Outside-in and Inside-out: taking inspiration from sheepherding to heal tissues faster and control cellular function

Living tissues are communities comprised of many thousands of cells, and healing even a 1 mm skin wound is an exercise in massive crowd dynamics. So, how can we heal faster or more effectively given this complexity? Our work applies principles from granular media, the biophysics of crowds, and sheepdog dynamics to develop new tools to 'herd' cellular motion. Here, we will present two crowd control paradigms for living cells focused on 'outside-in' and 'inside-out' control. 

Outside-in control of tissues is directly inspired by sheepherding and our group has relied on the use of bioelectric stimulation and 'electrotaxis' (cell migration along DC ion currents) as the sheepdog to direct both cell speed and direction. In our new work, we engineered and subsequently injured living skin layers and then applied precisely patterned bioelectric fields mapped to the specific size and shape of the injuries, demonstrating radically accelerated healing rates as well as a number of key examples of the unique challenges posed by trying to control granular groups. 

Inside-out control relies on the 'artificial agent' paradigm of crowd dynamics, where you engineer a synthetic object to mimic members of a living group and alter their crowd behaviors. In our new work, we 3D nanoprinted arrays of sub-cellular 'L'arc de triomphe' tunnel structures attached to a glass slide. Cells encountering these structures wrapped their membranes around the arches and proceeded to essentially adhere to themselves within the tunnels, akin to how you can hold onto a slender tree by wrapping your arms around it and holding on to yourself. This strategy produced stable adhesions that might help to improve implant integration into soft tissues, and again demonstrates the importance of adapting principles from crowd physics to control tissues.