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Successful Transplantation of a Human Tissue Engineered Bowel (hTEB) in an Athymic Rat Model

Zakhem, Elie1,2; Tamburrini, Riccardo3,4; Orlando, Giuseppe3; Koch, Kenneth L.2,5; Bitar, Khalil N.1,2,5,6

doi: 10.1097/01.tp.0000520328.62174.fa
117.13
Free

1Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, NC, United States; 2Program in Neuro-Gastroenterology and Motility, Wake Forest School of Medicine, Winston Salem, NC, United States; 3Department of Surgery, Wake Forest School of Medicine, Winston Salem, NC, United States; 4Department of General Surgery, PhD program in Experimental Medicine, University of Pavia, Pavia, Italy; 5Section on Gastroenterology, Wake Forest School of Medicine, Winston Salem, NC, United States; 6Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston Salem, NC, United States.

Wake Forest School of Medicine Institutional Funds.

Background: Intestinal failure is a condition that results from the loss of a large surface area of the small intestine. Patients lose the ability to digest and absorb nutrients.

Objective: The objective of this study was to transplant human-based engineered neo-intestines into athymic rats to assess their viability and the regeneration of the essential components for digestion and absorption.

Methods: (1) TEB was developed by wrapping bioengineered innervated human intestinal circular smooth muscle sheets around tubular scaffolds. (2) TEBs were implanted in the omentum of athymic rats for 6 weeks. (3) At the end of 6–8 weeks: i) biopsies were obtained from TEB for analysis and ii) TEBs were then anastomosed to the native small intestine of the same rats. (4) At the time of sacrifice, TEBs were analyzed histologically and functionally.

Results: (1) TEB biopsies before anastomosis revealed maintenance of cell morphology and function as demonstrated by histology and physiology testing, respectively. (2) Following anastomosis, the rats initially lost weight then started steadily regaining normal weight over the study period. (3) At time of harvest, TEB was pink in color and healthy with food digest observed inside the lumen. (4) Organ bath studies were conducted on TEB: (i) Potassium chloride caused a rapid and robust contraction of the smooth muscle (367 ± 8 μN) which was inhibited in the presence of calcium channel blocker, Nifedipine. (ii) Neural function was confirmed using electrical field stimulation (EFS). EFS caused relaxation of the smooth muscle of TEB (−246 ± 16 μN). This relaxation was partially inhibited in the presence of nitric oxide (NO) synthase inhibitor, indicating functional nitrergic neural population. (5) H&E demonstrated maintenance of smooth muscle circular alignment around the lumen of TEB. Re-epithelialization of TEB was also observed with well-defined crypts and villi structures. Alcian blue stain demonstrated the presence of Goblet cells.

Conclusion: The results shown in this study demonstrated the successful transplantation of an engineered intestinal tissue in rats. The bioengineered tissues were viable and have acquired epithelial components with villi structures necessary for digestion and absorption. TEB provides a therapeutic approach to lengthen the gut to treat patients with intestinal failure.

Wake Forest School of Medicine Institutional Funds.

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