The development of laser driven accelerators-on-chip has provided an opportunity to miniaturise devices for electron radiotherapy delivery. Laser driven accelerators produce highly time-compressed electron pulses, on the hundred femtoseconds to one picosecond scale. This delivers electrons at high peak power yet low average beam current compared to conventional delivery devices which generate pulses of around 3 microseconds. The biophysical effects of this time structure, however, are unclear. Here we use a Monte Carlo simulation approach to explore the effects of the electron beam time structure on the production of reactive oxygen species (ROS) in water. Our results show a power law increase in the generation of hydroxyl ions per deposited electron with decreasing pulse length over the pulse length range of 10 microseconds to 100 femtoseconds. Similar trends were observed for hydrogen peroxide, superoxide, hydroperoxyl, hydronium, and solvated electrons. In practical terms, this indicates a four-fold increase in the efficiency of free radical production for sub-picosecond pulses, relative to that of conventional microsecond pulses, for the same number of deposited electrons.

Simulations were performed using the TOPAS-nBio Monte Carlo package to trace particle trajectories, tracking energy exchange and free radical production from the physical electron interactions with the constituent atoms of the medium. This implementation of the Independent Reaction Times (IRT) Monte Carlo technique allows for calculation of time-dependent radiolytic yields and tracking of ROS via independent pair approximation to simulate reaction times between ROS created at the end of the pre-chemical stage. Prior to the main simulation run, the setup was verified using matched molecules, reactions, reaction rate coefficients, and diffusion coefficients from previous work. The single pulse analysis within TOPAS-nBio was adapted to accumulate data from all particles within the pulse, allowing direct comparison. In response to the significant computational demands of this particular study, multithreading was integrated to effectively reduce processing time. Furthermore, modifications were made to the original FLASH scorer to facilitate inspection of the single pulse results. Global variables were implemented to preserve key outputs across the parallel threads. Following calculation of G values that represents the production of a specific ROS of interest by every 100-eV deposited into the target for each thread, a Mutex lock and counter were activated to ensure the sequential execution of concurrent processes or threads. This approach facilitated the aggregation of individual G values generated by each thread, that could be managed and fed back into the single-thread design of the main code. The original conditional statement governing the processing of energy deposition and G values was revised, removing the dose parameter with the current count of histories scored, incremented by 1 to account for the initial count at 0. This value was assigned to a variable referred to as the ‘final count’, representing the total number of events to be processed divided by the number of active worker threads. This adjustment enabled the seamless functioning of the code across both single-thread and multithread operations, ensuring the comprehensive scoring of all particles before initiating the final output calculations. The modified section of code is provided. All simulations used a 5 µm (FWHM) Gaussian electron beam aligned with the z-axis into a 200 x 200 x 400 µm (x,y,z) water phantom, via a 100 µm air layer. Simulations were performed for a range of pulse durations (10^-13 – 10^-6 s), electron energies (10⁴ – 10⁶ eV), and number of electrons per pulse (1-100). TOPAS output was analysed using in-house MATLAB code enabling a description of overall ROS production from each parameter set. A second simulation applied and compared characteristic parameters from DLA (300 fs, 100 keV, 28 electrons, 100 kHz repetition rate), FLASH (2 µs, 500 keV, 0.2 Gy, 20 Hz repetition rate), and conventional (4 µs, 500 keV, 0.002 Gy, 100 Hz repetition rate), recording the same output parameters.