MOTIVATION: Biological reality can in silico only be comprehensively represented in multi-scaled models. To this end, cell behavioural models addressing the multi-cellular level have to be semantically linked with mechanistic molecular models. These requirements have to be met by flexible software workflows solving the issues of different time scales, inter-model variable referencing and flexible sub-model embedding. RESULTS: We developed a novel software workflow (EPISIM) for the semantic integration of Systems Biology Markup Language (SBML)-based quantitative models in multi-scaled tissue models and simulations. This workflow allows to import and access SBML-based models. SBML model species, reactions and parameters are semantically integrated in cell behavioural models (CBM) represented by graphical process diagrams. By this, cellular states like proliferation and differentiation can be flexibly linked to gene-regulatory or biochemical reaction networks. For a multi-scale agent-based tissue simulation executable code is automatically generated where different time scales of imported SBML models and CBM have been mapped. We demonstrate the capabilities of the novel software workflow by integrating Tyson's cell cycle model in our model of human epidermal tissue homeostasis. Finally, we show the semantic interplay of the different biological scales during tissue simulation. AVAILABILITY: The EPISIM platform is available as binary executables for Windows, Linux and Mac OS X at http://www.tiga.uni-hd.de. Supplementary data are available at http://www.tiga.uni-hd.de/supplements/SemSBMLIntegration.html. CONTACT: [email protected].

MOTIVATION: For the efficient application of multi-agent systems to spatial and functional modeling of tissues flexible and intuitive modeling tools are needed, which allow the graphical specification of cellular behavior in a tissue context without presuming specialized programming skills. RESULTS: We developed a graphical modeling system for multi-agent based simulation of tissue homeostasis. An editor allows the intuitive and hierarchically structured specification of cellular behavior. The models are then automatically compiled into highly efficient source code and dynamically linked to an interactive graphical simulation environment. The system allows the quantitative analysis of the morphological and functional tissue properties emerging from the cell behavioral model. We demonstrate the relevance of the approach using a recently published model of epidermal homeostasis as well as a series of cell-cycle models. AVAILABILITY: The complete software is available in binary executables for MS-Windows and Linux at tiga.uni-hd.de.