@article{bibcite_8041, keywords = {Gastrointestinal system, Stem-cell differentiation, Tissue engineering}, author = {Holly M. Poling and Th{\'e}o No{\"e}l and Akaljot Singh and Garrett W. Fisher and Konrad Thorner and Praneet Chaturvedi and Kalpana Nattamai and Kalpana Srivastava and Matthew R. Batie and Taylor Hausfeld and Amy L. Pitstick and Nicole E. Brown and S{\'e}verine M{\'e}noret and Ignacio Anegon and Riccardo Barrile and Christopher N. Mayhew and Takanori Takebe and James M. Wells and Michael A. Helmrath and Maxime M. Mahe}, title = {Large-scale and innervated functional human gut tissues for transplantation via transient spheroid confinement}, abstract = {Key limitations of current human gastrointestinal organoids include incomplete physiological maturation and the need for complex, time-consuming assembloid approaches to integrate a functional nervous system for transplantation. Here we present a confined culture system (CCS) method that generates large-scale, elongated and functional human small intestinal, colonic and gastric tissues with a de novo enteric nervous system (ENS). We use a 3D-printed scaffolding tray to restrict spheroid fusion and growth, promoting the spontaneous co-development of a functional ENS. Transcriptomic and electrophysiological data demonstrate selective neuromuscular function and the presence of excitatory and inhibitory neurons within the tissues. When compared to traditional methods, the CCS expedites tissue maturation for transplantation, yielding organoids that are up to ten times larger, reaching widths of 8 cm after 10 weeks, and exhibit enhanced engraftment rate. CCS organoids integrate and adapt to murine luminal environment while maintaining barrier integrity and functional capacity. The CCS methodology simplifies current protocols while accelerating the production of complex, functional and clinically relevant gut tissues.}, year = {2026}, journal = {Nature Biomedical Engineering}, pages = {1-17}, month = {2026-05-22}, issn = {2157-846X}, url = {https://www.nature.com/articles/s41551-026-01688-6}, doi = {10.1038/s41551-026-01688-6}, language = {en}, }