4D Materials with Photoadaptable Properties Instruct and Enhance Intestinal Organoid Development.

Intestinal organoids are self-organized tissue constructs, grown <i>in vitro</i>, that resemble the structure and function of the intestine and are often considered promising as a prospective platform for drug testing and disease modeling. Organoid development <i>in vitro</i> is typically instructed by exogenous cues delivered from the media, but cellular responses also depend on properties of the surrounding microenvironmental niche, such as mechanical stiffness and extracellular matrix (ECM) ligands. In recent years, synthetic hydrogel platforms have been engineered to resemble the <i>in vivo</i> niche, with the goal of generating physiologically relevant environments that can promote mature and reproducible organoid development. However, a few of these approaches consider the importance of intestinal organoid morphology or how morphology changes during development, as cues that may dictate organoid functionality. For example, intestinal organoids grown <i>in vitro</i> often lack the physical boundary conditions found <i>in vivo</i> that are responsible for shaping a collection of cells into developmentally relevant morphologies, resulting in organoids that often differ in structure and cellular organization from the parent organ. This disconnect relates, in part, to a lack of appropriate adaptable and programmable materials for cell culture, especially those that enable control over colony growth and differentiation in space and time (i.e., 4D materials). We posit that the future of organoid culture platforms may benefit from advances in photoadaptable chemistries and integration into biomaterials scaffolds, thereby allowing greater user-directed control over both the macro- and microscale material properties. In this way, synthetic materials can begin to better replicate changes in the ECM during development or regeneration <i>in vivo</i>. Recapitulation of cellular and tissue morphological changes, along with an appreciation for the appropriate developmental time scales, should help instruct the next generation of organoid models to facilitate predictable outcomes.