The gastrointestinal (GI) tract is a structurally complex hollow organ that displays diverse motility patterns to perform a variety of functions that aid ingestion, digestion, absorption of nutritive elements, and excretion of waste. Gastrointestinal motility is a result of chemical and electrical interactions between smooth muscle, intramural innervation, interstitial cells, and mucosal epithelial layers. This innate anatomical and physiological complexity dictates the requirement for a multi-disciplinary approach to regeneration of functional tissue replacements.
Anatomic complexity is recreated by engineering biomaterial microenvironments with characterized porosity and stiffness. Remodeling of the scaffold occurs upon cellular seeding according to the microenvironment, thereby dictating the functionality of the final bioengineered product. The primary goal of tissue engineering is to manufacture/engineer a physiological functional replacement tissue, using materials with appropriate biologic activity and biodegradability. Various strategies, including flow/perfusion or mechanical conditioning, are employed to maximize the functionality of the engineered ‘replacement tissue’ before implantation. Although the flow of the process is fairly logical, there are multiple hurdles involved in each step. Fig. 1 shows a schematic representation of the complexity involved in intestinal tissue engineering.
This review will focus on the multiple approaches used to reconstruct the neuromusculature of the gut, classified under the following functional segments: esophagus, stomach, small intestine, and colon that are interspersed with ‘sphincters’– closure zones that prevent backflow and reflux. These sphincteric regions include the lower esophageal sphincter (LES), pyloric sphincter, and the internal anal sphincter (IAS). Table 1 summarizes different GI neuromuscular disorders that could directly benefit from intestinal tissue engineering.
|Organ system||Disorder||Regenerative medicine alternative|
|Esophagus||Congenital long-gap atresia, esophageal cancer||Tubular constructs that allow neomucosa formation and perform conduit function |
Muscular layers and enteric plexuses for motility
Integrate with central nervous system for ‘at-will’ peristalsis
|Lower Esophageal Sphincter||Gastro-esophageal reflux disease||Sphincteric augmentation with sphincter-specialized aligned circular smooth muscle |
Maintenance of pressure to prevent reflux
Enteric neuronal plexuses for receptive relaxation to allow passage of luminal contents to stomach
|Stomach||Gastroparesis, altered gastric emptying||Elastic reservoir for accommodation of food (Fundus) |
Intrinsically innervated smooth muscle layer for propulsive mixing (Antrum)
Neomucosa for secretion
Repopulation of interstitial cells of Cajal for adequate pacemaking
|Pyloric sphincter||Hypertensive pylorus, dumping syndrome||Sphincteric augmentation with sphincter-specialized aligned circular smooth muscle to maintain high pressure closure |
Enteric neuronal plexuses for adequate relaxation to allow passage of chyme
|Small intestine||Short bowel syndrome||Tubular constructs with mucosal villi and crypts for adquate nutrient absorption |
Circular and longitudinal smooth muscle and enteric plexuses for peristalsis, absorption and motility
|Large intestine||Aganglionosis, inflammatory bowel disorders||Tubular constructs with concentrically aligned circular and longitudinal smooth muscle for peristalsis, motility and emptying |
Enteric neuronal plexuses for neurotransmission and motility
|Internal anal sphincter||Fecal incontinence, hypertensive sphincter||Sphincteric augmentation with sphincter-specialized aligned circular smooth muscle to maintain anorectal closure pressure |
Enteric neuronal plexuses to mediate relaxation of the sphincter to allow defecation