Cell-Sheet Shape Transformation by Internally-Driven, Oriented Forces

During morphogenesis, cells collectively execute directional forces that drive the programmed folding and growth of the layers, forming tissues and organs. The ability to recapitulate aspects of these processes in  vitro will constitute a significant leap forward in the field of tissue engineering. Free-standing, self-organizing, cell-laden matrices are fabricated using a sequential deposition approach that uses liquid crystal-templated hydrogel fibers to direct cell arrangements. The orientation of hydrogel fibers is controlled using flow or boundary cues, while their microstructures are controlled by depletion interaction and probed by scattering and microscopy. These fibers effectively direct cells embedded in a collagen matrix, creating multilayer structures through contact guidance and by leveraging steric interactions amongst the cells. In uniformly aligned cell matrices, oriented cells exert traction forces that can induce preferential contraction of the matrix. Simultaneously, the matrix densifies and develops anisotropy through cell remodeling. Such an approach can be extended to create cell arrangements with arbitrary in-plane patterns, allowing for coordinated cell forces and pre-programmed, macroscopic shape changes. This work reveals a fundamentally new path for controlled force generation, emphasizing the role of a carefully designed initial orientational field for manipulating shape transformations of reconstituted matrices.