed at such a rate that compact and potentially more cost-effective accelerators are promised for medical application, e.g. for high precision hadron radiotherapy. Necessary requirements are the supply of stable and reliable particle beams with reproducible properties, sufficient particle intensities and monoenergetic spectra. Additionally, a precise dose delivery in an appropriate time and the exposure of a desired irradiation field are needed. Beside these physical demands, the consequences on detection and dosimetry as well as the radiobiological effect on living cells have to be investigated for the ultra-short pulsed laser-based particle beams. As a first step, the laser accelerator facility at the Jena Titanium:Sapphire system was customized for in vitro cell irradiation experiments and the delivered electron beam was im-proved with regard to its spectrum, diameter, dose rate and dose homogeneity. Furthermore, a custom-designed beam and dose monitoring system was established that enables real-time monitoring of the irradiation experiments and a precise determination of the dose delivered to the cells. Moreover, stable and reproducible beam properties were achieved during the whole three month experiment campaign. Dose-effect-curves were obtained for four cell lines and two endpoints, generally displaying a lower biological effectiveness for short-pulsed laser-accelerated electrons relative to the continuous 200 kV X-ray reference irradiation. Possible reasons will be discussed.

The radiation source ELBE delivers different types of secondary radiation, which is used for cell irradiation studies in radiobiological research. Thereby an important issue is the determination of the biological effectiveness of photon radiation as a function of photon energy by using low energetic, monochromatic channeling radiation (10-100 keV) and high energetic bremsstrahlung (up to 40 MV). Radiobiological studies at the research facility ELBE demand special technical and dosimetric prerequisites. Therefore, a cell irradiation system (CIS) has been designed, constructed and installed at the beam line. The CIS allows automatic irradiation of a larger cell sample number and the compensation of spatial inhomogeneity of the dose distribution within the beam spot. The recently introduced GafChromic EBT radiochromic film model has been used to verify the cell irradiation dose deposition achieving a dose uncertainty of

A prototype system for radiobiological studies has been investigated. It is based on thermally stimulated exoelectron emission (TSEE) detectors and can be used for precise determination of the absorbed dose in a live cell monolayer of several μ m thickness. In the present study, five types of BeO detectors, different in structure and method of production, were tested in combination with a Geiger–Muller counter. The dose response and dose range, reproducibility and long-time stability of response, as well as the applicability in a simulated cell culture environment have been studied. The dose response was found to be linear over two orders of magnitude and limited by the counter resolution. However, by a variation of detector sensitivity, the whole dose range of interest for radiobiological experiments can be covered. The irradiation in a simulated cell environment was successful only for one detector type. The system performance was found to be limited by the variation in the system response for time periods longer than several hours, therefore, it is suitable for absolute dose measurement with calibrated detectors if reproducible laboratory conditions are provided.

The broad application of low energy X-rays below about 50 keV in radiation therapy and diagnostics and especially in mammography substantiates the precise determination of their relative biological effectiveness (RBE). A quality factor of 1 is stated for photons of all energies in the International Commission on Radiological Protection Recommendations. However, the RBE of low-energy X-rays compared to high-energy photons was found to be dependent on photon energy, cell line and endpoints studied, hence varying from less than one up to about four. In the present study, the human mammary epithelial cell line MCF-12A has been chosen due to the implementation of the results in the estimation of risk from mammography procedures. The RBE of 25 kV X-rays (W anode, 0.3 mm Al filter) relative to 200 kV X-rays (W anode, 0.5 mm Cu filter) was determined for clonogenic survival in the dose range 1–10 Gy and micronuclei (MN) induction in the range 0.5–3.5 Gy. The RBE for clonogenic survival was found to be significantly higher than 1 for surviving fractions in the range 0.005 < S < 0.2. The RBE decreased with increasing survival, with an RBE0.1 at 10% survival of 1.13 ± 0.03. The effectiveness of soft X-rays for MN induction was found to be 1.40 ± 0.07 for the fraction of binuclear cells (BNC) with MN and 1.44 ± 0.17 for the number of MN per BNC. In contrast, the RBE determined from the number of MN per MN-bearing BNC was found to be 1.08 ± 0.32. This indicates that the effectiveness of 25 kV X-rays results from an increase in the number of damaged cells, which, however, do not have higher number of MN per cell.

We report on the first irradiation of in vitro tumour cells with laser-accelerated proton pulses showing dose-dependent biological damage. This experiment, paving the way for future radiobiological studies with laser-accelerated protons, demonstrates the simultaneous availability of all the components indispensable for systematic radiobiological studies: a laser-plasma accelerator providing proton spectra with maximum energy exceeding 15MeV and applicable doses of a few Gy within a few minutes; a beam transport and filtering system; an in-air irradiation site; and a dosimetry system providing both online dose monitoring and absolute dose information applied to the cell sample and the full infrastructure for analysing radiation-induced damage in cells.

Purpose: Before the novel technology of laser‐based particle acceleration can be used for clinical applications, several requirements have to be fulfilled. These are the supply of stable and reliable particle beams with reproducible properties, sufficient particle intensity and useable energy spectra. Additionally, a precise dosedelivery in an appropriate time and the exposure of a desired irradiation field are needed. Beside these demands, consequences on dosimetry as well as on the radiobiological effect have to be investigated for ultra‐short pulsed laser‐accelerated particle beams.Method and Materials: The joint project onCOOPtics, an interdisciplinary and multicenter institution focusing on the development of a laser particle accelerator for radiation oncology, is introduced. The worldwide first systematic in vitroirradiations with laser‐accelerated electrons performed with the JeTi laser system will be presented focusing on the experimental setup, practical experiences and on dosimetric and radiobiological results. In a next step, cell irradiation experiments with laser‐accelerated protons have been prepared. Therefore, a dedicated dosimetric system was developed. It is integrated into a device that can be installed at different laser and conventional accelerators and serves also as cell or animal irradiation device. Results: A laser accelerator was successfully optimized for systematic radiobiological experiments performed over 3 months. No significant differences between laser‐accelerated and conventional 6 MeV electron beams were found. An integrated dosimetry and cell irradiation device for systematic in vitro and in vivo experiments with laser‐accelerated protons was developed, characterized, calibrated and successfully tested with both continuous and pulsed protonbeams. Cell irradiations with protons have been started. Conclusion: Laser accelerators can be used for radiobiological experiments, meeting all necessary requirements like homogeneity, stability and precise dosedelivery. Nevertheless, before fulfilling the much higher requirements for clinical application, several improvements concerning i.e. proton energy, spectral shaping and patient safety are necessary. Supported by BMBF (03ZIK445).

Recent oncological studies identified beneficial properties of radiation applied at ultrahigh dose rates, several orders of magnitude higher than the clinical standard of the order of Gy min–1. Sources capable of providing these ultrahigh dose rates are under investigation. Here we show that a stable, compact laser-driven proton source with energies greater than 60 MeV enables radiobiological in vivo studies. We performed a pilot irradiation study on human tumours in a mouse model, showing the concerted preparation of mice and laser accelerator, dose-controlled, tumour-conform irradiation using a laser-driven as well as a clinical reference proton source, and the radiobiological evaluation of irradiated and unirradiated mice for radiation-induced tumour growth delay. The prescribed homogeneous dose of 4 Gy was precisely delivered at the laser-driven source. The results demonstrate a complete laser-driven proton research platform for diverse user-specific small animal models, able to deliver tunable single-shot doses up to around 20 Gy to millimetre-scale volumes on nanosecond timescales, equivalent to around 109 Gy s–1, spatially homogenized and tailored to the sample. The platform provides a unique infrastructure for translational research with protons at ultrahigh dose rates.

Background and purpose Continuing recent experiments at the research electron accelerator ELBE at the Helmholtz-Zentrum Dresden-Rossendorf the influence of beam pulse time structure on the Flash effect should be investigated in a zebrafish embryo model. Materials and methods The pulse structures of an isochronous and a synchrocyclotron were mimicked at ELBE with mean dose rates of 287 Gy/s and 177 Gy/s and pulse dose rates of 106 Gy/s and 109 Gy/s, respectively; and a macro pulsing for the latter. For comparison, a maximum (mean dose rate 2.5 x 105 Gy/s, pulse dose rate ~109 Gy/s) and a reference (mean dose rate of ~8 Gy/min) regime were applied. Radiation induced changes were assessed in zebrafish embryos over four days post irradiation. Results A significant protecting Flash effect with a clear dependence on mean dose rate was revealed for almost all endpoints and all electron pulse regimes relative to the reference. The macro pulse dependent prolongation of treatment time of the synchrotron-like regime reduce the protecting effect compared to the maximum regime delivered at same pulse but higher mean dose rate. The protecting Flash effect of the cyclotron-like regime was confirmed at a clinical isochronous proton cyclotron comparing the effects induced by 300 Gy/s relative to conventional proton beam delivery. Conclusion The mean dose rate or treatment time are more important than pulse dose rate for the extent of the normal tissue protecting Flash effect.

Background/aim The importance of hadron therapy in the cancer management is growing. We aimed to refine the biological effect detection using a vertebrate model. Materials and methods Embryos at 24 and 72 h postfertilization were irradiated at the entrance plateau and the mid spread-out Bragg peak of a 150 MeV proton beam and with reference photons. Radiation-induced DNA double-strand breaks (DSB) and histopathological changes of the eye, muscles and brain were evaluated; deterioration of specific organs (eye, yolk sac, body) was measured. Results More and longer-lasting DSBs occurred in eye and muscle cells due to proton versus photon beams, albeit in different numbers. Edema, necrosis and tissue disorganization, (especially in the eye) were observed. Dose-dependent morphological deteriorations were detected at ≥10 Gy dose levels, with relative biological effectiveness between 0.99±0.07 (length) and 1.12±0.19 (eye). Conclusion Quantitative assessment of radiation induced changes in zebrafish embryos proved to be beneficial for the radiobiological characterization of proton beams.