Towards a novel small animal proton irradiation platformthe SIRMIO project Background: Precision small animal radiotherapy research is a young emerging field aiming to provide new experimental insights into tumour and tissue models in different microenvironments, to unravel the complex mechanisms of radiation damage in target and non-target tissues and assess the efficacy of novel therapeutic strategies. To this end, for photon therapy, modern small animal radiotherapy research platforms have been developed over the last years and are meanwhile commercially available. Conversely, for proton therapy, which holds a great potential for an even superior outcome than photon therapy, no commercial system exists yet. Material and methods: The project SIRMIO (Small Animal Proton Irradiator for Research in Molecular Image-guided Radiation-Oncology) aims at realizing and demonstrating an innovative portable prototype system for precision small animal proton irradiation, suitable for integration at existing clinical treatment facilities. The proposed design combines precise dose application with novel insitu multi-modal anatomical image guidance and in-vivo verification of the actual treatment delivery for precision small animal irradiation. Results and conclusions: This manuscript describes the status of the different components under development, featuring a dedicated beamline for degradation and focusing of clinical proton beams, along with novel detector systems for insitu imaging. The foreseen workflow includes pre-treatment proton transmission imaging for treatment planning and position verification, complemented by ultrasonic tumour localization, followed by image-guided delivery with on-site range verification by means of ionoacoustics (for pulsed beams) and positronemission-tomography (PET, for continuous beams). The proposed compact and cost-effective system promises to open a new era in small animal proton therapy research, contributing to the basic understanding of in-vivo radiation action to identify areas of potential breakthroughs in radiotherapy for future translation into innovative clinical strategies.

Proton computed tomography (pCT) promises to reduce or even eliminate range uncertainties inherent in the conversion of Hounsfield units into relative stopping power (RSP) for proton therapy treatment planning. This is of particular interest for proton irradiation studies in animal models due to the high precision required and uncertainties in tissue properties.We propose a dedicated single-particle tracking pCT system consisting of low material budget floating strips Micromegas detectors for tracking and a segmented time-projection-chamber with vertical Mylar absorbers, functioning as a range telescope. Based on Monte Carlo simulations of a realistic in silico beam and detector implementation, a geometrical optimization of the system components was conducted to safeguard an ideal operation close to intrinsic performance limits at 75 MeV. Moreover, the overall imaging capabilities relevant for pre-clinical proton therapy treatment planning were evaluated for a mouse model.In order to minimize extrinsic uncertainties in the estimated proton trajectories, a spacing of the two tracking planes of at least 7 cm is required in both tracking detectors. Additionally, novel in-house developed and produced aluminum-based readout electrodes promise superior performance with around 3 mm −1 spatial resolution due to the reduced material budget. Concerning the range telescope, an absorber thickness within 500 µm to 750 µm was found to yield the best compromise between waterequivalent path length resolution and complexity of the detector instrumentation, still providing sub-0.5% RSP accuracy. The optimized detector configuration enables better than 2% range accuracy for proton therapy treatment planning in pre-clinical data sets.This work outlines the potential of pCT for small animal imaging. The performance of the proposed and optimized system provides superior treatment planning accuracy compared to conventional X-ray CT. Thus, pCT can play an important role in translational and pre-clinical cancer research.

Objectives Image guidance and precise irradiation are fundamental to ensure the reliability of small animal oncology studies. Accurate positioning of the animal and the in-beam monitoring of the delivered radio-therapeutic treatment necessitate several imaging modalities. In the particular context of proton therapy with a pulsed beam, information on the delivered dose can be retrieved by monitoring the thermoacoustic waves resulting from the brief and local energy deposition induced by a proton beam (ionoacoustics). The objective of this work was to fabricate a multimodal phantom (x-ray, proton, ultrasound, and ionoacoustic) allowing for sufficient imaging contrast for all the modalities. Approach The phantom anatomical parts were extracted from mouse computed tomography scans and printed using polylactic acid (organs) and a granite / polylactic acid composite (skeleton). The anatomical pieces were encapsulated in silicone rubber to ensure long term stability. The phantom was imaged using x-ray cone-beam computed tomography, proton radiography, ultrasound imaging, and monitoring of a 20 MeV pulsed proton beam using ionoacoustics. Main results The anatomical parts could be visualized in all the imaging modalities validating the phantom capability to be used for multimodal imaging. Ultrasound images were simulated from the x-ray cone-beam computed tomography and co-registered with ultrasound images obtained before the phantom irradiation and low-resolution ultrasound images of the mouse phantom in the irradiation position, co-registered with ionoacoustic measurements. The latter confirmed the irradiation of a tumor surrogate for which the reconstructed range was found to be in reasonable agreement with the expectation. Significance This study reports on a realistic small animal phantom which can be used to investigate ionoacoustic range (or dose) verification together with ultrasound, x-ray, and proton imaging. The co-registration between ionoacoustic reconstructions of the impinging proton beam and x-ray imaging is assessed for the first time in a pre-clinical scenario.

A novel irradiation platform for preclinical proton therapy studies foresees proton imaging for accurate setup and treatment planning. Imaging at modern synchrocyclotron-based proton therapy centers with high instantaneous particle flux is possible with an integration mode setup. The aim of this work is to determine an object’s water-equivalent thickness (WET) with a commercially available large-area CMOS sensor. Image contrast is achieved by recording the proton energy deposition in detector pixels for several incoming beam energies (here, called probing energies) and applying a signal decomposition method that retrieves the water-equivalent thickness. A single planar 114 mm × 65 mm CMOS sensor (49.5 µm pixel pitch) was used for this study, aimed at small-animal imaging. In experimental campaigns, at two isochronous cyclotron-based facilities, probing energies suitable for small-animal-sized objects were produced once with built-in energy layer switching and the other time, using a custom degrader wheel. To assess water-equivalent thickness accuracy, a micro-CT calibration phantom with 10 inserts of tissue-mimicking materials was imaged at three phantom-to-detector distances: 3 mm, 13 mm, and 33 mm. For 3 mm and 13 mm phantom-to-detector distance, the average water-equivalent thickness error compared to the ground truth was about 1% and the spatial resolution was 0.16(3) mm and 0.47(2) mm, respectively. For the largest separation distance of 33 mm air gap, proton scattering had considerable impact and the water-equivalent thickness relative error increased to 30%, and the spatial resolution was larger than 1.75 mm. We conclude that a pixelated CMOS detector with dedicated post-processing methods can enable fast proton radiographic imaging in a simple and compact setup for small-animal-sized objects with high water-equivalent thickness accuracy and spatial resolution for reasonable phantom-to-detector distances.

Pre-treatment proton radiography and computed tomography can improve precision of proton therapy. A compact imaging setup for small-animal proton radiography, based on a miniaturized Timepix detector is presented along with results from proof-of-concept experiments. The MiniPIX detector was placed behind a µ-CT calibration phantom with 10 different tissue-equivalent inserts. The intensity of the 70 MeV proton beam was adjusted such that pixel signal clusters from individual protons on the detector could be resolved. Analysis and event filtering on various cluster properties were used to suppress unwanted events. The energy deposition of the selected clusters was converted to water-equivalent thickness (WET) of the traversed material using a conversion curve based on Monte Carlo simulations and measured clusters of protons after traversing PMMA slabs of known thickness. Despite a systematic underestimation of up to 3%, retrieved WET values are in good agreement with ground truth values from literature. The achieved spatial resolution ranges from 0.3 to 0.7 mm for phantom-detectordistances of 1 to 5 cm. Applicability to living animals is currently limited by the relatively long acquisition time of up to 20 minutes per radiography. This obstacle can however be overcome with the latest detector generation Timepix3, allowing to handle higher particle rates and thus requiring shorter irradiation times.