Scientific programme at the Laser Laboratory for Acceleration and Applications

. In recent years, laser-driven accelerators have emerged as a promising technology for the development of compact and cost-e ff ective sources of high-energy particles and radiation. Here, we introduce our research programme at the Laser Laboratory for Acceleration and Applications, which focusses on high-power laser systems, development of high-repetition rate targetry, and biomedical applications of laser-based accelerators. Our recent results include the generation of high-energy proton and ion beams through laser-plasma acceleration, which have potential applications in materials activation for medical imaging. We have also investigated the feasibility of using laser-driven X-rays and ion beams for radiobiological research, including FLASH therapy and hadron therapy.


Introduction
Laser-plasma accelerators have attracted significant interest as a promising technology for generating high-energy particle beams with unprecedented characteristics.These compact accelerators benefit from the stronger accelerating electric fields that can be withstood by a plasma, orders of magnitude higher than those achieved in state-ofthe-art conventional RF accelerators, enabling the acceleration of charged particles to very high energies over short distances.Thanks to this, laser-plasma accelerators have the potential to revolutionize the field of particle acceleration, offering a cost-effective and compact alternative to traditional accelerators, Significant progress has been made in recent years in laser-plasma acceleration, with several key milestones achieved.These include the generation of high-quality electron beams with energies up to 8 GeV [1], acceleration of protons to energies in excess of 100 MeV [2], as well as demonstration of high-quality secondary radiation sources, such as X-rays, positrons, or neutrons [3,4].Furthermore, the ongoing progress in laser-driven accelerators and the unique characteristics of the produced radiation -e.g.ultra-short duration or very low emittance-have opened up the possibility of using these beams in proof-ofprinciple applications in a wide range of fields.including FLASH radiation therapy for cancer treatment, nuclear activation of materials for medical imaging, or sample characterisation in material science.
In this paper, we describe our research programme at the Laser Laboratory for Acceleration and Applications (L2A2), focused on high-power laser systems, development of high-repetition rate targetry for laser-plasma experiments, and biomedical applications of laser-based accelerators, with a specific focus on the acceleration of ion beams, particularly protons, for medical imaging applications.We highlight our efforts to develop stable laser-driven radiation sources operating at high repetition rates, by means of both the stabilisation of the inhouse high-power laser STELA, and the development of new target systems.We also describe our ongoing work to explore the potential of laser-plasma accelerators for real-life applications, including the production of isotopes for Positron Emission Tomography medical imaging and phase-contrast imaging.

STELA laser system
The Laser Laboratory for Acceleration and Applications (L2A2) is a recently-built infrastructure at the Universidade de Santiago de Compostela (USC) for the investigation of laser-plasma interaction, which hosts a clean room, laboratory for development of acceleration targets and beam diagnostics, and a radio-protected experimental hall (Fig. 1) [5].The core facility of L2A2 is STELA (Santiago TErawatt LAser), a compact Ti:Sapphire laser system built by Thales (Alpha 10/XS).The STELA laser offers two different outputs, each of which powers an independent beamline.
The main laser beamline, or high-energy beamline, delivers ultra-short pulses (25 fs) with energy per pulse up to 1 J at a 10 Hz repetition rate and peak power around 50 TW.As this beamline is mainly devoted to ion acceleration using solid targets, the laser chain has been modified to improve its operation.For instance, a key requirement for efficient ion acceleration is a high contrast ratio.In our case, the contrast is enhanced, reaching a ratio of > 10 10 at 5 ps, thanks to the implementation the Crossed-Polarised Wave (XPW) technique early in the laser chain.In addition to this, the interaction of the laser with a solid target can lead to the back-propagation of a significant amount of energy back into the laser chain, which can result in damage of key components of the system.To mitigate this, a pulse picker has been installed at the end of the final amplification stage, which prevents the propagation of these retro-reflections into the system.Currently, there are significant efforts to further improve the stability of the laser system, a key requirement to achieve a stable laser-based accelerator, particularly in the context of laser chain evolution due to heating of the different components in the case of high-power, high-repetition-rate laser systems [6].
The second beamline, or low-energy beamline, which takes advantage of the pulses generated at the system front-end and extracted before the final amplification stages, is a versatile tool for a range of laser-based experiments, such as X-ray generation or material processing.In this case, the laser operates at a repetition rate of 1 kHz and an energy output of 1 mJ, producing pulses with 30 fs pulse duration.

High-repetition rate targetry and diagnostics
In the past, the production of stable, laser-driven radiation sources has been limited by the reduced repetition rate of the laser systems capable of producing such sources.However, as the ongoing developments in laser-technology remove this bottleneck, improvements on the targetry have become crucial to advancing the field of laser-plasma ac-celerators, particularly relevant in the case of solid targets.As these targets are destroyed after their irradiation, they need to be replaced for a fresh one and re-aligned with few-microns-precision before a new irradiation takes place.
Several solutions are currently being actively studied to address this limitation [7].In our case, we are particularly focussed on the development of targetry systems for solid targets, specifically rotating wheels and tape drives.In the first case, targets are regularly distributed in the radial and angular dimensions of a precisely-machined wheel, attached to a motorised system allowing for threedimensional movement.Albeit this target design has advantages, such as allowing for a large number of irradiations or the broad variety of target material and thickness that can be used, some limitations need to be addressed in order to be able to shoot continuously at multi-Hertz rates.In our case, the solution is based on pre-characterising the surface of each target using an optical position sensor, which allows to rapidly change between targets and precisely position them on the focal plane of the focussing optics, with micron-level precisions.Using this system, continuous stable ion acceleration at rates up to 10 Hz have been demonstrated, with a standard deviation of the proton cut-off energy < 10%.
Despite the flexibility and robustness of the rotating wheel, this solution presents intrinsic shortcomings in the context of state-of-the-art laser systems, such as the maximum number of targets, typically constrained to a few thousand, or the maximum repetition rate of operation, due to the required separation between targets and maximum velocity for the wheel movements involved.For these reasons, we are currently working on the development of a tape-drive system [7].In this case, a thin tape is used as target, ensuring a fresh surface interacts with the laser as the tape is wound onto a motorised spool [8].By ensuring the tape remains at a constant tension as it slides between the rods defining the interaction point, the tape surface is ensured to remain stable on the focal plane as the target is replaced.Our tape drive system is currently being commissioned at the Laser Laboratory for Acceleration and Applications, with preliminary stability measurements already indicating standard deviations of the tape position <10 µm [7].

Biomedical applications
Laser-driven radiation sources have attracted significant attention for their potential use in different biomedical applications.Among these applications, at L2A2 we particularly focus on the generation of radio-isotopes of relevance for positron emission tomography (PET), and nextgeneration radio-therapy cancer treatments.
Medical imaging based on radiation emitted by unstable nuclei is used on a daily basis as a fundamental tool to diagnose a number of diseases, including cancer.Arguably, one of the most powerful imaging techniques is positron emission tomography (PET).In PET, a positron emitting isotope is injected into the patient, accumulating in the target tissue.As the radionuclides decay, low-energy positrons are emitted and promptly annihilate from the combination with a nearby electron, resulting in the emission of two counter-propagating 511 keV photons, which can be detected and back-traced, enabling the characterisation of the distribution of the radioisotope in the tissue, and hence the tissue of interest.
However, the bottleneck in the use of certain radioisotopes currently lies on their short lifetimes.The production of these nuclides relies on the use of radiofrequency acceleration cavities, commonly cyclotrons, facilities characterised for their sizeable footprints (∼10 m 3 ), the shielding requirements (∼180 m 3 of concrete) and large costs (∼ 10Me).As a result, a single production facility must provide nuclides to different hospitals in the area, in distances that range up to 100s of km.In order to ensure that sufficient activation levels are still present upon arrival to the hospital, only a narrow range of radioisotopes with longer lifetimes are being used for imaging, commonly 18 F with a half-life of ∼ 110 minutes.However, there are radioisotopes with shorter lifetimes, such as 11 C with a half-life of ∼ 20 minutes, that are highly demanded for particular diagnostics, such as neurodegenerative diseases, but cannot be provided by the available facilities as the nuclides will have decayed before being injected into the patient.In this context, there has been a growing interest in the development of cost-effective and compact accelerator systems capable of generating such nuclides on-demand, such as laser-driven ion accelerators.At L2A2, we are actively investigating the production of 11 C radio-isotopes using laser-driven ions, potentially capable of generating activation levels up to tens of MBq using the in-house laser, with the experimental setup shown in Fig. 2. The other biomedical application being actively studied is novel radiation therapy techniques, particularly those related to Ultra-High Dose Rate (UHDR) effects, also known as FLASH effects.Conventional radiotherapy relies on the delivery of the required radiation dose at rates <1 Gy/s.Instead, in FLASH radiotherapy the dose is fractioned and delivered in the form of short bunches, allowing for an increase in the average dose rate to >40 Gy/s.Laser-driven radiation sources are ideally suited for such an irradiation, typically being delivered as separate ultra-short bunches, with durations ranging from picoseconds up to nanoseconds, leading to dose rates as high as 10 9 Gy/s.Such ultra-high peak dose rates, alongside the ongoing developments on laser technology enabling Hertz-repetition rates to reach the required average dose rates, have opened up the possibility of characterising the radiobiological effects of pulsed ionising radiation at ultra-high dose rates.

Boron target
UHDR techniques have been shown to present beneficial effects in pre-clinical in-vivo studies, which have been explained in terms of a lowering of the radiation effects over healthy tissue, while maintaining the antitumoral efficacy with respect to conventional treatment.Different hypotheses have been proposed to explain the underlying biochemical mechanism responsible of FLASH effects, such as the healthy cells undergoing a transient hypoxic state that enhances their radiorresistance, or an increase in the immune response repairing healthy cells due to the reduced number of lymphocytes damaged when higher dose rates are employed.There is, therefore, significant scope to explore the functioning of living tissues when exposed to UHDR of radiation.
In this context, L2A2 offers the unique possibility of studying FLASH effects of radiation on living cells using ultra-short bunches of protons or X-rays.Following initial developments to ensure the stability of the laser-driven sources, a key requirement for radiobiological studies, we are currently performing the first commissioning experiments using in-vitro cell cultures [9].

Phase contrast X-ray imaging
Tomographic imaging is a powerful technique used in various fields, including medical imaging, material science, and biology.It allows for the reconstruction of threedimensional images of the internal structure of an object, which is crucial in many applications.X-ray imaging is one of the most widely used techniques for tomography due to its high penetration depth and spatial resolution.However, conventional X-ray imaging relies on the absorption of X-rays, which limits its sensitivity to soft tissues and low-density materials.
Phase contrast imaging is an emerging technique that overcomes the limitations of absorption-based imaging by detecting the phase shift of X-rays passing through an object.This shift can be induced by changes in the refractive index of the object, which is related to the object's internal structure.Phase contrast imaging can provide highcontrast images of soft tissues and low-density materials that are difficult to see using conventional X-ray imaging.
Despite the appeal of phase contrast imaging, the use of this technique has been constrained due to the limitations of conventional X-ray sources, such as their incoherence, large source size and low brightness.Laserdriven X-ray sources have recently appeared as a promising alternative for phase contrast imaging, thanks to the extremely small source size (few micron).They can produce X-rays with high brightness and coherence, making them ideal for phase contrast imaging applications, with additional benefits such as compactness, portability, and cost-effectiveness.
At L2A2, we have developed a stable, laser-driven kHz X-ray source operating in air capable of producing copious amounts of X-rays with energies up to tens of keV, narrow divergence and few micron source size.This source has recently been shown to be capable of producing radiography images with phase-contrast enhancement, and is currently being employed for imaging of samples of interest in biomedicine.

Conclusions
Laser-driven sources of radiation have attracted significant attention due to their unparalleled intrinsic properties, such as ultra-short duration, high brightness and low emittance, alongside the compactness and cost-effectiveness with respect to conventional accelerators.The ongoing progress in laser technology is allowing for an increase in the number of installations that can reach the required laser intensities to produce these beams, including the laser at L2A2, a 50 TW commercial system operating at 10 Hz.
Here, we have described our research program, which is heavily based on the production of stable X-ray and ion beams for a variety of applications in fields such as medical imaging and cancer therapy.Our work on highrepetition rate targetry has enabled us to produce stable beams that can operate for the extended periods of time required.We have presented some of the main applications currently being studied, including using laser-driven ion beams for the production of radio-isotopes for medical imaging, studies of ultra-high dose rate effects on cells, and improvements on X-ray imaging thanks to phasecontrast techniques.

Figure 1 .
Figure 1.(a) Picture of the Laser Laboratory for Acceleration and Applications building.(b) Picture of the STELA laser system as installed in the clean room.

Figure 2 .
Figure 2. Experimental setup for the production of 11 C radioisotopes.