Cellular Micro-Masonry: Assembling Perfect Tissue Models Cell-by-Cell

The different cell types that constitute living tissue are often structured into highly heterogeneous and complex spatial patterns; cell type can differ over length-scales as small as a single cell within a given tissue. For example, to maintain high rates of molecular exchange in the liver, a network of endothelial cells, called the sinusoid, permeates the periportal zone where every hepatocyte can be found within one or two cell diameters of an endothelial capillary. Another dramatic example is found in the pancreatic islet, where the five main cell types of the islet are located within a few cell diameters of one another. Small-scale structural heterogeneity is also exhibited by glandular acini in vitro. These hollow spheres are made from single epithelial monolayers surrounded by a basement membrane. While glandular acini represent an in vitro system in which the link between tissue structure and function can be studied in detail, it remains exceedingly challenging to reproduce the complex cellular patterns found more generally in vivo. Spontaneous or guided processes of multi-cellular self-assembly and advanced 3D bioprinting methods cannot precisely reproduce the detailed structural and functional heterogeneity at the single-cell scale found within in vivo tissues. In this talk we will describe a method for creating tissue models that exhibit the small-scale spatial heterogeneities found within in vivo tissue. With this method, 3D structures are built cell-by-cell, like a mason would build with stones or bricks. Thus, we call this method "Cellular Micro-Masonry." We will show that single-cell precision can be achieved with cellulular micro-masonry and that the micro-fabricated cellular structures are functional.