Tissue-Attachable Intestinal Organoids as Injectable Therapeutics for Reconstruction of Intestinal Injuries

Crohn’s disease, a type of inflammatory bowel disease, can often lead to loss of intestinal function due to impaired intestinal barrier performance and exposure to noxious antigens that cause chronic inflammation. Organoids transplantation has emerged as a promising strategy for restoration of the damaged intestinal epithelial barrier in treating several intestinal diseases. However, most organoids culture commonly relies on the use of an ill-defined tumor-derived basement membrane extract, Matrigel, which restricts practical applications to transplantation with aim of regenerating tissues <i>in vivo</i>. Here, we develop tissue-adhesive hyaluronic acid (HA) hydrogels for generation and <i>in vivo </i>transplantation of intestinal organoids as an alternative substitute to Matrigel. The morphological and functional features of intestinal organoids cultured in the well-defined, biocompatible HA hydrogels are comparable to those in Matrigel by providing extracellular matrix-mimetic microenvironments. Moreover, superior tissue-adhesion ability of catechol-functionalized HA facilitates their use in transplantation of intestinal organoids to target tissues even under wet conditions. These results suggest the possiblity of only a single hydrogel in generating and transplanting intestinal organoids to accomplish an effective recovery of small intestinal wounds. Therefore, our chemically-defined, tissue-adhesive HA hydrogels can be a novel, simple therapeutic platform for organoids-based regeneration of intestinal injuries with further expansion to general tissue recovery.