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Simple Precision Creation of Digitally Specified, Spatially Heterogeneous, Engineered Tissue Architectures

Natural organs are spatially heterogeneous, both in material composition and in the cell types within. Engineered tissues, in contrast, remain challenging to create, especially if the goal is to spatially position multiple cell types in a heterogeneous pattern in three dimensions (3D). Here, we describe a simple, inexpensive, yet extremely precise method to create tissue architectures in a digitally specifiable fashion, with morphological and compositional tuning. Specifically, we pattern hydrogel crosslinking via a novel photolithographic process that can trap solutions of extracellular matrix (ECM) components, cells, and diffusible factors in defined 3D shapes, without requiring specialized expensive optics or robotics. By iterating this process with different patterns and different cellular compositions, engineered tissues of varying heterogeneity, size, and complexity can be designed and implemented with microscale precision, in a fashion practical for individual laboratories to perform. We demonstrate the power of this process by engineering tissue building blocks in defined geometries, creating engineered tissues that encapsulate different cells (e.g., primary neurons, embryonic stem cells (ESCs), human umbilical vein endothelial cells (HUVECs), and fibroblasts) at specified locations throughout a single 3D tissue volume. We used the ability to rapidly synthesize tissue volumes of varying scale to examine how tissue volume governs neuron development.