Programmable Tissue Folding Patterns in Structured Hydrogels

Folding of mucosal tissues, such as the tissue within the epithelium of the upper respiratory airways, is critical for organ function. Studying the influence of folded tissue patterns on cellular function is challenging mainly due to the lack of suitable cell culture platforms that can recreate dynamic tissue folding in vitro. Here, a bilayer hydrogel folding system, composed of alginate/polyacrylamide double-network (DN) and hyaluronic acid (HA) hydrogels, to generate static folding patterns based on mechanical instabilities, is described. By encapsulating human fibroblasts into patterned HA hydrogels, human bronchial epithelial cells form a folded pseudostratified monolayer. Using magnetic microparticles, DN hydrogels reversibly fold into pre-defined patterns and enable programmable on-demand folding of cell-laden hydrogel systems upon applying a magnetic field. This hydrogel construction provides a dynamic culture system for mimicking tissue folding in vitro, which is extendable to other cell types and organ systems.