RT Journal Article SR Electronic T1 PhysiCell: an Open Source Physics-Based Cell Simulator for 3-D Multicellular Systems JF bioRxiv FD Cold Spring Harbor Laboratory SP 088773 DO 10.1101/088773 A1 Ahmadreza Ghaffarizadeh A1 Samuel H. Friedman A1 Shannon M Mumenthaler A1 Paul Macklin YR 2016 UL http://biorxiv.org/content/early/2016/11/19/088773.abstract AB Many multicellular systems problems can only be understood by studying how cells move, grow, divide, interact, and die. Tissue-scale dynamics emerge from systems of many interacting cells as they respond to and influence their microenvironment. The ideal “virtual laboratory” for such multicellular systems simulates both the biochemical microenvironment (the “stage”) and many mechanically and biochemically interacting cells (the “players” upon the stage).PhysiCell—physics-based multicellular simulator—is an open source agent-based simulator that provides both the stage and the players for studying many interacting cells in dynamic tissue microenvironments. It builds upon a specialized multi-substrate biotransport solver so that modelers can link cell phenotype to multiple diffusing substrates and signaling factors. It includes biologically-driven sub-models for cell cycling, apoptosis, necrosis, solid and fluid volume changes, mechanics, and motility “out of the box,” allowing modelers to concentrate on microenvironment-driven hypotheses. The C++ code has minimal dependencies, making it simple to maintain across platforms. PhysiCell has been parallelized with OpenMP, and its performance scales linearly with the number of cells. Simulations up to 105-106 cells are feasible on quad-core desktop workstations; larger simulations are attainable on single HPC compute nodes.We demonstrate PhysiCell by simulating impact of necrotic core biomechanics, 3-D geometry, and stochasticity on the dynamics of hanging drop tumor spheroids and ductal carcinoma in situ (DCIS) of the breast. PhysiCell is a powerful multicellular systems simulator that will be continually improved with new sub-models, capabilities, and performance improvements. It also represents a significant independent code base for replicating results from other simulation platforms. The PhysiCell source code, examples, documentation, and support are available under the BSD license at http://PhysiCell.MathCancer.org and http://PhysiCell.sf.net.Author Summary This paper introduces PhysiCell: an open source, agent-based model for 3-D multicellular simulations. It includes a standard library of sub-models for cell fluid and solid volume changes, cell cycle progression, apoptosis, necrosis, and mechanics. The code is directly coupled to a specialized biotransport solver to simulate many diffusing substrates and cell signals. Each cell can release diffusing signals, and dynamically update its phenotype according to its microenvironmental conditions. Users can customize or replace the included sub-models.PhysiCell was designed to work on a variety of platforms (Linux, OSX, and Windows) with a minimum number of software dependencies. Its computational cost scales linearly in the number of cells. It is feasible to simulate 500,000 cells on current quad-core desktop workstations, and millions of cells on single HPC compute nodes. In this paper, we demonstrate PhysiCell to test the impact of necrotic core biomechanics, 3-D geometry, and stochasticity on hanging drop tumor spheroids (HDS) and ductal carcinoma in situ (DCIS) of the breast.We developed PhysiCell to help the scientific community tackle multicellular systems biology problems involving many interacting cells in multi-substrate microenvironments. PhysiCell also represents an important independent, cross-platform code base for replicating simulation results from other simulation platforms.