PhysiCell: An open source physics-based cell simulator for 3-D multicellular systems

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 multi-substrate biotransport solver to 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.” The C++ code has minimal dependencies, making it simple to maintain and deploy 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 the 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. We demonstrate stochastic motility, chemical and contact-based interaction of multiple cell types, and the extensibility of PhysiCell with examples in synthetic multicellular systems (a “cellular cargo delivery” system, with application to anti-cancer treatments), cancer heterogeneity, and cancer immunology. PhysiCell is a powerful multicellular systems simulator that will be continually improved with new 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.

诸多多细胞系统相关问题，唯有通过探究细胞的运动、生长、分裂、相互作用与死亡过程，方能获得透彻理解。组织尺度的动态行为，源自大量相互作用的细胞系统——这类细胞既会响应自身所处的微环境，也会反过来对微环境施加影响。针对此类多细胞系统的理想“虚拟实验室”，需同时模拟生化微环境（即“舞台”）与众多在力学、生化层面相互作用的细胞（即“舞台上的参与者”）。
PhysiCell——一款基于物理学原理的多细胞模拟器——是一款开源的基于智能体（agent）的模拟器，可为动态组织微环境中大量相互作用细胞的相关研究同时提供“舞台”与“参与者”两类核心要素。该模拟器依托多底物生物输运求解器，可将细胞表型与多种扩散性底物及信号因子建立关联。其内置了一系列由生物学机制驱动的子模型，涵盖细胞周期、细胞凋亡、细胞坏死、固/液体积变化、细胞力学特性与细胞运动能力，可直接开箱即用。该软件采用C++编写，依赖项极少，便于跨平台维护与部署。
PhysiCell已通过OpenMP实现并行化，其性能随细胞数量呈线性扩展。在四核桌面工作站上，即可运行包含10^5至10^6个细胞的模拟任务；在单个高性能计算（High Performance Computing，HPC）计算节点上，更可完成更大规模的模拟任务。
我们通过模拟坏死核心生物力学特性、三维几何结构与随机性对悬滴肿瘤球体及乳腺导管原位癌（ductal carcinoma in situ，DCIS）动态行为的影响，对PhysiCell的性能进行了验证。此外，我们还通过多个示例展示了PhysiCell在随机运动、多细胞类型化学与接触相互作用方面的表现，以及其可扩展性：包括合成多细胞系统（一种可应用于抗癌治疗的“细胞货物递送”系统）、肿瘤异质性与肿瘤免疫学相关场景。
PhysiCell是一款功能强大的多细胞系统模拟器，后续将持续新增功能并优化性能。同时，其作为一套独立完整的代码库，可用于复现其他模拟平台的研究结果。PhysiCell的源代码、示例代码、文档与技术支持均遵循BSD开源许可协议，可通过http://PhysiCell.MathCancer.org与http://PhysiCell.sf.net获取。