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PLoS One. 2019 Mar 8;14(3):e0211339. doi: 10.1371/journal.pone.0211339. eCollection 2019.

Regeneration of esophagus using a scaffold-free biomimetic structure created with bio-three-dimensional printing.

Author information

1
Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
2
Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki,Japan.
3
Biomedical Engineering Course, Advanced Technology Fusion, Graduate School of Science and Engineering, Saga University, Saga, Japan.

Abstract

Various strategies have been attempted to replace esophageal defects with natural or artificial substitutes using tissue engineering. However, these methods have not yet reached clinical application because of the high risks related to their immunogenicity or insufficient biocompatibility. In this study, we developed a scaffold-free structure with a mixture of cell types using bio-three-dimensional (3D) printing technology and assessed its characteristics in vitro and in vivo after transplantation into rats. Normal human dermal fibroblasts, human esophageal smooth muscle cells, human bone marrow-derived mesenchymal stem cells, and human umbilical vein endothelial cells were purchased and used as a cell source. After the preparation of multicellular spheroids, esophageal-like tube structures were prepared by bio-3D printing. The structures were matured in a bioreactor and transplanted into 10-12-week-old F344 male rats as esophageal grafts under general anesthesia. Mechanical and histochemical assessment of the structures were performed. Among 4 types of structures evaluated, those with the larger proportion of mesenchymal stem cells tended to show greater strength and expansion on mechanical testing and highly expressed α-smooth muscle actin and vascular endothelial growth factor on immunohistochemistry. Therefore, the structure with the larger proportion of mesenchymal stem cells was selected for transplantation. The scaffold-free structures had sufficient strength for transplantation between the esophagus and stomach using silicon stents. The structures were maintained in vivo for 30 days after transplantation. Smooth muscle cells were maintained, and flat epithelium extended and covered the inner surface of the lumen. Food had also passed through the structure. These results suggested that the esophagus-like scaffold-free tubular structures created using bio-3D printing could hold promise as a substitute for the repair of esophageal defects.

Conflict of interest statement

The authors of this manuscript have read the journal's policy and have the following competing interests: Koichi Nakayama is co-founder and a shareholder of Cyfuse. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

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