World J Gastroenterol. 2012 December 21; 18(47): 6918-6925.
Published online 2012 December 21. doi: 10.3748/wjg.v18.i47.6918.
©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
Tissue engineering for neuromuscular disorders of the gastrointestinal tract
Kenneth L Koch, John E Fortunato, Section on Gastroenterology, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, United States
Khalil N Bitar, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States
Received April 19, 2012; Revised November 19, 2012; Accepted November 24, 2012;
The digestive tract is designed for the optimal processing of food that nourishes all organ systems. The esophagus, stomach, small bowel, and colon are sophisticated neuromuscular tubes with specialized sphincters that transport ingested food-stuffs from one region to another. Peristaltic contractions move ingested solids and liquids from the esophagus into the stomach; the stomach mixes the ingested nutrients into chyme and empties chyme from the stomach into the duodenum. The to-and-fro movement of the small bowel maximizes absorption of fat, protein, and carbohydrates. Peristaltic contractions are necessary for colon function and defecation.
Keywords: Neuromuscular disorders, Gastrointestinal tract, Dysfunction, Esophagus, Stomach, Small bowel, Colon
NEUROMUSCULAR FUNCTION OF THE GUT: NEUROMUSCULAR TUBES AND SPHINCTERS
The digestive tract is designed for the optimal processing of food that nourishes all organ systems. The esophagus, stomach, small bowel, and colon are sophisticated neuromuscular tubes with specialized sphincters that transport ingested food-stuffs from one region to another. Peristaltic contractions move ingested solids and liquids from the esophagus into the stomach[1
]; the stomach mixes the ingested nutrients into chyme and empties chyme from the stomach into the duodenum[2
]. The to-and-fro movement of the small bowel maximizes absorption of fat, protein, and carbohydrates[3
]. Peristaltic contractions are necessary for colon function and defecation[4
Sphincters of the digestive tract, on the other hand, have intrinsic muscle tone that produces sustained (tonic) pressure zones. The sphincteric pressures regulate movement of luminal content produced by the peristaltic contractions. Relaxation of the lower esophageal sphincter (LES), for example, allows the entry of esophageal content into the stomach[5
]; contraction and relaxation of the pyloric sphincter regulates movement of gastric content into the duodenum[6
]. The ileocecal valve regulates flow of content from the ileum into the cecum[7
]. The internal anal sphincter (IAS) regulates the elimination of rectal-sigmoid content[8
]. Sphincters not only provide resistance to flow in the areas distal to the sphincter but also limit the retrograde movement of intraluminal content into the areas proximal to the sphincter. Thus, normal neuromuscular function of the esophagus, stomach, small bowel, and colon requires the coordination of the tubular neuromuscular structures and the relevant sphincters. Symptoms such as dysphagia, nausea and vomiting, diarrhea, constipation, or incontinence may occur if neuromuscular function of the esophagus, stomach, intestine, and colon is disturbed, resulting in neuromuscular disorders such as achalasia, gastroesophageal reflux, gastroparesis, intestinal pseudo-obstruction, colonic inertia, and fecal incontinence, respectfully[1-4,9,10
The wall of gastrointestinal tract organs contains circular and longitudinal smooth muscle layers, the enteric nervous system including the myenteric plexus, and the interstitial cells of Cajal (ICCs) which control the rhythmicity of contractions[11,12
], all of which are targets for tissue bioengineering[13
]. The gastrointestinal tract wall is innervated by vagal afferent and efferent fibers and inputs from the sympathetic nervous system. Thus, neuromuscular disorders of the gastrointestinal tract may involve damage to the smooth muscle, enteric nerves, ICCs, extrinsic neurons, or all cell types. Neuromuscular diseases such as achalasia, gastroparesis, intestinal pseudo-obstruction, and colonic inertia represent the most severe forms of neuromuscular diseases of the gastrointestinal (GI) tract[14-17
]. These disorders are very difficult to treat, and very few drugs are designed to improve GI neuromuscular function. Table shows a summary of the human neuromuscular disorders from selected areas of the GI tract, the key neuromuscular abnormalities, the clinical neuromuscular diagnosis, and the medical and surgical treatments currently available for these diseases.
Neuromuscular disorders of the gastrointestinal tract, current treatments and future regenerative medicine approaches
In the most severe neuromuscular diseases, surgery is often required to improve symptoms. For example, a myotomy of the LES may be necessary to treat severe dysphagia due to achalasia. Partial resection of the colon and pull-through operations may also be necessary to treat drug-refractory, severe constipation or marked colonic dilation. Colectomy may be needed to correct aganglionic segments of colon as seen in Hirschsprung’s disease. While a surgical approach may relieve one set of symptoms, the consequence is often secondary neuromuscular disorders. After myotomy is performed for achalasia, for example, gastroesophageal reflux may occur and require drug treatment or fundoplication. Problems with fecal incontinence may also occur after colonic resection.
In this review, the normal neuromuscular function and disorders of neuromuscular function of the digestive organs in humans are discussed. We will focus on advances in regenerative medicine as an innovative and potential cure for GI neuromuscular diseases. The goal of this novel technology is restoration of the neuromuscular function of the bowel wall. A regenerative medicine approach aims to bioengineer “functional” circular and longitudinal smooth muscle, enteric neurons, ICCs, and mucosa in the correct anatomical configurations in order to produce normal physiologic gut functions. GI neuromuscular disorders are particularly suited to regenerative medicine approaches because drug and surgical therapies are extremely limited.
ESOPHAGUS: NEUROMUSCULAR FUNCTION AND DYSFUNCTION
The esophagus is a neuromuscular tube with an upper esophageal sphincter formed by the cricopharyngeus muscle, the esophageal body, and the lower esophageal sphincter at the esophagogastric junction. Peristaltic waves in the esophageal body move ingested solid and liquid foods from the proximal esophagus to the distal esophagus and into the stomach during relaxation of the lower esophageal sphincter (The upper esophageal sphincter is striated muscle and disorders will not be addressed). Neuromuscular disorders of the esophagus involve the esophageal body, the lower esophageal sphincter, or both and are listed on Table . For example, peristaltic esophageal contractions with abnormally high amplitudes are associated with chest pain and dysphagia and are termed the “nutcracker esophagus”[18
]. On the other hand, low amplitude and simultaneous contractions of the esophageal body are associated with achalasia and scleroderma[19
]. High amplitude contractions of the nutcracker esophagus may be treated with nitrates, but there are no medical or surgical treatments for low-amplitude simultaneous contractions of the esophageal body.
Neuromuscular disorders also occur in the LES. Increased LES pressure and decreased LES relaxation after swallows are the key neuromuscular features of achalasia[19
]. The hypertensive lower esophageal sphincter may be treated with nitrates, Botox injections, balloon dilation, or surgical myotomy. In contrast, a low amplitude LES pressure is associated with gastroesophageal reflux. There are no specific drug treatments available to increase LES pressure, but radiofrequency ablation[20
] and augmentation of the LES are device-related treatments that increase LES pressure[21
Regenerative medicine methods to produce patches or segmental portions of the esophageal wall have been studied in dogs. In a study by Nakase et al[22
], keratinocytes and fibroblasts (KF+ group) were cultured on human amniotic membrane opposed to smooth muscle tissue on a polyglycolic acid scaffold which was rolled around a polypropylene tube. Three weeks after implantation of this construct in the omentum, the KF (+) constructs had developed into tubes with stratified squamous epithelium and smooth muscle-like tissue. The KF (-) constructs lacked keratinocytes and fibroblast layers and developed luminal obstructions 2-3 wk after implantation into the esophagus. On the other hand, the 3 cm length KF (+) constructs showed distensibility, but no peristaltic contractions, when implanted in the esophagus. Shrinkage of the keratinocytes and smooth muscle also resulted in a shorter segment of restored esophagus that was durable up to 420 d in some dogs. Two of the six KF (+) dogs eventually developed esophageal structures. Scar formation and shrinkage of tissue engineered oral mucosa epithelial sheets were also major problems in bioengineered esophageal constructs[22
Takimoto et al[23
] used 5 cm silicone tubes to shape a collagen sponge matrix into an artificial esophagus. The construct was implanted in 43 dogs. Strictures occurred in 27 dogs if the Teflon support tube was removed 2-3 wk after implantation; but, the regenerated esophageal tissue replaced the esophageal defect if the stent was removed 4 wk after implantation. These regenerated tissues showed stratified epithelium, glands, and striated muscle, suggesting that cervical esophageal muscle had grown into the implant area, not smooth muscle of the esophageal body.
Regenerative medicine approaches to bioengineering the LES have been reported. In canine studies, the baseline LES pressure increased after skeletal muscle derived stem cells were injected into the LES area. The cells integrated within the native GI smooth muscle, but no differentiation of the cells into smooth muscle genotypes was noted[24
]. Regenerated lower esophageal sphincters need adequate myogenic tone to prevent gastroesophageal reflux, but also need to relax in response to swallows and the arrival of food boluses in the distal esophageal body. Furthermore, the LES must relax in response to distension of the fundus to allow physiological venting of stomach air. At this time, functioning neuromuscular constructs to restore animal or human esophageal body or sphincter functions are not available.
STOMACH: NEUROMUSCULAR FUNCTION AND DYSFUNCTION
Fundus and corpus-antrum
The key functional neuromuscular regions of the stomach are the fundus, body/antrum, and pylorus. In healthy subjects, the fundus relaxes through vagal mediated nitric oxide pathways in response to swallowing and in response to solids and liquids entering the gastric fundus from the esophagus[2
]. Ingested solids are triturated by the corpus/antrum until appropriate particle size is achieved. In humans, peristaltic activities are controlled by 3 cycle per minute gastric myoelectric activity or gastric slow waves[2
]. The triturated food is termed “chyme” and is emptied through the pylorus into the duodenum by body/antral peristaltic contractions.
Patients with paralysis of the stomach (or gastroparesis) may have neuromuscular dysfunction of the fundus, body/antrum, pylorus, or all of these areas. Symptoms of gastroparesis include early satiety, prolonged fullness, nausea, and the vomiting of undigested food[25
]. Table summarizes major gastric neuromuscular defects and the associated clinical diagnoses and treatments in gastroparesis. In patients with gastroparesis, the fundus fails to relax appropriately in response to ingestion of meals; other patients have excessive relaxation of the fundus. Abnormalities of fundic relaxation affect the ability of the stomach to accommodate ingested food. There are no established medical or surgical treatments for fundic dysfunction.
Low amplitude contractions of the corpus and antrum and abnormalities of gastric slow waves (e.g., presence of tachygastrias) results in disturbed peristalsis and gastroparesis[2,26
]. There are few medications available to treat gastroparesis[27
]. Gastric electrical stimulation is a device used to treatment for the nausea and vomiting symptoms of severe gastroparesis[28
Regenerative medicine approaches for the development of gastric tissues are evolving. Araki et al[29
] implanted a 5 cm collagen scaffold with silicone layers on the mucosa side and fabric on the serosa side. The scaffold was soaked in blood or bone marrow aspirate before implantation. Seven dogs were implanted. During the 16-wk study, the construct developed ulcers that healed, showed 59%-77% shrinkage in length, and developed alpha-smooth muscle actin positive cells, but no calponin staining cells. Maemura et al[30
] used rat stomach epithelium organoid cells, a preparation of minced rat stomach wall that was centrifuged, washed, and placed onto a tubular mesh. The organoid cells were wrapped in omentum in vivo
, harvested after 3 wk, and used to replace the resected stomach in the same rat. Barium studies showed emptying from the neo-stomach, but weight in these rats was no better than rats with total gastrectomy. Histology showed neo-mucosa and smooth muscle orientation similar to the normal stomach. In the study by Hori et al[31
], mucosal and smooth muscle layers of the canine stomach were bioengineered, but the construct exhibited no contractions. Ultimately, bioengineered constructs need to restore peristaltic contractions in the corpus/antrum for restoring gastric mixing and emptying of food.
On the other hand, dumping syndrome results when ingested foods are emptied exceedingly rapidly from the stomach into the duodenum[32
]. Increased antral contractions or decreased pyloric resistance to emptying are putative underlying mechanisms of dumping syndrome. Dumping syndrome may develop after resection of the antrum-pylorus for treatment of ulcers or cancer. Thus, pyloric function affects gastric emptying rates. Hypotensive pylorus is another mechanism that may underlie the dumping syndrome. There are no medical approaches to increasing pyloric pressure at this time. On the other hand, a hypertensive pyloric sphincter which does not relax (example: pylorospasm) is associated with gastroparesis[33
]. Medical approaches to the treatment of pylorospasm include injection of Botox or balloon dilation of the pylorus[34
]. In some patients, a myotomy may be performed to reduce pyloric pressure and increase gastric emptying.
Micci et al[35
] described transplantation of neural stem cells to the pylorus and results showed improved relaxation of pylorus muscle strips and improved gastric emptying in neural nitric oxide synthetase (nNOS) deficient mice. Results suggested the stem cells restored nNOS function regarding relaxation of the pylorus. The pylorus is a target for stem cell and regenerative medicine treatments. At this time, the bioengineered stomach and pylorus have not reached development for clinical deployment.
SMALL INTESTINE: NEUROMUSCULAR FUNCTION AND DYSFUNCTION
The small intestine is a hollow neuromuscular tube that comprises the duodenum, jejunum, and ileum[36
]. In the small intestine, chyme is broken down into smaller nutritional fragments: amino acids, carbohydrates, and fatty acids. Normal small intestinal motility and digestive enzymes from the pancreas and bile from the gallbladder are needed for normal digestion and absorption of nutrients. The ileum has special features for absorption of bile salts[37
]. The ileocecal valve is positioned between the distal ileum and the cecum, controls emptying of ileal effluent into the cecum, and prevents the reflux of cecal contents into the ileum. The regulation of this process is poorly understood because the ileocecal valve area is difficult to study in humans. Normal small intestinal motility includes phase 3, the interdigestive migrating motor complex, which consists of strong peristaltic contractions that move distally from the duodenum to the ileum in a cycle every 90 min during fasting[38
]. These contractions transport indigestible fibers from the small bowel into the colon.
Neuromuscular disorders of the small intestine are uncommon in adults. Scleroderma is associated with low amplitude, poorly organized small intestinal contractions and idiopathic chronic intestinal pseudo-obstruction involves disorders of the enteric nervous system and smooth muscle of the small bowel. In disorders with poor small intestinal peristaltic contractions, as seen in chronic intestinal pseudo-obstruction, bacterial overgrowth of the small bowel occurs and leads to malabsorption and diarrhea. There are no treatments for hypocontractility of the jejunum and ileum; however, small bowel bacterial overgrowth is treated with antibiotics and somatostatin which may increase the incidence of phase 3 migrating motor complexity. Jejunal diverticula can be resected surgically if they are thought to be the cause of symptomatic bacterial overgrowth. Short bowel syndromes occur in adults when the jejunum is resected due to ischemia and in neonates with severe enterocolitis that required resection[39
In regards to the ileocecal valve, a narrow nipple-like structure is positioned between the distal ileum and the cecum[7
]. Specific neuromuscular disorders have not been described. Mechanical obstructions due to tumors such as adenocarcinoma of the ileum or cecum may cause ileal obstruction and are treated with appropriate operations. Dysfunction or loss of the ileocecal valve may lead to “backwash ileitis”.
Regenerative medicine approaches to small bowel neuromuscular diseases include studies to increase the length of the small bowel to treat short bowel syndromes. Kim et al[40
] used polyglycolic tubes seeded with intestinal fragments (epithelial organoid units) which were implanted in the omentum of rats. These constructs developed into neointestinal cysts that were well vascularized, had a neomucosa with crypts, and some areas had smooth muscle[40
]. Anastomosis of the constructs with native small intestine was successful and no stenoses or obstructions developed[41
The small intestinal submucosa (SIS) was used to form a scaffold for bioengineered small intestine in dogs[42
]. SIS sheets were wrapped around glass tubes to form segments which were used to patch defects, approximately 7 cm × 3 cm in size, or for tubular implants in the small intestine. Most dogs with tubular implants had obstructions, anastomotic leaks, or appeared ill. Dogs with patch implants survived, but the implants shrunk approximately 35% in size, the mucosal layers were not well organized, and the amount of smooth muscle was variable or absent. Hori et al[43
] used autologous mesenchymal stem cells (MSC) from bone marrow seeded onto a collagen scaffold to induce smooth muscles to regenerate small intestine. A 5 cm area was resected and replaced with scaffold and a silicone tube stent to prevent contraction and stenosis. All six dogs survived. Although mucosa developed, no smooth muscle layers regenerated. Grikscheit et al[44
] used intestinal organoid units loaded into polymer tubes to form intestine-like segments. The units were implanted into the omentum. Four weeks later, small bowel resections were performed and the regenerated cysts and the native small bowel were connected with anastomoses. The regenerated cysts contained villi, crypts, ganglion cells, and some muscularis. Transit time was 1825 min in animals with regenerated cysts vs
982 min in those without implants, but weight gain was better in the former group. Nakase et al[45
] seeded a collagen scaffold with autologous smooth muscle cells isolated from the canine stomach. After implantation in the ileum, mucosal villi and circular smooth muscle cells developed in orderly alignment at 12 wk in animals with ileal reanastomosis at 8 wk after implantation. Scaffolds coated with basic fibroblast growth factor enhanced smooth muscle growth and angiogenesis, but distinct smooth muscle layers and contractions were not seen in these constructs[46
]. Some smooth muscle cells differentiated into fibroblast-like cells. More recently, Koga et al[47
] showed that the porcine small bowel was successfully lengthened with a hydraulic-lengthening device. The elongated jejunum retained near normal motility and absorption when implanted in the native jejunum.
No studies using human tissue have been reported for small bowel regeneration, although there is an extensive clinical need for small intestine segments as therapies for short gut syndromes. In adults with short bowel syndrome, increased length of small bowel would help ongoing problems with malabsorption and dehydration.
COLON: NEUROMUSCULAR FUNCTION AND DYSFUNCTION
The anatomical regions of the colon include the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and anorectum. The cecum and ascending colon receives up to 1.5 L of ileal effluent each day and absorbs 90% of the effluent. Subsequently, approximately 200 g of semi-solid stool are normally eliminated by defecation each day. Evacuation of the rectum requires coordination between peristaltic waves in the rectal-sigmoid area of the colon and relaxation of the anal sphincter and the pelvic floor muscles[4,8
Neuromuscular diseases related to the colon include irritable bowel syndrome in which increased and decreased contractility of the colon produces alternating constipation and diarrhea. Treatments for irritable bowel syndrome are confined to fiber supplements, cholinergic agents, and tricyclic antidepressants. There are no surgical options for irritable bowel syndrome. Colonic inertia is a disorder with weak contractions throughout the colon resulting in severe constipation. For patients with colonic inertia, there are very few medications other than laxatives and lubiprostone. In severe cases of colonic inertia, a colectomy may be performed. The colectomy (with ileo-sigmoid or ileo-rectal anastomosis) often results in loose stools four to six times per day. In some patients, the recto-sigmoid segment has significant neuromuscular dysfunction and constipation persists despite the colectomy[48,49
]. Similarly, functional constipation with associated fecal incontinence, often due to colonic dilation and megarectum, generally responds poorly to medical management. Surgical approaches such as cecostomy or appendicostomy (ACE) have been widely used in the treatment of refractory constipation. However, some patients are unable to have a bowel movement on their own despite the use of the cecostomy/ACE, while others demonstrate recurrent symptoms after discontinuation of antegrade enemas[50
]. When this occurs, further surgical intervention including placement of a diverting colostomy or colonic resection becomes an option[51
Regenerative medicine approaches to the colon have been explored in rats. A bioengineered colon segment, colonic mucosa, and smooth muscle was produced by seeding colon organoid units from autologous sigmoid colon onto polymer scaffolds. After implantation for 12 wk, the regenerated cysts showed correct colon micro-architecture[52
]. Hecker et al[53
] bioengineered colon tissues with normal three dimensional smooth muscle orientation around a central lumen; the tissue exhibited peristalsis. These experiments suggest that multiple smooth muscle rings may be an alternative method compared to regenerating long segments of the colon organ itself. There is much work remaining to be done to prepare the way for human studies related to the regeneration of the colon.
IAS: NEUROMUSCULAR FUNCTION AND DYSFUNCTION
The IAS is a smooth muscle that is under anonomic nervous system control, whereas the external sphincter is striated muscle under voluntary control[54
]. A hypertensive IAS with poor relaxation results in rectal outlet obstruction associated with severe constipation[4,8
]. Medical treatments include physical therapy, laxatives, Botox injections, and myotomy of the sphincter[55
]. On the other hand, a hypotensive or weak anal sphincter results in fecal incontinence. Fecal incontinence results in significant psychosocial issues and poor quality of life. Treatments of fecal incontinence include stool bulking agents, sphincteroplasty, injection of the sphincter with bulking agents, and sacral nerve stimulation[56
Neuronal disorders of the gut such as Intestinal Neuronal Dysplasia and Hirschsprung’s disease involve a developmental or degenerative loss of enteric neurons[57
]. Aganglionosis results in serious motility problems due to lack of adequate peristalsis. Symptoms include painful abdominal distention, stool retention, and fecal incontinence. Currently, surgical excision of the aganglionic segment is the most effective treatment strategy. Despite technical advances in surgery, the complications in Hirschsprung’s patients after corrective surgery include fecal incontinence (10%-16%) and enterocolitis (10%)[58,59
Considerable progress has been made using regenerative methods to bioengineer an internal anal sphincter that has properly aligned circular smooth muscle, and importantly, neural innervation. Hecker et al[53
] showed that IAS smooth muscle cells in fibrin-based gels developed into three dimensional smooth muscle rings which showed relaxation and contraction in response to 8-bromo-c AMP and acetylcholine, respectively. Somara et al[60
] used human IAS cells to form bioengineered three dimensional smooth muscle rings which exhibited basal myogenic tone that was dependent on prokein kinase C (PKC) pathways not rho kinase. Bioengineered mouse IAS constructions were grown for 28 d after implantation in the backs of mice. The harvested rings developed basal tone, responded normally to vascularization, had no ICCs, but smooth muscle cells (smooth muscle actin and h-caldesmon positive cells) were present and responded normally to stimulating and relaxing drugs[61
]. Thus, the implanted IAS constructions had traits of the native IAS. Raghavan et al[62
] reported the successful implantation of the bioengineered IAS comprised of human smooth muscle cells and immortomouse fetal enteric neurons. The harvested construct, implanted into RAGI-1-mice for 25-28 d developed neovascularization, myogenic tone, and normal contraction and relaxation characteristics in response to testing. These advances in bioengineering the IAS reflect increasing sophistication in combining the enteric nerve and GI smooth muscle components that will be critical in providing treatment for clinical neuromuscular diseases such as fecal incontinence.
Neuromuscular disorders of the GI tract are excellent but complex targets for regenerative medicine approaches designed to restore function. In many of these human diseases, the symptoms are severe, but treatments are extremely limited. Many challenges for regenerative medicine approaches remain: identifying sources for cells, construction of scaffolds that result in the proper three-dimensional growth of the selected cells into the desired organ, physiological orientation of the component layers of the wall of the GI organs, and the functional integration of the key cells (smooth muscle, enteric nerves, ICCs). Implantation, integration, and growth of the regenerated patches, grafts, and organs require growth factors, vascularization of the bioengineered tissues, and restoration of neuromuscular function. Many challenges must be overcome to bioengineer functional regions of the GI tract, but the needs and the opportunities are great.
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