Tissue engineering of the gastroesophageal junction

Abstract

The gastroesophageal junction has been of clinical interest for some time due to its important role in preventing reflux of caustic stomach contents upward into the esophagus. Failure of this role has been identified as a key driver in gastroesophageal reflux disease, cancer of the lower esophagus, and aspiration-induced lung complications. Due to the large population burden and significant morbidity and mortality related to reflux barrier dysfunction, there is a pressing need to develop tissue engineering solutions which can replace diseased junctions. While good progress has been made in engineering the bodies of the esophagus and stomach, little has been done for the junction between the two. In this review, we discuss pertinent topics which should be considered as tissue engineers begin to address this anatomical region. The embryological development and adult anatomy and histology are discussed to provide context about the native structures which must be replicated. The roles of smooth muscle structures in the esophagus and stomach, as well as the contribution of the diaphragm to normal anti-reflux function are then examined. Finally, engineering considerations including mechanics and current progress in the field of tissue engineering are presented.

Keywords: (MeSH): tissue engineering; esophageal sphincter, lower; esophagogastric junction; esophagus; regenerative medicine; stomach.

Figure 1:

Development of the gastroesophageal junction and embryonic contribution to layers of the adult histology. A) The trilaminar disc folding into a “tube within a tube”, as seen on the craniocaudal axis. B) Formation of posterior stomach bulge and 90-degree rotation to final position. C) Key layers of the adult lower esophagus, showing the locations of vasculature (arterial only), innervation, and muscle alignment.

Figure 2:

Anatomy and histology of the adult human GEJ. A) A longitudinal section of the GEJ, stained with hematoxylin and eosin. At the top of the image, a sharp division is seen between the esophageal and gastric mucosae. This image was provided by, and edited and reproduced with permission of, Dr. T. Clark Brelje and Dr. Robert J. Sorenson from the University of Minnesota. A high-resolution image is available online at histologyguide.org. B) Human cadaveric gastroesophageal junction, demonstrating its normal position in the abdominal cavity and key anatomical elements. The upper panel shows the anatomy in situ, after removal of the abdominal wall and some visceral adipose tissue. The lower panel shows the GEJ ex vivo, with a longitudinal incision made on the left-anterior surface of the junction to display the z-line. (Fig. 2B are primary images provided by the authors).

Figure 3:

A representative diagram detailing the components of the GEJHPZ, showing the sling and clasp fibers of the UGS, the LECS, and the diaphragm components.

Figure 4:

Averaged high-resolution 3D manometry of 10 healthy adult humans, presented as 3D and 2D unraveled images. The 3 o’clock position points to the greater curvature and the 9 o’clock position to the lesser curvature. 12 o’clock is anterior. Left-most image set shows end-expiration (EE) pressures. Middle set shows tidal inspiration (TI). Right-most set shows forced inspiration (FI), note change in color scale bar. Reproduced and adapted with permission from Mittal R.K., et al., Functional morphology of the lower esophageal sphincter and crural diaphragm determined by three-dimensional high-resolution esophago-gastric junction pressure profile and CT imaging, American Journal of Physiology - Gastrointestinal and Liver Physiology, 313(3): G212-G219. Copyright 2017 by the American Physiological Society.