Hydrogel design for intestinal organoids: principles governing translational regenerative medicine

Intestinal organoids (IOs) are self-organized tissue constructs, grown in vitro, that closely replicate the structural and functional characteristics of the intestinal epithelium. The advent of IOs has significantly advanced research in areas such as intestinal development, disease modeling, drug screening, personalized medicine, regenerative medicine, etc. The development and functional maturation of organoids in vitro is heavily reliant on the presence of an extracellular matrix with appropriate biophysical properties. The significant breakthrough of polymer hydrogels offers tunable biochemical and biophysical properties, enabling efficient and high-quality cultivation of organoids. In this review, we provide a comprehensive evaluation of IO culture systems and discuss how mechanobiological signaling dynamics at the cell-matrix interface can guide the rational engineering of biomimetic extracellular matrix to standardize and regulate IO culture phenotypes. We systematically classify hydrogel-based matrices encompassing natural and synthetic hydrogel. We focus on how hydrogel properties affect the growth and development of IOs. We highlight biomimetic hydrogel innovations for applications in disease modeling, drug screening, regenerative medicine, and therapeutic delivery. By summarizing the challenges that hinder the development of IO hydrogels, we aim to provide insights into future directions for their advancement and promote the broader application of IOs in biomedicine.