Figure 2: Proposed
simulation replicating cell activation and expansion (a) Process and
permitted actions by the cells in each simulated step. (b) Simulated
life trajectory of a naïve starting cell to activated with full potency,
and natural exhaustion caused by aging. Also defined are two modes of
division – symmetric and asymmetric. (c) Sample simulation trajectories
for three control strategies – top to bottom row depicts optimum,
sub-optimum and random bead additions; bar plot at left indicates the
number of cells separated by type at each simulation step, the symbols
at the x axis represents the action taken: (+) refers to bead addition,
(-) refers to removal and (o) refers to no action; the right three
windows are simulation screens at 1, 5 and 19 steps.
Each cell has several attributes that are tracked through the
simulation, such as activated potency which starts at 0 with naïve cells
and steps to value of one when activated (Figure 2b). Step 5: An
activated cell can proliferate under condition of matured age, potency,
and stochastic probability (Figure 2a and detailed in Supplement 2).
The control agent can add beads,
take out beads or skip taking any action at the time step. A set number
of beads are added in each control step (e.g., 10, 20, 40). It is
observed that optimum bead to cell ration vary widely from 3:1 to 9:1
depending on bead and cell type . Keeping this in consideration, as the
system is seeded with 50 cells, 10 beads are allowed to be added in each
control step (beads can be added in consecutive steps). If a control
step occurs every 3.2 hours, there are 32 simulation steps between
actions and the agent can take a total of 50 control actions for each
simulation 1600/32). As an action the agent can either add, remove, or
keep beads the same. In the removal step all the beads are taken out at
once by a magnet (assuming use of commercial paramagnetic beads). This
is one important real-world constraint where the agent does not have the
choice to incrementally add or take out beads, it must add in a
specified amount or take out all together at a single step. Based on the
properties of cell (such as regeneration rate, how much it exhausts over
time, chance of getting converted if encountering a bead) the sequence
of action chosen by the agent can be optimal (ensuring high throughput
of robust effector cells marked with bright blue), or sub-optimal (low
number of effector cells or low potency effector cells marked with
yellow) at the end of expansion steps (Figure 2c).