TOPAS-Tissue: A Framework for the Simulation of the Biological Response to Ionizing Radiation at the Multi-Cellular Level.

This work aims to develop and validate a framework for the multiscale simulation of the biological response to ionizing radiation in a population of cells forming a tissue. We present TOPAS-Tissue, a framework to allow coupling two Monte Carlo (MC) codes: TOPAS with the TOPAS-nBio extension, capable of handling the track-structure simulation and subsequent chemistry, and CompuCell3D, an agent-based model simulator for biological and environmental behavior of a population of cells. We verified the implementation by simulating the experimental conditions for a clonogenic survival assay of a 2-D PC-3 cell culture model (10 cells in 10,000 µm) irradiated by MV X-rays at several absorbed dose values from 0-8 Gy. The simulation considered cell growth and division, irradiation, DSB induction, DNA repair, and cellular response. The survival was obtained by counting the number of colonies, defined as a surviving primary (or seeded) cell with progeny, at 2.7 simulated days after irradiation. DNA repair was simulated with an MC implementation of the two-lesion kinetic model and the cell response with a p53 protein-pulse model. The simulated survival curve followed the theoretical linear-quadratic response with dose. The fitted coefficients α = 0.280 ± 0.025/Gy and β = 0.042 ± 0.006/Gy agreed with published experimental data within two standard deviations. TOPAS-Tissue extends previous works by simulating in an end-to-end way the effects of radiation in a cell population, from irradiation and DNA damage leading to the cell fate. In conclusion, TOPAS-Tissue offers an extensible all-in-one simulation framework that successfully couples Compucell3D and TOPAS for multiscale simulation of the biological response to radiation.