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Folding artificial mucosa with cell-laden hydrogels guided by mechanics models

Significance While mucosal folding is a ubiquitous phenomenon observed in many hollow or tubular human tissues/organs, recapitulating the process for tissue engineering has yet to be achieved. Here we fold a cell-laden hydrogel film to recapitulate the folding of a physiologically mimicking artificial mucosa. We attach the cell-laden hydrogel film onto a prestretched tough-hydrogel substrate, which after relaxation induces controlled patterns in the artificial mucosa. A combination of theory and numerical simulations predicts the folding conditions and the morphologies, thereby guiding the design of surface folding. This simple strategy can facilitate the understanding and engineering of mucosa for tissues/organs such as stomach, colon, and intestine. The work also demonstrates a paradigm in tissue engineering via harnessing mechanical instabilities guided by quantitative mechanics models. The surfaces of many hollow or tubular tissues/organs in our respiratory, gastrointestinal, and urogenital tracts are covered by mucosa with folded patterns. The patterns are induced by mechanical instability of the mucosa under compression due to constrained growth. Recapitulating this folding process in vitro will facilitate the understanding and engineering of mucosa in various tissues/organs. However, scant attention has been paid to address the challenge of reproducing mucosal folding. Here we mimic the mucosal folding process using a cell-laden hydrogel film attached to a prestretched tough-hydrogel substrate. The cell-laden hydrogel constitutes a human epithelial cell lining on stromal component to recapitulate the physiological feature of a mucosa. Relaxation of the prestretched tough-hydrogel substrate applies compressive strains on the cell-laden hydrogel film, which undergoes mechanical instability and evolves into morphological patterns. We predict the conditions for mucosal folding as well as the morphology of and strain in the folded artificial mucosa using a combination of theory and simulation. The work not only provides a simple method to fold artificial mucosa but also demonstrates a paradigm in tissue engineering via harnessing mechanical instabilities guided by quantitative mechanics models.