Tissue engineering of the gastrointestinal tract: the historic path to translation

Abstract

The gastrointestinal (GI) tract is imperative for multiple functions including digestion, nutrient absorption, and timely waste disposal. The central feature of the gut is peristalsis, intestinal motility, which facilitates all of its functions. Disruptions in GI motility lead to sub-optimal GI function, resulting in a lower quality of life in many functional GI disorders. Over the last two decades, tissue engineering research directed towards the intestine has progressed rapidly due to advances in cell and stem-cell biology, integrative physiology, bioengineering and biomaterials. Newer biomedical tools (including optical tools, machine learning, and nuanced regenerative engineering approaches) have expanded our understanding of the complex cellular communication within the GI tract that lead to its orchestrated physiological function. Bioengineering therefore can be utilized towards several translational aspects: (i) regenerative medicine to remedy/restore GI physiological function; (ii) in vitro model building to mimic the complex physiology for drug and pharmacology testing; (iii) tool development to continue to unravel multi-cell communication networks to integrate cell and organ-level physiology. Despite the significant strides made historically in GI tissue engineering, fundamental challenges remain including the quest for identifying autologous human cell sources, enhanced scaffolding biomaterials to increase biocompatibility while matching viscoelastic properties of the underlying tissue, and overall biomanufacturing. This review provides historic perspectives for how bioengineering has advanced over time, highlights newer advances in bioengineering strategies, and provides a realistic perspective on the path to translation.

Acute Exposure to Pyridostigmine Bromide Disrupts Cholinergic Myenteric Neuroimmune Function in Mice

“…[20] In our study, we aimed to demonstrate that acute PB exposure manifests as colonic neuroinflammation, that alters all cellular compartments associated with colonic motility (namely, myenteric neurons and ENSCs, SMCs, and muscularis macrophages). [13] We first evaluated colonic motility as the ability of the colon to increase baseline force (upon a contractile stimulation) or decrease baseline forces (upon a relaxation stimulant). In previous studies, we have demonstrated that exogenous addition of Acetylcholine (ACh) elicits a contraction through two synergistic mechanisms: i) acting directly upon the smooth muscle; and ii) acting on the enteric nerves.…”

“…[ 20 ] In our study, we aimed to demonstrate that acute PB exposure manifests as colonic neuro‐inflammation, that alters all cellular compartments associated with colonic motility (namely, myenteric neurons and ENSCs, SMCs, and muscularis macrophages). [ 13 ]…”

“…Specific to GI motility, disruptions of which result in FGIDs, the interplay between the ENS and the SMCs of the musculature is paramount. [13] Acetylcholine (ACh) is an important neurotransmitter in the ENS, and cholinergic neurotransmission contributes to the regulation of smooth muscle motility. [14][15][16][17] Disruption of cholinergic transmission (via PB exposure in GWI for example) in the intestine causes cholinergic desensitization through a redistribution of transmitters and disruption of gut motility.…”

Immunoglobulin superfamily member 3 is required for the vagal neural crest cell migration and enteric neuronal network organization

“…Four general concentric layers make up the gastrointestinal tract: from the innermost lumen facing mucosa, followed by submucosa, muscularis externa (muscularis propria), and the outermost protective serosa. Additionally, each layer consists of structural and functional subcomponents 16 – 19 . The epithelium, lamina propria, and muscularis mucosae make up the mucosa; the submucosal plexus constitutes the submucosa.…”

“…Furthermore, there are three segments of the muscularis externa: a circular smooth muscle layer, a myenteric plexus, and a longitudinal smooth muscle layer 18 – 20 . Thus, two plexuses compose the ENS: the myenteric plexus sits between the outer longitudinal smooth muscle cell layer and the inner circular smooth muscle layer; the submucosal plexus sits between the inner circular smooth muscle cell layer and the epithelial/mucosal layers of the gut 16 , 17 , 21 , 22 .…”