Chemomechanically voxelated niches for programmable histogenesis

Tissue and organoid models have been established with increasingly physiological shape, size, and function[1][1]–[3][2]. However, histogenesis proceeds stochastically within these models, relying on ‘self-organization’ mechanisms that limit their ability to form recapitulative organotypic structures with controlled architecture and composition. To address this, we develop a printing technology to program histogenesis using material-guided instructive cues. We print voxelated niche microenvironments with independently tunable chemical and mechanical microproperties, or ‘chemomechanics’. This includes the voxelization of conjugated peptides, proteins, and morphogens across a range of Young’s Moduli. We show that these niches are capable of the cellular-scale programming of functions that underpin histogenesis, including mechanosensing and the differentiation of selective cell types. By rationally designing these niches with specific voxelated properties, we can program histogenesis and generate spatially reproducible tissues from a single cell-source. These tissues include a bone-fat-osteoid from stromal mesenchyme and a polarized assembly of germ-layer tissues derived from pluripotent stem cells. While programming germ-layer tissues, we reveal that polarized matrix mechanics can direct human germ-layer histogenesis in a model of tissue development. Thus, chemomechanically voxelated niches are a valuable tool to program and structure cellular-scale behaviors into well-defined tissues. Their continued study potentiates a better understanding of how extrinsic niche factors regulate histogenesis, and their application enhances capabilities for generating tissues and organ systems with a well-defined composition and architecture. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-3