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Cells self-organize into functional, ordered structures during tissue morphogenesis, a process that is evocative of colloidal self-assembly into engineered soft materials. Understanding how intercellular mechanical interactions may drive the formation of ordered and functional multicellular structures is important in developmental biology and tissue engineering. Here, by combining an agent-based model for contractile cells on elastic substrates with endothelial cell culture experiments, we show that substrate deformation–mediated mechanical interactions between cells can cluster and align them into branched networks. Motivated by the structure and function of vasculogenic networks, we predict how measures of network connectivity like percolation probability and fractal dimension as well as local morphological features including junctions, branches, and rings depend on cell contractility and density and on substrate elastic properties including stiffness and compressibility. We predict and confirm with experiments that cell network formation is substrate stiffness dependent, being optimal at intermediate stiffness. We also show the agreement between experimental data and predicted cell cluster types by mapping a combined phase diagram in cell density substrate stiffness. Overall, we show that long-range, mechanical interactions provide an optimal and general strategy for multicellular self-organization, leading to more robust and efficient realizations of space-spanning networks than through just local intercellular interactions. 

Abstract We investigate the effect of bis(imino)pyridine (BIP) ligands in guiding self-assembly of semiconducting CdSe/ZnS quantum dots (QDs) into three-dimensional multi-layered shells with diameters spanning the entire mesoscopic range, from 200 nm to 2 μm. The assembly process is directed by guest–host interactions between the BIP ligands and a thermotropic liquid crystal (LC), with the latter’s phase transition driving the process. Characterization of the shell structures, through scanning electron microscopy and dynamic light scattering, demonstrates that the average shell diameter depends on the BIP structure, and that changing one functional group in the chemical scaffold allows systematic tuning of shell sizes across the entire range. Differential scanning calorimetry confirms a relationship between shell sizes and the thermodynamic perturbation of the BIP molecules to the LC phase transition temperature, allowing analytical modeling of shell assembly energetics. This novel mechanism to controllably tune shell sizes over the entire mesoscale via one standard protocol is a significant development for research on in situ cargo/drug delivery platforms using nano-assembled structures.