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HOME > Clin Endosc > Volume 59(1); 2026 > Article
Review Natural orifice transluminal endoscopic surgery: history and current development
Zaheer Nabiorcid, D. Nageshwar Reddyorcid
Clinical Endoscopy 2026;59(1):21-32.
DOI: https://doi.org/10.5946/ce.2025.009
Published online: July 1, 2025

Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India

Correspondence: Zaheer Nabi Department of Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500082, India E-mail: zaheernabi1978@gmail.com
• Received: January 6, 2025   • Revised: February 15, 2025   • Accepted: March 25, 2025

© 2026 Korean Society of Gastrointestinal Endoscopy

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Natural orifice transluminal endoscopic surgery (NOTES) represents an innovative advancement in minimally invasive surgery, utilizing natural body orifices to access the peritoneal cavity to minimize surgical trauma, reduce postoperative pain, and avoid visible scars. Since its inception, NOTES has faced challenges such as technical complexity and securing safe access closure, which initially limited its widespread adoption. However, advancements in endoscopic techniques and technology, closure devices, and hybrid approaches may revitalize its clinical utility. Hybrid NOTES, particularly transvaginal techniques, has demonstrated significant benefits, including reduced postoperative pain, faster recovery, and improved cosmesis, without compromising safety or efficacy. Innovations such as flexible endoscopic platforms, robotic assistance, and novel suturing techniques address previous limitations and enable broader applications across various gastrointestinal indications. Comparative studies have shown comparable outcomes between NOTES and traditional laparoscopy, with specific advantages in terms of patient comfort and recovery time. As technology evolves, NOTES continues to expand its clinical indications, and its future holds promise with the integration of robotics and artificial intelligence. Further research and structured training programs are crucial to overcome existing barriers and ensure safe and effective implementation in diverse clinical settings.
  • Keywords: Endoscopy, gastrointestinal; Minimally invasive surgical procedures; Natural orifice endoscopic surgery
The foundation of minimally invasive surgery (MIS) was laid with the introduction of laparoscopy, which revolutionized surgical practice by enabling procedures through small incisions. Building on this success, natural orifice transluminal endoscopic surgery (NOTES) emerged as a natural evolution of MIS, driven by the desire to minimize surgical trauma, eliminate visible scarring, and accelerate recovery. Early studies demonstrated the feasibility of accessing the peritoneal cavity via the transgastric route, allowing procedures such as peritoneoscopy, cholecystectomy, and appendectomy.1 However, the technical complexity of pure NOTES, predominantly due to limitations of the flexible endoscopic platforms and secure gastrotomy closure, halted its further progress. These issues have paved the way for hybrid NOTES, especially via the transvaginal route, which provides a safer and less demanding access point in addition to the benefits of rigid laparoscopic instruments. Numerous studies have established the feasibility, safety, and efficacy of this approach, which has significant advantages over traditional laparoscopy including better cosmesis, reduced postoperative pain, and faster recovery.2,3
With continued innovations in endoscopic technology, closure devices, and robotics, NOTES may re-emerge as a transformative approach to MIS, warranting renewed attention and research.
In 2004, Kalloo et al.1 at Johns Hopkins University reported transgastric peritoneoscopy in a porcine model. This landmark study proved the feasibility of accessing the peritoneal cavity through the stomach using a flexible endoscope. In the coming years, various NOTES approaches were tested in animal models to assess their feasibility, safety, and outcomes. The first human cases demonstrated the technical feasibility of NOTES for various procedures, including cholecystectomy, peritoneoscopy/liver biopsy, and appendectomy.4 Reddy and Rao reported the first pure transgastric appendectomy in 2004.5
The Natural Orifice Surgery Consortium for Assessment and Research, a joint initiative by the American Society for Gastrointestinal Endoscopy and the Society of American Gastrointestinal and Endoscopic Surgeons, was established in 2005 to advance NOTES research, formulate safety standards, and promote collaboration. While several studies confirmed the feasibility of NOTES during this period, the challenges associated with transgastric access to NOTES were soon realized. These were predominantly related to the difficulty in securely closing the access sites and the limitations of endoscopes and other instruments not designed for performing NOTES. Early technical challenges led to the development of transvaginal hybrid NOTES, which combines NOTES with laparoscopic assistance for safety and visualization. Zorrón et al.6 reported the first transvaginal cholecystectomy in a 43-year-old female patient with symptomatic gallstones. Transvaginal appendectomy was first reported by Palanivelu et al. (1 pure and 5 hybrid).4 The authors emphasized the advantages of the transvaginal approach, which provided a normal image of the target organ, unlike the inverted image of a transgastric approach.
Common access routes for NOTES include the transgastric and transvaginal procedures. Other access points, including the transrectal and transesophageal, have been utilized less frequently because of feared complications, especially infections (Fig. 1, Table 1).
Transgastric NOTES
The transgastric approach involves accessing the peritoneal cavity via the stomach wall using flexible endoscopy. The feasibility of flexible transgastric peritoneoscopy was reported in an animal study by Kalloo et al. in 2004.1 Subsequent animal studies confirmed the feasibility of transgastric NOTES for gastrojejunal anastomosis and fallopian tube ligation.7-10 Early human studies demonstrated NOTES to be a scarless alternative for staging abdominal malignancies or investigating ascites of unknown origin.11-14 The transgastric approach was then explored for other procedures, especially cholecystectomy and appendectomy. While feasibility was demonstrated unanimously, the major concerns were technical complexity, leading to prolonged procedure duration and difficulty ensuring secure watertight gastrotomy closure. Several studies have reported new techniques (over-the-scope clip and T-bar) for the secure closure of gastric defects.15,16 However, without a dedicated platform, the challenges of adapting a flexible endoscopy system for pure transgastric NOTES hampered its further development (Fig. 2A).
Transvaginal NOTES
Transvaginal NOTES offers several advantages over the transgastric approach, making it a more favorable option, particularly for female patients. The straight-line trajectory and stability provided by rigid instruments in transvaginal NOTES have made it the preferred route for various abdominal and pelvic procedures, with superior outcomes in procedure duration and safety.17 Initial concerns regarding the potential negative impact of transvaginal NOTES on female sexual function have been alleviated by several studies demonstrating no such adverse effects.18-20 Despite its advantages, sex-related barriers have indeed been a limiting factor in its broader adoption (Fig. 2B).
Other access points
The esophagus and colon are other routes of access for NOTES. However, literature regarding the safety and utility of NOTES through these entry points is sparse. The predominant reasons are the high risk of bacterial contamination and potentially fatal complications such as mediastinitis. Transrectal (also transanal or transcolonic) NOTES interventions include colon resections (rectosigmoidectomy), total mesorectal resections of cancers in stage T2 or T3, and specimen retrieval. More recently, transanal endoscopic appendectomy was reported in 23 patients with appendiceal lesions.21 The en bloc resection rate was 95.7%. The mean procedure duration was 91.1±45.5 minutes, and the mean wound closure time was 29.4±18.6 minutes. The defects after endoscopic appendectomy were closed using clips (21.7%) or a combination of clip closure and endoloop reinforcement (78.3%). Three patients (13.0%) experienced major adverse events: two had delayed perforations requiring laparoscopic surgery, and one had an infection (Fig. 2C).
Pure NOTES is performed entirely through natural orifices (e.g., mouth, rectum, or vagina) without any external incisions. Therefore, it relies solely on flexible endoscopic techniques and accessories for endoscopic resection procedures. The potential advantages of pure NOTES include no external scars, better cosmetic outcomes, reduced postoperative pain due to the absence of abdominal wall incisions, and the potential for faster recovery and lower risk of wound infections. However, pure NOTES is technically challenging, has a steep learning curve, and is limited by current endoscopic instruments and navigation capabilities.
Hybrid NOTES combines the natural orifice approach with percutaneous or laparoscopic assistance, such as adding small incisions for enhanced visualization, stability, or tool access.22 For example, during hybrid transgastric cholecystectomy, peritoneal access is gained using a flexible endoscope under laparoscopic visualization, the cystic duct and artery are clipped laparoscopically, and finally, the gastrotomy is closed intralumenally and over-sewed laparoscopically. The gallbladder is extracted through the mouth.23 Hybrid NOTES is less technically demanding than pure NOTES, making it easier to use in clinical practice. The disadvantages include postoperative pain and scarring, as small incisions are still required; extended procedure time due to the dual approach; and potentially higher costs due to combined equipment requirements (Fig. 2D).
The broad clinical applications of NOTES specific to gastrointestinal (GI) diseases include cholecystectomy, appendectomy, and peritoneoscopy for evaluating ascites and staging malignancies. Other less frequently reported applications include liver biopsy, gastrojejunostomy, fenestration in polycystic liver disease, epigastric ventral hernia repair, colon resection, and extraction of extraluminally migrated foreign bodies.24-27
Peritoneoscopy
In a seminal study, the peritoneal cavity was accessed by needle-knife puncture of the gastric wall, followed by extension of the incision with a pull-type sphincterotome or balloon dilation.1 The peritoneal cavity was examined, a liver biopsy specimen was obtained, and finally, the gastric wall incision was closed with clips. This study paved the way for future studies in which the role of NOTES was explored for various surgeries, especially cholecystectomy and appendicectomy. The potential limitations of NOTES peritoneoscopy have been highlighted in a porcine study comparing transgastric NOTES and laparoscopic peritoneoscopy for the detection of peritoneal metastases.28 Transgastric peritoneoscopy was inferior to laparoscopic peritoneoscopy for the detection of simulated metastases, particularly those located in the liver. Subsequent studies in porcine and human cadaver models confirmed the superiority of standard laparoscopy for organ visualization, lesion detection, and biopsy capability over transgastric and transcolonic NOTES approaches.29-31 These studies emphasized the need for improved access, especially to the inferior surface of the liver, and enhanced endoscopic optics and performance (Fig. 3).
NOTES cholecystectomy
Cholecystectomy has been the classical indication for NOTES. Transgastric access for NOTES cholecystectomy did not gain widespread acceptance owing to technical challenges and a lack of reliable closure techniques. Transgastric cholecystectomy requires endoscopic retroflexion to access the gallbladder. Moreover, tasks such as identifying Calot’s triangle, dissecting the cystic artery and duct, and achieving hemostasis are particularly difficult in this position. Another challenge was the limited size of the specimen that could be extracted transorally. These limitations have paved the way for laparoscopy-assisted NOTES (hybrid NOTES) via the transvaginal route. Consequently, most studies have reported the outcomes of hybrid transvaginal cholecystectomy.
The international prospective multicenter trial on clinical NOTES (IMTN study) reported the outcomes of transvaginal cholecystectomy (240 cases) and transgastric cholecystectomy (29 cases).32 While the operating times were similar in both groups, the challenges during transgastric cholecystectomy included difficult gastric opening and closure and restricted dissection possibilities due to the retroflexed scope position. In one transgastric cholecystectomy, the specimen could not be retrieved through the mouth because of its large size.
The outcomes of NOTES cholecystectomy were subsequently reported by the Euro and the German NOTES registries, including a large number of patients.33,34 The Euro-NOTES registry reported one of the largest series of cholecystectomies, including 435 patients.33 All the procedures were performed via hybrid technique utilizing the transvaginal approach in 423 cases (97.2%) and a transgastric hybrid approach in 12 (2.8%). The mean operative time of all transvaginal techniques was significantly shorter than that of the transgastric approach (60.7 vs. 125.4 minutes, p<0.001). Intraoperative complications included bleeding and injury to the urinary bladder in one case each. Postoperative complications (2.5%) included hematoma, bile leak, and pelvic abscesses. In a systematic review and meta-analysis of 730 patients in nine controlled clinical trials, transvaginal cholecystectomy and laparoscopic cholecystectomy had similar morbidity and return to work after surgery.35 However, the transvaginal cholecystectomy group had a lower pain score, required less postoperative analgesic medication, and had a shorter hospital stay. Transvaginal cholecystectomy had no significant effect on postoperative sexual function or quality of life (Table 2).17,19,27,32-34
Gallbladder-preserving NOTES
Several recent studies have evaluated the feasibility and safety of gallbladder-preserving NOTES in cases of benign gallbladder polyps and gallstones.36,37 A retrospective study involving six tertiary care hospitals in China assessed the feasibility, safety, and efficacy of pure NOTES for gallbladder-preserving therapy in 207 patients with symptomatic gallstones and/or gallbladder polyps.38 The procedure achieved a 99% technical success rate. Adverse events included conversion to cholecystectomy (one patient), bile peritonitis (2.4%), and fever (13%). At a follow-up of 12 to 48 months, symptomatic gallstone and gallbladder polyp recurrence rates were 13% and 13.5%, respectively.
In a propensity-matched study, Liu et al. compared the safety and effectiveness of pure NOTES gallbladder-preserving polypectomy versus laparoscopic cholecystectomy for gallbladder polyps (19 patients in each group).39 Both methods achieved 100% technical success; however, NOTES demonstrated significant advantages, including no postoperative pain, faster recovery, and no long-term complications, such as post-cholecystectomy syndrome. While laparoscopic cholecystectomy has shorter procedure times, NOTES offers benefits such as organ preservation, quicker recovery, and fewer long-term symptoms. NOTES is a promising alternative for gallstone management. However, further large-scale randomized studies are required to establish its utility.
NOTES appendectomy
The German NOTES Registry reported the largest data on NOTES appendectomies, including 181 transvaginal appendectomies and 36 transgastric appendectomies.17 Hybrid NOTES (with a median of one percutaneous trocar) was the predominant approach, with only one case of pure NOTES. Transvaginal appendectomies had significantly shorter procedural times (35 minutes) than transgastric appendectomies (96 minutes, p<0.001). Furthermore, no conversions to laparotomy occurred in the transvaginal appendectomy group, compared with a 5.6% conversion rate in the transgastric appendectomy group. Postoperative complication rates were 5.5% in the transvaginal appendectomy group (intra-abdominal infections, urinary tract infections) and 11.1% in the transgastric appendectomy group (pelvic abscesses, gastric closure leakage). In the Euro-NOTES clinical registry that included 33 appendectomy cases, most were performed via the hybrid transgastric approach.33 The mean procedure duration was significantly shorter in the transvaginal group (59 vs. 99.8 minutes). Complications occurred only in the transgastric appendectomy group, including conversion to laparotomy because of a tear in the cecum serosa and a pelvic abscess treated with laparoscopic drainage in one case each. This study also highlighted the utility of over-the-scope clip closure of the gastric access, which was effective in all but one patient who required further laparoscopic suturing. No complications were observed with any of the transvaginal techniques. These studies confirmed that transvaginal NOTES is a promising alternative for appendectomy, with a superior safety profile compared with transgastric access (Table 2).17,19,27,32-34
Comparative data between NOTES appendectomy and laparoscopic appendectomy are limited. A prospective cohort study including 40 patients compared transvaginal and laparoscopic appendectomy.3 While mean operating time and hospital stay were similar, transvaginal appendectomy was superior, with a reduced need for postoperative analgesia and faster return to normal activities. However, quality randomized trials to support the utility of NOTES with conventional surgery over and above better cosmesis are lacking.
Colorectal surgeries
The German NOTES Registry reported 139 colon resection procedures in cases of sigmoid diverticulitis (85.6%), colon carcinoma (9.4%), and ulcerative colitis (3.6%).27 Most procedures involved sigmoid resection (87.1%) and proctocolectomy (3.6%). All the procedures were performed using the hybrid technique via transvaginal (87.8%) or transrectal (12.2%) access routes. The rates of conversion to laparoscopy technique, intraoperative complications, and postoperative complications were 3.6%, 2.9%, and 12.2%, respectively. In a small trial comparing transvaginal hybrid NOTES and traditional laparoscopic sigmoid resection for diverticulitis, both procedures were comparable in terms of procedure time and complications.40 However, morphine requirement on days 7 and 8 and length of hospital stay were lower in the NOTES group.
Oncological applications
Oncological indications for NOTES include tumor staging and peritoneoscopy, endoscopic resection of GI tumors, lymphadenectomy, and specimen extraction (natural orifice specimen extraction [NOSE]). In colorectal cancers, transanal total mesorectal excision (TME) for rectal cancer and hybrid transvaginal NOTES for rectosigmoid resection and specimen extraction have been reported. The potential advantage of NOTES in this scenario is improved access to deep pelvic structures. A systematic review and meta-analysis including seven studies and 573 patients with rectal cancer compared the oncological and perioperative outcomes between transanal and laparoscopic TME.41 No difference was observed in harvested lymph nodes, positive distal rectal margin, and complications between the two groups, suggesting that transanal TME has comparable oncologic and perioperative outcomes. Another application of NOTES in GI oncosurgery is the removal of surgically resected specimens through natural orifices, i.e., NOSE, rather than through an abdominal incision. This approach is primarily used in colorectal and gastric cancer surgeries and has the potential advantages of reduced postoperative pain, faster recovery, and improved cosmetic outcomes.42-45
NOTES is an evolving technique in GI oncology. Further high-quality studies are required to define its role as a viable alternative to oncological procedures.
Other applications
The non-GI applications of NOTES include trans-vestibular endoscopic thyroidectomy, benign adnexal diseases, ovarian cysts, hysterectomy, and staging of endometrial cancers.46-49 Initial cadaver and animal studies suggested the feasibility of completing the critical steps of a NOTES sigmoid resection, en bloc lymphadenectomy, primary anastomosis, and retrieval of an intact specimen without any incisions using transanal endoscopic microsurgery instrumentation.50 Subsequent clinical trials confirmed comparable safety, technical success, and oncologic and perioperative outcomes with transanal TME to those with laparoscopic TME.41 In these studies, laparoscopic or transgastric assistance was frequently used to aid upper rectal dissection and get a longer rectal specimen.51
Although third-space endoscopy is not a direct form of NOTES, it is an innovative technique derived from the NOTES principles. It applies similar concepts of minimally invasive endoscopy but focuses on creating and utilizing the submucosal space as a surgical working area rather than accessing the peritoneal cavity or other organs.52 This targeted approach has revolutionized therapeutic endoscopy, offering safer and highly effective treatments for various GI conditions. Such procedures include peroral endoscopic myotomy (POEM) for treating achalasia and other esophageal motility disorders, submucosal tunneling endoscopic resection (STER) for removing submucosal tumors, gastric POEM (G-POEM) for gastroparesis, and division of septum in Zenker’s diverticulum (Z-POEM) and epiphrenic diverticular POEM (D-POEM) (Fig. 4).52,53
Additionally, endoscopic ultrasound (EUS)-guided therapeutic interventions share conceptual similarities with NOTES as they utilize transluminal access to perform procedures within the peritoneal cavity. Techniques such as EUS-guided pancreatic necrosectomy, gastroenterostomy, and gallbladder drainage are minimally invasive alternatives to surgical interventions. These procedures involve the creation of controlled transmural access routes, allowing effective drainage, anastomosis, or necrosectomy while reducing the need for open or laparoscopic surgery. With the continued evolution of EUS-guided therapies, the spectrum of endoscopic surgeries based on NOTES principles may expand further.
The patient’s perception of NOTES is crucial because it directly affects the acceptance and success of this minimally invasive technique. Understanding patient concerns regarding safety, recovery, and outcomes helps shape communication strategies, informed consent, and the development of patient-centered care pathways. Positive perceptions can also drive broader adoption and enhance trust in innovative surgical approaches. A cross-sectional study assessed patient perceptions of NOTES as an alternative to laparoscopic cholecystectomy in a cohort undergoing EUS or endoscopic retrograde cholangiopancreatography.54 Among 100 surveyed patients, 78% preferred NOTES, primarily owing to the lack of external pain (99%) and scarring (89%). The oral route was the most favored approach (92% of men and 81% of women). Preference for NOTES declined with increased complication rates but remained high if complications were ≤3%. No significant demographic differences influenced the preferences, although younger age, female sex, and prior endoscopy experience showed a non-significant trend toward favoring NOTES. In another cross-sectional survey in Hungary, inpatients’ and specialists’ opinions on NOTES for cholecystectomy were evaluated.55 Among 155 patients surveyed, 53% preferred NOTES over laparoscopy if complication rates were equivalent. Preference for NOTES was higher among those with prior endoscopy (p=0.03) or open surgery (p=0.03) and men (p=0.05). Transvaginal and transcolonic approaches were favored by women (49%) and men (66%), respectively. While these findings support further innovation and refinement in NOTES technology and techniques, several other studies have suggested significant concern among women (especially younger and nulliparous women) regarding the potential impact of transvaginal NOTES on sexual function, its experimental nature, and future pregnancies.56,57
The steep learning curve for NOTES requires structured training modules, including hands-on simulations, animal models, and mentorship from experts in advanced endoscopy. The utility of NOTES over other minimally invasive techniques remains debated, and further research is needed to establish its clear advantages. While the transvaginal approach is the most successful access route in NOTES, with well-documented safety and efficacy, gender-related barriers have been a limiting factor in its broader adoption. Therefore, training programs must incorporate NOTES and conventional surgical techniques to ensure that surgeons are comfortable with both approaches. Future development of transgastric NOTES relies on a safe blind access method, improved retraction, endoscopic hemostatic clips, and reliable closure methods. The high cost of the equipment remains a barrier to its widespread adoption, underscoring the need for cost-effective innovation and healthcare system support (Table 3).
The major limitations of pure NOTES include the technical complexity and challenges associated with the secure closure of the access route, especially at the gastrotomy site. The development of flexible multifunctional instruments with improved precision, durability, and maneuverability could address some of the current limitations of NOTES. Recent advances in endoscopic closure techniques and submucosal endoscopy are expected to play a key role in the revival of pure NOTES (Fig. 5).58 The technical feasibility and safety of submucosal endoscopy with mucosal flap in accessing the peritoneal cavity and mediastinum have been demonstrated.59,60 Submucosal endoscopy procedures, including POEM, STER, and G-POEM, have cemented their role for respective indications and may re-open gates for pure NOTES procedure.53 Integration of advanced imaging techniques, such as real-time three-dimensional imaging, augmented reality, or artificial intelligence (AI)-assisted visualization, can potentially enhance procedural safety and efficacy. Furthermore, miniaturizing robotic systems will allow insertion through natural orifices, enabling precise manipulation in areas currently challenging to access, thus expanding the scope of NOTES. The convergence of robotics and NOTES could lead to the development of semiautonomous endoscopic platforms capable of performing intricate maneuvers with enhanced stability and precision (Fig. 6, Table 3).61
The future of NOTES appears to be highly promising as technology progresses. NOTES can become the cornerstone of MIS by integrating advanced imaging, robotics, and AI. Its potential to reduce recovery time and minimize complications makes it a transformative approach in modern surgical practice. However, extensive research, rigorous training, and multidisciplinary collaboration are essential to overcome the current challenges and achieve widespread adoption.
Fig. 1.
Classification of natural orifice transluminal endoscopic surgery (NOTES) according to the site of access and laparoscopy assistance. GI, gastrointestinal; POEM, peroral endoscopic myotomy; E-POEM, esophageal POEM; G-POEM, gastric POEM; Z-POEM, Zenker's POEM; STER, submucosal tunneling endoscopic resection; POEM-F, POEM with fundoplication; POETRE, peroral endoscopic tunneling for restoration of the esophagus.
ce-2025-009f1.jpg
Fig. 2.
Images depicting pure and hybrid natural orifice transluminal endoscopic surgery (NOTES) procedure. (A) Pure transgastric cholecystectomy and appendectomy. (B) Pure transvaginal cholecystectomy and appendectomy. (C) Pure transcolonic appendectomy. (D) Hybrid transvaginal NOTES. Illustrations courtesy: Dr. Tanyaporn Chantarojanasiri, MD, Assistant Professor, Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, Ministry of Public Health College of Medicine, Rangsit University, Bangkok, Thailand.
ce-2025-009f2.jpg
Fig. 3.
Endoscopic view of a full-thickness defect in the gastric wall following endoscopic full-thickness resection of an exophytic submucosal lesion. (A) Full-thickness defect in the gastric wall. (B) Visualization of the peritoneal cavity through the gastric defect, showing adjacent bowel loops. This finding suggests the feasibility of transgastric intraperitoneal examination using an endoscopic approach. (C) Endoscopic view of the liver seen through the gastric defect, further demonstrating access to intra-abdominal structures during endoscopic full-thickness resection. (D) Closure of the full-thickness gastric defect using endoclips. The clips approximate the edges of the resected site, ensuring secure closure and preventing complications, such as leakage or peritonitis.
ce-2025-009f3.jpg
Fig. 4.
Current applications of third space endoscopy in gastrointestinal diseases. POEM, peroral endoscopic myotomy; Z-POEM, Zenker's POEM; STER, submucosal tunneling endoscopic resection; NOTES-F, natural orifice translumenal endoscopic surgery fundoplication; POETRE, peroral endoscopic tunneling for restoration of the esophagus; G-POEM, gastric POEM; PREM, perrectal endoscopic myotomy. Adapted from Nabi and Reddy. Clin Endosc 2023;56:23–37, according to the Creative Commons license.53
ce-2025-009f4.jpg
Fig. 5.
Novel endoscopic closure devices. (A) Innovative endoscopic clip with anchor prongs for the closure of large defects (MANTIS; Boston Scientific). (B) Endoclip with two independently operating arms that can grasp tissue separately, facilitating effective closure of mucosal defects (DAT Closure Device; Micro-Tech Endoscopy). (C) Over-the-scope clip for full-thickness closure of gastrointestinal (GI) wall defects (OTSC; Ovesco Endoscopy). (D) Over-the-scope clip for full-thickness closure of GI wall defects (Padlock Clip; STERIS Endoscopy). (E) Endoscopic suturing device for full-thickness closure of large GI wall defects (OverStitch System; Boston Scientific). (F) Through-the-scope suture-based device (X-Tack System; Boston Scientific).
ce-2025-009f5.jpg
Fig. 6.
Endoscope-compatible, flexible surgical robot platform with end effector arms for traction and closure assistance (EndoRobotics).
ce-2025-009f6.jpg
Table 1.
Comparison of transgastric, transvaginal, and transrectal natural orifice transluminal endoscopic surgery: access, advantages, and challenges
Transgastric Transvaginal Transrectal
Human trials Peritoneoscopy, cholecystectomy, appendicectomy, fallopian tube ligation Peritoneoscopy, abdominal and pelvic surgeries (e.g., cholecystectomy, appendectomy) Rectosigmoidectomy, umbilical hernia repair and appendectomy (cadaver models)
Advantages Suitable for both sexes, potentially broad application for abdominal surgeries Excellent visualization of the abdominal cavity, less risk of peritonitis compared with transgastric Direct access to pelvic organs, reduced distance to lower abdominal structures
Issues Inadequate examination, difficult closure, retrieval of large specimen perorally, difficulty approaching the gallbladder in retroflexed position Limited to female patients, potential stigma or reluctance from patients, concerns for sexuality and fertility Less investigated route, risk of fecal contamination leading to peritonitis, technically challenging owing to anatomic variability, difficulty in maintaining visualization and precise closure
Complications Peritonitis, pelvic abscess, leaks, injury to abdominal wall Infection, injury to adjacent organs Risk of rectal injury or fistula formation
Future implications Improved tools and closure devices Refinements in surgical techniques and instrumentations Requires technological advancements for safe and reliable access
Table 2.
Large studies reporting the outcome of NOTES in gastrointestinal diseases
Study Year n Procedure Conversion Complication
Zorron et al.32 (IMTN registry) 2010 362 TV-C 240, TV-A 37, TG-C 29, TG-A 14, TV-rectosigmoidectomy 12, others 30 9 Cases (laparoscopy 6, open 3) 8.8% (peritonitis, bile leak, esophageal hematoma)
Lehmann et al.34 (German NOTES Registry) 2010 551 (572 target organs) TV-C 488, TV-A 42, colon 14, others 28 4.9% 3.1% (bladder injury, small bowel injury, bleeding, pelvic abscess)
Arezzo et al.33 (Euro-NOTES Registry) 2013 533 TV-C 423, TG-C 12, TG-A 28, TV-A 5, sigmoidectomy 30, STC 2, POEM 20 0.5% (cholecystectomy group) 2.8% (bleeding, bile leak, pelvic abscess), 14.7% (cecal serosal tear, pelvic abscess), 12.5% (bleeding, leakage, ileus)
Mofid et al.19 2013 222 TV-C 220, TV-A 2 1% 3 (bladder injury, biliary fistula, pelvic abscess)
Bulian et al.27 (German NOTES Registry) 2014 139 TV colon resection 122, TR colon resection 17 4.1%, 0% 14.6% (TV), 11.8% (TR) (bleeding, anastomotic leak, infection)
Bulian et al.17 2017 217 TV-A 181, TG-A 36 0%, 5.6% 5.5% (intra-abdominal infection, bleeding, pain, urinary tract infection), 11.1% (pelvic abscess, leakage)

NOTES, natural orifice transluminal endoscopic surgery; IMTN, international prospective multicenter trial on clinical NOTES; TV, transvaginal; TR, transrectal; TV-C, transvaginal cholecystectomy; TV-A, transvaginal appendectomy; TG-C, transgastric cholecystectomy; TG-A, transgastric appendectomy; STC, sub-total colectomy.

Table 3.
Recent advances that could rejuvenate the adoption of NOTES in gastrointestinal procedures
Recent advances Description Impact on NOTES
Improved flexible endoscopes High-definition imaging, better maneuverability, and multi-lumen designs Enhances precision and reduces complications
Innovative closure devices Advanced suturing and stapling systems for secure closure of natural orifice entry sites Addresses concerns regarding leaks and perforations
EUS guidance Integration of EUS for accurate visualization and navigation Facilitates safer access to target organs and improves diagnostic capabilities
Miniaturized surgical tools Development of smaller, more versatile tools for dissection, resection, and hemostasis Increases efficiency and safety in complex NOTES procedures
Robotic endoscopy Robotic platforms for precise control and visualization in challenging anatomy Increases feasibility of complex NOTES procedures such as transgastric surgeries
AI AI-assisted endoscopic navigation, diagnosis, and tool deployment Improves procedural accuracy and decision-making during NOTES

NOTES, natural orifice transluminal endoscopic surgery; EUS, endoscopic ultrasound; AI, artificial intelligence.

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    Natural orifice transluminal endoscopic surgery: history and current development
    Image Image Image Image Image Image
    Fig. 1. Classification of natural orifice transluminal endoscopic surgery (NOTES) according to the site of access and laparoscopy assistance. GI, gastrointestinal; POEM, peroral endoscopic myotomy; E-POEM, esophageal POEM; G-POEM, gastric POEM; Z-POEM, Zenker's POEM; STER, submucosal tunneling endoscopic resection; POEM-F, POEM with fundoplication; POETRE, peroral endoscopic tunneling for restoration of the esophagus.
    Fig. 2. Images depicting pure and hybrid natural orifice transluminal endoscopic surgery (NOTES) procedure. (A) Pure transgastric cholecystectomy and appendectomy. (B) Pure transvaginal cholecystectomy and appendectomy. (C) Pure transcolonic appendectomy. (D) Hybrid transvaginal NOTES. Illustrations courtesy: Dr. Tanyaporn Chantarojanasiri, MD, Assistant Professor, Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, Ministry of Public Health College of Medicine, Rangsit University, Bangkok, Thailand.
    Fig. 3. Endoscopic view of a full-thickness defect in the gastric wall following endoscopic full-thickness resection of an exophytic submucosal lesion. (A) Full-thickness defect in the gastric wall. (B) Visualization of the peritoneal cavity through the gastric defect, showing adjacent bowel loops. This finding suggests the feasibility of transgastric intraperitoneal examination using an endoscopic approach. (C) Endoscopic view of the liver seen through the gastric defect, further demonstrating access to intra-abdominal structures during endoscopic full-thickness resection. (D) Closure of the full-thickness gastric defect using endoclips. The clips approximate the edges of the resected site, ensuring secure closure and preventing complications, such as leakage or peritonitis.
    Fig. 4. Current applications of third space endoscopy in gastrointestinal diseases. POEM, peroral endoscopic myotomy; Z-POEM, Zenker's POEM; STER, submucosal tunneling endoscopic resection; NOTES-F, natural orifice translumenal endoscopic surgery fundoplication; POETRE, peroral endoscopic tunneling for restoration of the esophagus; G-POEM, gastric POEM; PREM, perrectal endoscopic myotomy. Adapted from Nabi and Reddy. Clin Endosc 2023;56:23–37, according to the Creative Commons license.53
    Fig. 5. Novel endoscopic closure devices. (A) Innovative endoscopic clip with anchor prongs for the closure of large defects (MANTIS; Boston Scientific). (B) Endoclip with two independently operating arms that can grasp tissue separately, facilitating effective closure of mucosal defects (DAT Closure Device; Micro-Tech Endoscopy). (C) Over-the-scope clip for full-thickness closure of gastrointestinal (GI) wall defects (OTSC; Ovesco Endoscopy). (D) Over-the-scope clip for full-thickness closure of GI wall defects (Padlock Clip; STERIS Endoscopy). (E) Endoscopic suturing device for full-thickness closure of large GI wall defects (OverStitch System; Boston Scientific). (F) Through-the-scope suture-based device (X-Tack System; Boston Scientific).
    Fig. 6. Endoscope-compatible, flexible surgical robot platform with end effector arms for traction and closure assistance (EndoRobotics).

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    Natural orifice transluminal endoscopic surgery: history and current development
    Transgastric Transvaginal Transrectal
    Human trials Peritoneoscopy, cholecystectomy, appendicectomy, fallopian tube ligation Peritoneoscopy, abdominal and pelvic surgeries (e.g., cholecystectomy, appendectomy) Rectosigmoidectomy, umbilical hernia repair and appendectomy (cadaver models)
    Advantages Suitable for both sexes, potentially broad application for abdominal surgeries Excellent visualization of the abdominal cavity, less risk of peritonitis compared with transgastric Direct access to pelvic organs, reduced distance to lower abdominal structures
    Issues Inadequate examination, difficult closure, retrieval of large specimen perorally, difficulty approaching the gallbladder in retroflexed position Limited to female patients, potential stigma or reluctance from patients, concerns for sexuality and fertility Less investigated route, risk of fecal contamination leading to peritonitis, technically challenging owing to anatomic variability, difficulty in maintaining visualization and precise closure
    Complications Peritonitis, pelvic abscess, leaks, injury to abdominal wall Infection, injury to adjacent organs Risk of rectal injury or fistula formation
    Future implications Improved tools and closure devices Refinements in surgical techniques and instrumentations Requires technological advancements for safe and reliable access
    Study Year n Procedure Conversion Complication
    Zorron et al.32 (IMTN registry) 2010 362 TV-C 240, TV-A 37, TG-C 29, TG-A 14, TV-rectosigmoidectomy 12, others 30 9 Cases (laparoscopy 6, open 3) 8.8% (peritonitis, bile leak, esophageal hematoma)
    Lehmann et al.34 (German NOTES Registry) 2010 551 (572 target organs) TV-C 488, TV-A 42, colon 14, others 28 4.9% 3.1% (bladder injury, small bowel injury, bleeding, pelvic abscess)
    Arezzo et al.33 (Euro-NOTES Registry) 2013 533 TV-C 423, TG-C 12, TG-A 28, TV-A 5, sigmoidectomy 30, STC 2, POEM 20 0.5% (cholecystectomy group) 2.8% (bleeding, bile leak, pelvic abscess), 14.7% (cecal serosal tear, pelvic abscess), 12.5% (bleeding, leakage, ileus)
    Mofid et al.19 2013 222 TV-C 220, TV-A 2 1% 3 (bladder injury, biliary fistula, pelvic abscess)
    Bulian et al.27 (German NOTES Registry) 2014 139 TV colon resection 122, TR colon resection 17 4.1%, 0% 14.6% (TV), 11.8% (TR) (bleeding, anastomotic leak, infection)
    Bulian et al.17 2017 217 TV-A 181, TG-A 36 0%, 5.6% 5.5% (intra-abdominal infection, bleeding, pain, urinary tract infection), 11.1% (pelvic abscess, leakage)
    Recent advances Description Impact on NOTES
    Improved flexible endoscopes High-definition imaging, better maneuverability, and multi-lumen designs Enhances precision and reduces complications
    Innovative closure devices Advanced suturing and stapling systems for secure closure of natural orifice entry sites Addresses concerns regarding leaks and perforations
    EUS guidance Integration of EUS for accurate visualization and navigation Facilitates safer access to target organs and improves diagnostic capabilities
    Miniaturized surgical tools Development of smaller, more versatile tools for dissection, resection, and hemostasis Increases efficiency and safety in complex NOTES procedures
    Robotic endoscopy Robotic platforms for precise control and visualization in challenging anatomy Increases feasibility of complex NOTES procedures such as transgastric surgeries
    AI AI-assisted endoscopic navigation, diagnosis, and tool deployment Improves procedural accuracy and decision-making during NOTES
    Table 1. Comparison of transgastric, transvaginal, and transrectal natural orifice transluminal endoscopic surgery: access, advantages, and challenges

    Table 2. Large studies reporting the outcome of NOTES in gastrointestinal diseases

    NOTES, natural orifice transluminal endoscopic surgery; IMTN, international prospective multicenter trial on clinical NOTES; TV, transvaginal; TR, transrectal; TV-C, transvaginal cholecystectomy; TV-A, transvaginal appendectomy; TG-C, transgastric cholecystectomy; TG-A, transgastric appendectomy; STC, sub-total colectomy.

    Table 3. Recent advances that could rejuvenate the adoption of NOTES in gastrointestinal procedures

    NOTES, natural orifice transluminal endoscopic surgery; EUS, endoscopic ultrasound; AI, artificial intelligence.

    Table 1.

    Table 2.

    Table 3.

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