Self-assembly is a fundamental process that drives structural organization in both inanimate and living systems. It is in the course of self-assembly of cells and tissues in early development that the organism and its parts eventually acquire their final shape. Even though developmental patterning through self-assembly is under strict genetic control it is clear that ultimately it is physical mechanisms that bring about the complex structures. Here we show, both experimentally and by using computer simulations, how tissue liquidity can be used to build tissue constructs of prescribed geometry in vitro. Spherical aggregates containing many thousands of cells, which form because of tissue liquidity, were implanted contiguously into biocompatible hydrogels in circular geometry. Depending on the properties of the gel, upon incubation, the aggregates either fused into a toroidal 3D structure or their constituent cells dispersed into the surrounding matrix. The model simulations, which reproduced the experimentally observed shapes, indicate that the control parameter of structure evolution is the aggregate-gel interfacial tension. The model-based analysis also revealed that the observed toroidal structure represents a metastable state of the cellular system, whose lifetime depends on the magnitude of cell-cell and cell-matrix interactions. Thus, these constructs can be made long-lived. We suggest that spherical aggregates composed of organ-specific cells may be used as ''bio-ink'' in the evolving technology of organ printing.

Understanding the principles of biological self-assembly is indispensable for developing efficient strategies to build living tissues and organs. We exploit the self-organizing capacity of cells and tissues to construct functional living structures of prescribed shape. In our technology, multicellular spheroids (bio-ink particles) are placed into biocompatible environment (bio-paper) by the use of a three-dimensional delivery device (bio-printer). Our approach mimics early morphogenesis and is based on the realization that the genetic control of developmental patterning through self-assembly involves physical mechanisms. Three-dimensional tissue structures are formed through the postprinting fusion of the bio-ink particles, in analogy with early structure-forming processes in the embryo that utilize the apparent liquid-like behavior of tissues composed of motile and adhesive cells. We modeled the process of self-assembly by fusion of bio-ink particles, and employed this novel technology to print extended cellular structures of various shapes. Functionality was tested on cardiac constructs built from embryonic cardiac and endothelial cells. The postprinting self-assembly of bio-ink particles resulted in synchronously beating solid tissue blocks, showing signs of early vascularization, with the endothelial cells organized into vessel-like conduits.