Stress-Adaptive Biomaterials With Tunable Yielding Architectures Regulate Organoid Morphogenesis

The yield stress at which biomaterials undergo plastic deformation limits the stresses that can be developed in encapsulated growing tissues. While matrix mechanical properties such as stiffness and viscoelasticity have a profound effect on cells, the role of yield stress has remained challenging to define. Here, we design a granular hydrogel platform with supramolecular host-guest dynamic crosslinkers to precisely and quantitatively tune the stress at which the matrix repeatedly yields and reconfigures around tissues as they grow. Designed to provide similar mechanical constraints as a mesh stress ball, matrix yield stresses can be tuned between 12 and 370 Pa, while maintaining a storage modulus below ∼0.1 kPa. Our study suggests that this range of yield stress is sufficient to promote or limit peripheral shedding in a model of non-adhesive cancer migration, and that early development of midbrain organoids is exquisitely sensitive to these matrix mechanics. Yield stresses of only 25 Pa promoted bud-like protrusions and large, luminized neural rosettes, while variations as small as 10 Pa limited these phenotypes. These studies indicate that morphogenesis and tissue organization can be controlled via the material's yield stress, suggesting a new mechanical parameter to target in designing biomaterials for disease modeling and regenerative medicine.