Human Sphincter Research Articles

A Mechanics-Based Perspective on the Function of Human Sphincters During Functional Luminal Imaging Probe Manometry.

Functional luminal imaging probe (FLIP) is used to measure cross-sectional area (CSA) and pressure at sphincters. It consists of a catheter surrounded by a fluid filled cylindrical bag, closed on both ends. Plotting the pressure-CSA hysteresis of a sphincter during a contraction cycle, which is available through FLIP testing, offers information on its functionality, and can provide diagnostic insights. However, limited work has been done to explain the mechanics of these pressure-CSA loops. This work presents a consolidated picture of pressure-CSA loops of different sphincters. Clinical data reveal that although sphincters have a similar purpose (controlling the flow of liquids and solids by opening and closing), two different pressure-CSA loop patterns emerge: negative slope loop (NSL) and positive slope loop (PSL). We show that the loop type is the result of an interplay between (or lack thereof) two mechanical modes: (i) neurogenic mediated relaxation of the sphincter muscle or pulling applied by external forces, and (ii) muscle contraction proximal to the sphincter which causes mechanical distention. We conclude that sphincters which only function through mechanism (i) exhibition NSL whereas sphincters which open as a result of both (i) and (ii) display a PSL. This work provides a fundamental mechanical understanding of human sphincters. This can be used to identify normal and abnormal phenotypes for the different sphincters and help in creating physiomarkers based on work calculation.

795 AXIN2+ PERIBILIARY GLAND CELLS IN PERIAMPULLARY REGION SERVE AS BILIARY EPITHELIAL STEM CELLS AND GIVE RISE TO AMPULLARY CARCINOMA

Background and aims Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited due to a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer. Methods We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-CreERT mice. Results Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Axin2+ cells in periampullary PBGs expressed stem cell markers as well as cell proliferation markers. Lineage tracing revealed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and CK19 was mutually exclusive in periampullary region, and fate tracing of CK19+ luminal surface BECs revealed gradual replacement by CK19- cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that R-spondin3 (Rspo3), an enhancer of Wnt signaling, was strongly expressed in the smooth muscle cells adjacent to the lower part of periampullary PBGs. These smooth muscle cells corresponded to human sphincter of Oddi, and similar expression pattern of Axin2 and Rspo3 was observed in human periampullary region. Notably, smooth muscle cell-specific deletion of Rspo3 in mice markedly decreased Axin2 expression in periampullary PBGs and induced significant atrophy of ampulla of Vater. Furthermore, introduction of PTEN deletion into Axin2+ PBG cells (Axin2;PTENΔ/Δ mice), but not CK19+ luminal surface BECs (CK19;PTENΔ/Δ mice), induced ampullary carcinoma. Ampullary carcinoma organoids generated from Axin2;PTENΔ/Δ mice were dependent on Rspo3 for their growth, suggesting that extrinsic stimulation of Wnt signaling is important for the growth of ampullary tumors. In fact, administration of Wnt inhibitor dramatically suppressed ampullary carcinoma development in Axin2;PTENΔ/Δ mice. Conclusion A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also cellular origin of ampullary carcinoma. These new findings can facilitate the development of new therapeutic strategies to induce biliary regeneration, as well as to treat ampullary carcinoma. Download : Download high-res image (147KB) Download : Download full-size image Graphical Abstract

Axin2+ Peribiliary Glands in the Periampullary Region Generate Biliary Epithelial Stem Cells That Give Rise to Ampullary Carcinoma

Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer. We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-CreERT mice. Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19+ luminal surface BECs showed gradual replacement by CK19- cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal-activating niche. Notably, introduction of PTEN deletion into Axin2+ PBG cells, but not CK19+ luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor. A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma.

Soft Pneumatic Actuator for Rendering Anal Sphincter Tone.

Sphincter tone examination, as part of digital rectal examination (DRE), can provide essential information to support the early detection of colorectal cancer. Mastering DRE skills for junior doctors is always challenging due to the lack of real training cases. In this article, we developed a soft pneumatic active actuator,made of a compound of silicone rubber materials, to mimic human sphincter muscles and simulate various anal sphincter tones for the purpose of training. Different pumping actuation (syringe and bellows) and driving mechanisms (linear, stepper, and servo motor) were implemented and compared for their effect on the rendered tones. A further comparison was made with a previous prototype based on a cable-driven mechanism. Both quantitative and qualitative assessments were conducted to evaluate the performance of each mechanism. A differential pressure sensor was used to measure applied pressure on a catheter balloon placed inside the sphincter, comparing the readings with anorectal manometry data obtained from real patients. Qualitative feedback was gathered through a user study with ten colorectal expert practitioners. Four questions were asked targeting reaction/response time, pressure level, pressure quality, and similarity to a real case. The results show the capacity and limitation of each mechanism, with the one based on a servo motor and a bellows being the most favourably rated.

Sa1997 - Myoarchitecture of the Human and Porcine Lower Esophageal Sphincter Studied with Micro CT Imaging Reveals Circular Smooth Muscle Fibers Cross Midline at the Angle of His and Continue as the Sling Fibers of the Stomach

Sa1997 - Myoarchitecture of the Human and Porcine Lower Esophageal Sphincter Studied with Micro CT Imaging Reveals Circular Smooth Muscle Fibers Cross Midline at the Angle of His and Continue as the Sling Fibers of the Stomach

Biomechanical properties of an implanted engineered tubular gut-sphincter complex.

Neuromuscular diseases of the gut alter the normal motility patterns. Although surgical intervention remains the standard treatment, preservation of the sphincter attached to the rest of the gut is challenging. The present study aimed to evaluate a bioengineered gut-sphincter complex following its subcutaneous implantation for 4weeks in rats. Engineered innervated human smooth muscle sheets and innervated human sphincters with a predefined alignment were placed around tubular scaffolds to create a gut-sphincter complex. The engineered complex was subcutaneously implanted in the abdomen of the rats for 4weeks. The implanted tissues were vascularized. In vivo manometry revealed luminal pressure at the gut and the sphincter zone. Tensile strength, elongation at break and Young's modulus of the engineered complexes were similar to those of native rat intestine. Histological and immunofluorescence assays showed maintenance of smooth muscle circular alignment in the engineered tissue, maintenance of smooth muscle contractile phenotype and innervation of the smooth muscle. Electrical field stimulation induced relaxation of the smooth muscle of both the sphincter and the gut parts. Relaxation was partly inhibited by nitric oxide inhibitor indicating nitrergic contribution to relaxation. The present study has demonstrated for the first time a successfully developed and subcutaneously implanted a tubular human-derived gut-sphincter complex. The sphincteric part of Tubular Gut-Sphincter Complex (TGSC) maintained the basal tone characteristic of a native sphincter. The gut part also maintained its specific neuromuscular characteristics. The results of this study provide a promising therapeutic approach to restore gut continuity and motility. Copyright © 2016 John Wiley & Sons, Ltd.

New Insights into the Anatomy of the Bulbospongiosus Muscle and Its Role in the Composition of the External Anal Sphincter in Humans

Traditional descriptions of the bulbospongiosus muscle in males and females describe a striated muscle overlying the most proximal portion of the corpus spongiosus, the bulb of the penis in males, and the bulbs of the vestibule in females. Likewise, in both sexes the bulbospongiosus muscle and the superficial transverse perineal muscles are described as inserting at the midline on the perineal body. In dissections of forty (40) human cadavers we found both of these descriptions do not accurately characterize the anatomy. In all forty cadavers examined, as suggested by the embryology literature, the adult bulbospongiosus continues from the urogenital triangle to the anal triangle as an uninterrupted ring of muscle that forms the superficial portion of the external anal sphincter and passes deep and lateral to the perineal body without insertion. Additionally, the superficial transverse perineal muscle passes anteriorly and superiorly to insert onto the bulbospongiosus muscle, and does not follow traditional descriptions asserting that this muscle continues medially from the ischial tuberosities to the perineal body. The perineal body is inferior to the rest of the perineum and in the great majority of cadavers we did not observe any muscle fibers inserting on the perineal body, again contradicting the published literature. Dissections of the external anal sphincter demonstrate that the subcutaneous external anal sphincter has a different fiber direction and is not continuous with the superficial external anal sphincter. Also, the deep external anal sphincter is continuous with the puborectalis muscle and is located deep to and separate from the superficial external anal sphincter. Therefore, we suggest that the traditionally conceived external anal sphincter, with three parts of a single muscle, is more usefully described as three individual muscles.Support or Funding InformationMidwestern University Intramural Funds

Development of an animal model to tissue engineer human lips and anal sphincters

Development of an animal model to tissue engineer human lips and anal sphincters

600 In Situ Implantation of Autologous Biosphincter™ Re-Instates Continence in a Large Animal Model of Passive Fecal Incontinence

sensitive responses to electrical field stimulation (EFS). Conclusion: This is the first demonstration of a bioengineered innervated human pyloric sphincter. Bioengineered pyloric sphincters maintained appropriate myogenic and neurogenic functionality. These bioengineered tissues have the potential for use as (1) functional replacement organs and (2) physiologically relevant models to investigate human pyloric sphincter disorders. This work was supported by Army, Navy, NIH, Air Force, VA and Health Affairs to support the AFIRM II effort, under Award No. W81XWH-13-2-0052; GU 7 and Wake Forest School of Medicine Internal Funds.

599 Human Pyloric Sphincters Bioengineered Using Autologous Pyloric Smooth Muscle Cells and Neural Progenitor Cells

599 Human Pyloric Sphincters Bioengineered Using Autologous Pyloric Smooth Muscle Cells and Neural Progenitor Cells

Expression of serotonin receptors in human lower esophageal sphincter.

Serotonin (5-HT) is a neurotransmitter and vasoactive amine that is involved in the regulation of a large number of physiological functions. The wide variety of 5-HT-mediated functions is due to the existence of different classes of serotonergic receptors in the mammalian gastrointestinal tract and nervous system. The aim of this study was to explore the expression of multiple types of 5-HT receptor (5-HT1AR, 5-HT2AR, 5-HT3AR, 5-HT4R, 5-HT5AR, 5-HT6R and 5-HT7R) in sling and clasp fibers from the human lower esophageal sphincter (LES). Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing esophagogastrectomy, and circular muscle strips from the esophagus and stomach were used as controls. Reverse transcription-polymerase chain reaction (RT-PCR), quantitative PCR and western blotting were used to investigate the expression of the various 5-HT receptor types. Messenger RNA for all seven 5-HT receptor types was identified in the sling and clasp fibers of the LES. At the mRNA level, the expression levels were highest for 5-HT3AR and 5-HT4R, and lowest for 5-HT5AR, 5-HT6R and 5-HT7R. At the protein level, the expression levels were highest for 5-HT3AR and 5-HT4R, followed by 5-HT1AR and 5-HT2AR; 5-HT7R was also detected at a low level. The expression of 5-HT5AR and 5-HT6R proteins was not confirmed. The results indicate that a variety of 5-HT receptor types can be detected in the human LES and probably contribute to LES function.

Newer and novel artificial urinary sphincters (AUS): the development of alternatives to the current AUS device

The current artificial urinary sphincter (AUS), AMS 800 (American Medical Systems, Minnesota, MN, USA) is considered the standard of care for the treatment of urinary incontinence (UI). While the long-term effectiveness, safety, and durability of the current model of the AMS 800 are well documented, it is not without its limitations and complications. Over the last few years, improvements in design and innovative research into AUS devices have increased the treatment arsenal in male UI. Articles from peer-reviewed journals, abstracts from scientific meetings and electronic literature searches formed the basis of this review. Newer AUS models, e.g. FlowSecure, Zephyr, Pro-ACT and other novel experimental AUS devices, are designed to simulate a healthy human sphincter and address the limitation of the existing AMS 800 device. Newer and novel AUS models are innovative and showed promising outcomes in short- to intermediate-term follow-up. However, there exists the need for prospective randomised clinical trials and complete reporting of adverse and long-term results before these AUS models can replace the existing AMS 800 device.

The expression of motilin receptor in lower esophageal sphincter and its contraction responses to motilin

Objective The aim of the study was to investigate the expression of motilin receptor in sling and clasp fibers of the human lower esophageal sphincter and different contraction. responses of the two muscles to motilin. Methods Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect MTLR in the human sling fibers and clasp fibers. Inverted microscope was used to measure length changes of the sling and clasp fibers which were induced by motilin. Results MTLR were expressed both in the sling fibers and clasp fibers. Expression of MTLR in sling fibers was higher than in clasp fibers. The contraction in the sling fibers was stronger than in clasp fibers. Conclusion The contraction of the sling and clasp fibers in human esophageal sphincter is induced by motilin through MTLR. The contraction in the sling fibers is stronger than in clasp fibers. Key words: MTLR; Lower esophageal sphincter; Contraction; RT-PCR; Western blot

A study of an anatomic–physiological cecocolonic sphincter in humans

We hypothesized an anatomical/physiological sphincter and investigated this hypothesis in current communication. The histomorphologic and morphometric studies were carried out in 14 cadavers and radiologic studies in 20; endoscopy studies were done in 16 healthy volunteers. Longitudinal sections along cecum, cecocolonic junction, and ascending colon were stained with H & E and Masson's trichrome stain. Morphometry study of musclethickness of cecum, cecocolonic junction, and ascending colon, radiological examination by method of small bowel barium meal administration, and endoscopic study by pancolonoscopy were studied. A cecocolonic fold was identified 2-2.5 cm distal to ileocecal nipple. It extended along gut circumference, shelf-like, and was marked by a shallow groove on outer aspect of colon. Microscopically, cecocolonic fold consisted of mucosa, submucosa, and muscularis externa. The circular muscle layer was thicker than that of cecum or ascending colon. Branching cells with ovoid nuclei representing probably intestinal cells of Cajal were identified in muscularis externa. Also morphometric study showed that circular muscle layer was significantly thicker than that of cecum or ascending colon, whereas longitudinal muscle exhibited no significant difference. Radiologic studies demonstrated narrowing at cecocolonic junction, which became wider on cecal contraction and narrower or closed on colonic contraction. Endoscopically, cecocolonic junction was narrow due to presence of cecocolonic fold, which exhibited spontaneous contractions. Our findings suggest an "anatomic" sphincter at cecocolonic junction as evidenced histomorphometrically, radiologically and endoscopically. Detection of interstitial cells of Cajal in cecocolonic fold postulates possible existence a pacemaker in cecocolonic fold, a point that needs further study.

T1362 Human External Anal Sphincter: Evidence That it Operates at Low Sarcomere Length

T1362 Human External Anal Sphincter: Evidence That it Operates at Low Sarcomere Length

Effects of gastrokinetic agents on human sphincter of Oddi motility

Effects of gastrokinetic agents on human sphincter of Oddi motility

Functional lumen imaging probe (FLIP) to study the three-dimensional profile of the human sphincter of Oddi (SO)

Functional lumen imaging probe (FLIP) to study the three-dimensional profile of the human sphincter of Oddi (SO)

Effect of somatostatin on human sphincter of Oddi motility

Effect of somatostatin on human sphincter of Oddi motility

Choledochoscope manometry about different drugs on the Sphincter of Oddi

To assess the effects of H(2)-receptor blocking pharmacon, protease inhibitor, and gastro kinetic agents on the human Sphincter of Oddi (SO) motility by choledochoscope manometry. One hundred and seventy-five patients with T tube installed after cholecystectomy and choledochotomy were assessed by choledochoscope manometry. They were randomly assigned into groups of H(2)-receptor blocking pharmacon, protease inhibitor, and gastro kinetic agents. The Sphincter of Oddi basal pressure (SOBP), amplitude (SOCA), frequency of contractions (SOF), duodenal pressure (DP), and common bile duct pressure (CBDP) were scored and analyzed. SOBP and SOCA were significantly decreased after cimetidine administration, and no statistical difference was seen in the famotidine group. In the gabexate mesilate group, SOBP had decreased significantly. In the ulinastatin group, SOCA decreased when ulinastatin was given at the rate of 2500 U/min; when ulinastatin administration was raised to 5000 U/min, SOBP, SOF and SOCA all experienced a fall. SOBP and SOCA for domperidone and SOCA for mosapride groups all decreased distinctly after administration. The regular dosage of cimetidine showed an inhibitory effect on the motility of SO, while famotidine had no obvious effects otherwise. Gabnexata mesilate, ulinastatin and gastro kinetic agents also showed inhibitory effects on the SO motility.

Inhibitory purinergic neurotransmission in human lower esophageal sphincter

Inhibitory purinergic neurotransmission in human lower esophageal sphincter