Stress-relaxing granular bioprinting materials enable complex and uniform organoid self-organization

Abstract Complex and robust tissue self-organization requires defined initial conditions and dynamic boundaries—neighbouring tissues and extracellular matrix that actively evolve to guide morphogenesis. A major challenge in tissue engineering is identifying material properties that are compatible with controlling initial culture conditions while mimicking dynamic tissue boundaries. Here we describe a highly tunable granular biomaterial, MAGIC matrix, that supports both long-term bioprinting and gold-standard tissue self-organization. We identify that significant stress relaxation at the long timescales and large deformation magnitudes relevant to self-organization is required for optimal morphogenesis. We apply optimized MAGIC matrices toward precise extrusion bioprinting of saturated cell suspensions directly into three-dimensional culture. Carefully controlling initial conditions for tissue growth yields dramatic increases in organoid reproducibility and complexity across multiple tissue types, enabling high-throughput generation of organoid arrays and perfusable three-dimensional microphysiological systems. Our results identify key biomaterial parameters for optimal organoid morphogenesis and lay the foundation for fabricating more complex and reproducible self-organized tissues.