Abstract
Diseases of the esophagus, damage of the esophagus due to injury or congenital defects during fetal esophageal development, i.e., esophageal atresia (EA), typically require surgical intervention to restore esophageal continuity. The development of tissue engineered tubular structures would improve the treatment options for these conditions by providing an alternative that is organ sparing and can be manufactured to fit the exact dimensions of the defect. An autologous tissue engineered Cellspan Esophageal ImplantTM (CEI) was surgically implanted into piglets that underwent surgical resection of the esophagus. Multiple survival time points, post-implantation, were analyzed histologically to understand the tissue architecture and time course of the regeneration process. In addition, we investigated CT imaging as an “in-life” monitoring protocol to assess tissue regeneration. We also utilized a clinically relevant animal management paradigm that was essential for long term survival. Following implantation, CT imaging revealed early tissue deposition and the formation of a contiguous tissue conduit. Endoscopic evaluation at multiple time points revealed complete epithelialization of the lumenal surface by day 90. Histologic evaluation at several necropsy time points, post-implantation, determined the time course of tissue regeneration and demonstrated that the tissue continues to remodel over the course of a 1-year survival time period, resulting in the development of esophageal structural features, including the mucosal epithelium, muscularis mucosae, lamina propria, as well as smooth muscle proliferation/migration initiating the formation of a laminated adventitia. Long term survival (1 year) demonstrated restoration of oral nutrition, normal animal growth and the overall safety of this treatment regimen.
Highlights
The esophagus is a tubular organ that enables passage of food from the oral cavity to the stomach
Cellspan Esophageal ImplantTM (CEI) Seeding and characterization adipose derived mesenchymal stromal cells (Ad-mesenchymal stromal cells (MSCs)) cultures were expanded in two-dimensional flasks, harvested and seeded onto the scaffold in a custom rotating bioreactor
The goal of this study was to apply this technology to a pediatric porcine model to: (1) understand the time course of the regeneration process in young animals; (2) demonstrate that the regenerated tissue leads to the restoration of esophageal function; and (3) demonstrate that the CEI is safe and well tolerated in young animals, which is essential for clinical translation into children
Summary
The esophagus is a tubular organ that enables passage of food from the oral cavity to the stomach. Several diseases of the esophagus, esophagitis, refractory chronic strictures, injury due to caustic burns, perforations, or other injuries can lead to end-stage organ dysfunction requiring surgical repair[2,3,4,5,6,7,8,9,10]. EA occurs in approximately 1 in 4000 live births[10,11,12,13,14,15,16], with Long Gap Esophageal Atresia (LGEA) accounting for 7–8% of all EA and is defined as a large gap in the developing esophagus resulting in two blind ends (Gross type A, Vogt type II; Supplementary Fig. 1)[17]. Position papers delineating optimal surgical repair for LGEA by both the International Network of Esophageal
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