PhysiCell Studio: a graphical tool to make agent-based modeling more accessible

Defining a multicellular model can be challenging. There may be hundreds of parameters that specify the attributes and behaviors of objects. Hopefully the model will be defined using some format specification, e.g., a markup language, that will provide easy model sharing (and a minimal step toward reproducibility). PhysiCell is an open source, physics-based multicellular simulation framework with an active and growing user community. It uses XML to define a model and, traditionally, users needed to manually edit the XML to modify the model. PhysiCell Studio is a tool to make this task easier. It provides a graphical user interface that allows editing the XML model definition, including the creation and deletion of fundamental objects, e.g., cell types and substrates in the microenvironment. It also lets users build their model by defining initial conditions and biological rules, run simulations, and view results interactively. PhysiCell Studio has evolved over multiple workshops and academic courses in recent years which has led to many improvements. Its design and development has benefited from an active undergraduate and graduate research program. Like PhysiCell, the Studio is open source software and contributions from the community are encouraged.


Add pressure mechanofeedback on cycling
We use the Rules tab to dynamically modify the cell cycle (behavior) as a function of cell pressure (signal).Specifically, we want an increase in pressure to decrease the transition rate of the ("live") cell cycle.The modeling grammar [1] used in the Rules tab was introduced in PhysiCell version 1.12.0.
In the "Rules" tab: • the top "Cell Type" combobox should only contain "cancer" • choose "pressure" as the Signal • choose "cycle entry" as the Behavior • choose "decreases" next to Behavior • enter 0 as the Saturation value of Behavior • enter 4 as the Hill power • enter 1 as the Half-max • optionally, you can click "Plot" (next to "Add rule") to see the Hill function (Figure 1) • click "Add rule" (rule should appear in the table at row #1, Figure 2) • at the bottom of the tab, set rules file name to "cell_rules.csv"• be sure "enable" is checked • optionally, click "Save" button to save the rule to "cell_rules.csv"(otherwise, it will be automatically saved when you Run a simulation) • in the Run tab, "Run simulation"     • in the "Plot" tab, select the ".mat" radio button for cells • click "full list" to show all options for cell scalar values • select "current_cycle_phase_exit_rate" as the scalar value • select the "jet" colormap for cells • check "fix" to limit the colormap ranges, with cmin=0 and cmax=0.00093(press Enter) • select the "YlOrRd" colormap for the substrate • click "Play" to show the simulation • notice the greatest cycling is on the outer periphery of the tumor Figure 8. Results with two rules (coloring cells with .matcycle phase exit rate)
• in the "Rules" tab, the "Cell Type" combobox should only contain "cancer" • choose "oxygen" as the Signal • chose "necrosis" as the Behavior • choose "decreases" as the response

Add a cytotoxic drug
• in the "Microenvironment" tab: ○ click "New", then select (e.g., double-click) the newly named one and rename it "drug" (and press Enter) ○ set its "diffusion coefficient" to 1600 ○ set its "decay rate" to 0.002 ○ set its "initial condition" to 10 Figure 15.Edit drug parameters.
• in the "Cell Types" tab, "Secretion" sub-tab: ○ select "drug" in the combobox of substrates ○ set "uptake rate" to 1

Add release of dead cell debris
• in the "Microenvironment" tab: ○ click "New", then select (e.g., double-click) the newly named one and rename it "debris" (and press Enter) ○ set its "diffusion coefficient" to 1 ○ set its "decay rate" to 0 ○ set its "initial condition" to 0 • in the "Cell Types" tab, "Secretion" sub-tab: ○ select "debris" in the combobox of substrates ○ set "target" to 1  Cell debris starts to accumulate in the region of the tumor.

Add macrophages
• in the "Cell Types" tab: ○ click "cancer" cell type and click Copy ○ rename the copy to be "macrophage" • in the "Death" sub-tab (with "macrophage" still selected): ○ set Apoptosis "death rate" to 0 ○ set Necrosis "death rate" to 0 Figure 25.Create macrophage cell types with death rates=0.

Add pro-inflammatory factor
• in the "Microenvironment" tab: ○ click "New", then select (e.g., double-click) the newly named one and rename it "pro-inflammatory factor" (and press Enter) ○ set its "diffusion coefficient" to 1000 ○ set its "decay rate" to 0.1 ○ set its "initial condition" to 0 Figure 35.Create pro-inflammatory factor signal and set its parameters.
• in the "Cell Types" tab: ○ click "macrophage" cell type and click Copy ○ rename the copy to be "M1 macrophage" • in the "Secretion" sub-tab (with "M1 macrophage" still selected): ○ select "pro-inflammatory factor" as the substrate ○ set "secretion rate" to 10 ○ set "target" to 1

Add effector T cells
• in the "Cell Types" tab: ○ click "macrophage" cell type and click Copy ○ rename the copy to be "Effector T cell" • in the "Motility" sub-tab (with "Effector T cell" still selected): ○ select "pro-inflammatory factor" as the substrate in Chemotaxis Figure 41.Create "Effector T cell" cell type.
• in the "Secretion" sub-tab (with "Effector T cell" still selected): ○ select "debris" as the substrate ○ set "uptake rate" to 0 ○ select "pro-inflammatory factor" as the substrate ○ set "uptake rate" to 1 Figure 42.Edit "Effector T cell" secretion parameters for debris.
Figure 43.Edit "Effector T cell" secretion parameters for pro-inflammatory factor.
• in the "Interactions" sub-tab (with "Effector T cell" still selected): ○ set "dead phagocytosis rate" to 0 ○ set "attack rate" for cancer to 10

Intracellular modeling
PhysiCell Studio also provides interfaces to intracellular modeling.Although intracellular modeling is not used in the tumor model presented above, we wanted to present it in this Supplemental material.Currently, only a boolean intracellular modeling [2] interface is provided in the Studio.In the future, we will also provide an interface for ODE intracellular models [3].
Figure 51.Interface for a boolean intracellular model.

Figure 3 .
Figure 3. Results with one rule.

Figure 4 .
Figure 4. Coloring cells with pressure values

Figure 7 .
Figure 7. Rule #2: Oxygen increases cycle entry After running a new simulation with this second rule, we visualize results as follows: Figure 10.(oxygen, necrosis) Hill function.

Figure 19 .
Figure 19.Results with four rules.

Figure 21 .
Figure 21.Edit target value for secretion of debris.

Figure 27 .
Figure 27.Edit macrophage secretion parameters for drug.

Figure 33 .
Figure 33.Debris field at 6 hours (uncheck filled cells to see better).

Figure 36 .
Figure 36.Create M1 macrophage cell type and set its secretion parameters.

Figure 48 .
Figure 48.Results using seven rules, at 12 hours, showing pro-inflammatory factor (with fixed colormap range.