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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.

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.

Laser-accelerated electron pulses have been used to irradiate human tumors grown on mice’s ears during radiobiological experiments. These experiments have been carried out with the JETI laser system at the Institute of Optics and Quantum Electronics in Jena, Germany. To treat a total of more than 50 mice, a stable and reliable operation of the laser-electron accelerator with a dose rate exceeding 1 Gy/min was necessary. To achieve this, a sufficient number of electrons at energies in excess of 5 MeV had to be generated. The irradiation time for a single mouse was a few minutes. Furthermore, the particle pulses’ parameters needed to remain achievable for a time period of several weeks. Due to the online detection of the radiation dose, the unavoidable shot-to-shot fluctuations, currently still typical for laser-based particle accelerators, could be compensated. The results demonstrate that particle pulses generated with laser-based accelerators have the potential to be a future alternative for conventional particle accelerators used for the irradiation of tumors.

Proton beams are a promising tool for the improvement of radiotherapy of cancer, and compact laser-driven proton radiation (LDPR) is discussed as an alternative to established large-scale technology facilitating wider clinical use. Yet, clinical use of LDPR requires substantial development in reliable beam generation and transport, but also in dosimetric protocols as well as validation in radiobiological studies. Here, we present the first dose-controlled direct comparison of the radiobiological effectiveness of intense proton pulses from a laser-driven accelerator with conventionally generated continuous proton beams, demonstrating a first milestone in translational research. Controlled dose delivery, precisely online and offline monitored for each out of ∼4,000 pulses, resulted in an unprecedented relative dose uncertainty of below 10 %, using approaches scalable to the next translational step toward radiotherapy application.

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.

Background: The long-term aim of developing a laser based acceleration of protons and ions towards clinical application requires not only substantial technological progress, but also the radiobiological characterization of the resulting ultra-short pulsed particle beams. Recent in vitro data showed similar effects of laser-accelerated versus “conventional” protons on clonogenic cell survival. As the proton energies currently achieved by laser driven acceleration are too low to penetrate standard tumour models on mouse legs, the aim of the present work was to establish a tumour model allowing for the penetration of low energy protons (~ 20 MeV) to further verify their effects in vivo. Methods: KHT mouse sarcoma cells were injected subcutaneously in the right ear of NMRI (nu/nu) mice and the growing tumours were characterized with respect to growth parameters, histology and radiation response. In parallel, the laser system JETI was prepared for animal experimentation, i.e. a new irradiation setup was implemented and the laser parameters were carefully adjusted. Finally, a proof-of-principle experiment with laser accelerated electrons was performed to validate the tumour model under realistic conditions, i.e. altered environment and horizontal beam delivery. Results: KHT sarcoma on mice ears showed a high take rate and continuous tumour growth after reaching a volume of ~ 5 mm 3 . The first irradiation experiment using laser accelerated electrons versus 200 kV X-rays was successfully performed and tumour growth delay was evaluated. Comparable tumour growth delay was found between X-ray and laser accelerated electron irradiation. Moreover, experimental influences, like anaesthesia and positioning at JETI, were found to be negligible. Conclusion: A small animal tumour model suitable for the irradiation with low energy particles was established and validated at a laser based particle accelerator. Thus, the translation from in vitro to in vivo experimentation was for the first time realized allowing a broader preclinical validation of radiobiological characteristics and efficacy of laser driven particle accelerators in the future.