Mechanically Active Hydrogel for Healing Intestinal Fistulas through the YAP‐Mediated Mechanosensitization of Intestinal Epithelial Cells

Abstract Intestinal fistula is a serious condition characterized by abnormal connections between the intestine and surrounding tissues. Despite advances in comprehensive management of intestinal fistulas, patients often need to undergo definitive surgery and face life‐threatening complications due to ineffective closure measures. Herein, a mechanically active hydrogel (GNGP) that actively constricts intestinal fistulas in response to body temperature is presented. It possesses broad‐spectrum antimicrobial properties, excellent adhesion, suitable degradation properties, and a balance between injectable properties and mechanical activity—which, together, enable the in situ sealing of intestinal fistulas. Moreover, GNGP hydrogel accelerates the re‐epithelialization process of rabbit intestinal fistulas, ameliorates the inflammation of the fistula tract, and promotes the deposition of collagen into the damaged area to effectively facilitate intestinal fistula healing. Mechanistically, shear stress is found to promote the proliferation of intestinal epithelial cells via Yes‐associated protein‐mediated mechanosensitization, through finite element simulations and in vitro experiments. Together, this mechanically active hydrogel with injectable properties offers a promising strategy for the sealing treatment of intestinal fistulas.