Optimal wound healing via localized electrically controlled collective tissues

Collective cell migration is a critical phenomenon underlying myriad physiological processes ranging from wound healing to cancer invasion. Control over cell migration is therefore critical. Here, we use exogenously applied electric fields to control the motion of 2D tissues of tens of thousands of primary mouse keratinocytes. This control method leverages electrotaxis, the biophysical phenomena in which cells bias their migration directionally in the presence of a DC ionic current, an effect which occurs naturally in injuries due to ion transport. Unlike all prior electrotaxis studies that deliver global, homogenous electric stimulation, we developed a system capable of generating local electric control fields. Electrotaxis can regulate both cell speed and direction, and we first demonstrated that applying a local electrical stimulus to only the center of a large tissue resulted in a localized increase in migration speed, but a broadened response in orientational order with the electric field across the tissue due to long range coupling of mechanical information. We then applied this motif of local stimuli producing broadened responses to healing 2D, circular wounds in engineered skin layers where we demonstrated how local ring-shaped stimuli could accelerate healing. Applying these ring fields led to an initial increase in wound healing rates, but continuous stimulation eventually caused cellular crowding and jamming-induced slowdowns in healing. To circumvent this slowdown, we applied a single, short DC pulse which boosts initial healing rates and then allows for viscoelastic relaxation and natural healing without jamming. Having experimentally demonstrated how both the spatial and temporal elements of the electrical input affect crowd behavior, we next developed a biophysics-informed optimal control model. This model formalized our strategies for when and where to apply stimulation, which we experimentally validated to accelerate healing ~5x faster than unstimulated controls.