Active foam dynamics of tissue spheroid fusion

Abstract Three-dimensional tissue spheroids are a key building block in biofabrication, yet the link between their material properties and active mechanics of individual cells is not fully understood. We study the material properties of small spheroids of human periosteum-derived cells as they effect spheroid fusion, an elementary operation for constructing large tissue structures. We use two-photon confocal microscopy to measure cell-cell tension and individual cell motility throughout fusion. Cytoskeletal inhibition through Y-27632 (ROCKi) results in more granular tissues with decreased cell rearrangements, but accelerated fusion. Further reducing cell contractility with blebbistatin and ROCKi increases tissue granularity, decreases rearrangements, and slows down fusion. In all conditions, complete fusion is associated with frequent cellular rearrangements. Using a novel computational model that represents tissue material as an active cellular foam, with cells depicted as viscous shells with interfacial tension and persistent, random motility, we construct a phase diagram of spheroid fusion in function of relative cell-cell tension and cell motility. Our results reveal a close relationship between microscopic tissue fluidity and the visco-elastic properties of spheroid fusion. Additionally, we find that cell-cell friction promotes arrested fusion by inducing jamming through a distinct physical mechanism. Combined, our findings offer a framework for understanding spheroid fusion dynamics that can aid in the robust generation of large tissue constructs for regenerative medicine.