# Whole Organ Engineering: Approaches, Challenges, and Future Directions
## 5 Recent Developments and Accomplishments
### Gastrointestinal  
Similar to bladder whole organ engineering, many of the early approaches to engineering organs of the gastrointestinal tract, including esophagus, stomach, small intestine, colon, and anal sphincter, consisted of a biodegradable polymer, decellularized ECM, or composite scaffold designed to recruit surrounding cells in order to regenerate the host tissue in rat and dog models [144; 145]. These approaches have seen successful in small animal models and small defect repair but may not be viable for regenerating larger defects or entire organs as they rely purely on host cells to regenerate the tissue. More recent approaches have also included intestinal organoids cultured in vitro from host cells incorporated into full thickness scaffolds to increase the regenerative potential of these grafts in vivo, which have shown some success in recovering organ function in rat models [146; 147]. Grafts of this type, however, only exhibited the most basic structural components of functional intestinal tissue and were not evaluated for barrier function as well as digestive and adsorptive capabilities [148]. A more recent study by [PERSON] et al., sought to improve this model by generating intestinal organoids from human and mouse intestinal mesenchymal stem cells and endothelial cells and seeding them onto the surface of biodegradable polyglycolic acid tubes to create a tissue-engineered small intestine (TESI) [148; 149]. The TESI constructs were then implanted into transgenic mice and evaluated 4 weeks later ex vivo [148]. The results of this study showed that TESI formed from both human and mouse intestinal stem cells were shown to be highly similar to native tissue in both its ultrastructural components and its secretory, digestive, and absorptive capabilities, indicating a high potential for clinical translation [148]. This technique of using mesenchymal stem cells to regenerate gastrointestinal tissue has been applied to tissue engineering of the stomach in other studies, such as one conducted by [PERSON] et al., which used bone marrow-derived mesenchymal stem cells (MSC) cultured on small intestinal submuc to patch artificial stomach defects in rats [150]. The presence of mesenchymal stem cells enhanced the regeneration of smooth muscle in the SIS graft compared to an unseeded control, indicating that mesenchymal stem cells have wide applicability in regeneration of hollow organs, especially in the GI tract and bladder [150]. The esophagus is a similar tissue in the GI tract that is a focus of tissue engineering but presents unique challenges as it has a much lower capacity for in vivo regeneration than the intestines and stomach and has to have superior mechanical properties in order to function properly [151]. A recent and highly experimental technique developed by [PERSON] et al., uses a composite polymer scaffold composed of an inner layer of electrospun polyurethane nanofibers and an outer layer of 3D-printed polycaprolactone microfibers seeded with human adipose-derived mesenchymal stem cells [151]. The inner electrospun layer enhances cell migration by providing 3D topical cues and the outer layer provides mechanical strength and flexibility to the construct [151]. The seeded constructs were then either cultured in a perfusion bioreactor or transplanted into omental tissue and then used as a full circumferential graft in a rat esophagus [151]. This technique resulted in the regeneration of the mucosa and smooth muscle around the full circumference of the grafted construct, which is not achievable with decellularized constructs alone; however, there were many complications associated with the surgical implantation and mechanical properties of the scaffold, indicating the need for further research on different polymers and natural biomaterials and the need to conduct large animal studies [151].