Purpose: FLASH radiotherapy (RT) is an emerging technique in which beams with ultra‐high dose rates (UH‐DR) and dose per pulse (UH‐DPP) are used. Commercially available active real‐time dosimeters have been shown to be unsuitable in such conditions, due to severe response nonlinearities. In the present study, a novel diamond‐based Schottky diode detector was specifically designed and realized to match the stringent requirements of FLASH‐RT.Methods: A systematic investigation of the main features affecting the diamond response in UH‐DPP conditions was carried out. Several diamond Schottky diode detector prototypes with different layouts were produced at Rome Tor Vergata University in cooperation with PTW‐Freiburg. Such devices were tested under electron UH‐DPP beams. The linearity of the prototypes was investigated up to DPPs of about 26 Gy/pulse and dose rates of approximately 1 kGy/s. In addition, percentage depth dose (PDD) measurements were performed in different irradiation conditions. Radiochromic films were used for reference dosimetry.Results: The response linearity of the diamond prototypes was shown to be strongly affected by the size of their active volume as well as by their series resistance. By properly tuning the design layout, the detector response was found to be linear up to at least 20 Gy/pulse, well into the UH‐DPP range conditions. PDD measurements were performed by three different linac applicators, characterized by DPP values at the point of maximum dose of 3.5, 17.2, and 20.6 Gy/pulse, respectively. The very good superimposition of three curves confirmed the diamond response linearity. It is worth mentioning that UH‐DPP irradiation conditions may lead to instantaneous detector currents as high as several mA, thus possibly exceeding the electrometer specifications. This issue was properly addressed in the case of the PTW UNIDOS electrometers.Conclusions: The results of the present study clearly demonstrate the feasibility of a diamond detector for FLASH‐RT applications.

Background: Conventional air ionization chambers (ICs) exhibit ion recombination correction factors that deviate substantially from unity when irradiated with dose per pulse magnitudes higher than those used in conventional radiotherapy. This fact makes these devices unsuitable for the dosimetric characterization of beams in ultra‐high dose per pulse as used for FLASH radiotherapy.Purpose: We present the design, development, and characterization of an ultra‐thin parallel plate IC that can be used in ultra‐high dose rate (UHDR) deliveries with minimal recombination.Methods: The charge collection efficiency (CCE) of parallel plate ICs was modeled through a numerical solution of the coupled differential equations governing the transport of charged carriers produced by ionizing radiation. It was used to find out the optimal parameters for the purpose of designing an IC capable of exhibiting a linear response with dose (deviation less than 1%) up to 10 Gy per pulse at 4 s pulse duration. As a proof of concept, two vented parallel plate IC prototypes have been built and tested in different ultra‐high pulse dose rate electron beams.Results: It has been found that by reducing the distance between electrodes to a value of 0.25 mm it is possible to extend the dose rate operating range of parallel plate ICs to ultra‐high dose per pulse range, at standard voltage of clinical grade electrometers, well into several Gy per pulse. The two IC prototypes exhibit behavior as predicted by the numerical simulation. One of the so‐called ultra‐thin parallel plate ionization chamber (UTIC) prototypes was able to measure up to 10 Gy per pulse, 4 s pulse duration, operated at 300 V with no significant deviation from linearity within the uncertainties (ElectronFlash Linac, SIT). The other prototype was tested up to 5.4 Gy per pulse, 2.5 s pulse duration, operated at 250 V with CCE higher than 98.6% (Metrological Electron Accelerator Facility, MELAF at Physikalisch‐Technische Bundesanstalt, PTB).Conclusions: This work demonstrates the ability to extend the dose rate operating range of ICs to ultra‐high dose per pulse range by reducing the spacing between electrodes. The results show that UTICs are suitable for measurement in UHDR electron beams.

Ultra-high dose rate (UHDR) beams for FLASH radiotherapy present significant dosimetric challenges. Although novel approaches for decreasing or correcting ion recombination in ionization chambers are being proposed, applicability of ionimetric dosimetry to UHDR beams is still under investigation. Solid-state sensors have been recently investigated as a valuable alternative for real-time measurements, especially for relative dosimetry and beam monitoring. Among them, Silicon Carbide (SiC) represents a very promising candidate, compromising between the maturity of Silicon and the robustness of diamond. Its features allow for large area sensors and high electric fields, required to avoid ion recombination in UHDR beams. In this study, we present simulations and experimental measurements with the low energy UHDR electron beams accelerated with the ElectronFLASH machine developed by the SIT Sordina company (IT). The response of a newly developed 1 × 1 cm² SiC sensor in charge as a function of the dose-per-pulse and its radiation hardness up to a total delivered dose of 90 kGy, was investigated during a dedicated experimental campaign, which is, to our knowledge, the first characterization ever done of SiC with UHDR-pulsed beams accelerated by a dedicated ElectronFLASH LINAC. Results are encouraging and show a linear response of the SiC detector up to 2 Gy/pulse and a variation in the charge per pulse measured for a cumulative delivered dose of 90 kGy, within ±0.75%.

Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MS-associated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes. In this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35–55-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load. Treatment of MOG35–55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35–55-pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35–55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score. Electroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS.