Natural orifice transluminal endoscopic surgery: The true frontier of gastrointestinal endoscopy

Abstract

Natural orifice transluminal endoscopic surgery (NOTES) remains a frontier that continues to blur the boundaries between surgery and interventional endoscopy. Since its inception as an idea, NOTES has witnessed remarkable progress, from early animal experiments to its gradual translation into human applications as a minimally invasive approach for various mediastinal, thoracic, peritoneal, retroperitoneal, and pelvic diseases. The initial phase of NOTES was met with significant technical and safety challenges, often requiring hybrid laparoscopic assistance. A decade after inception of the idea of NOTES, the first pure NOTES procedure, a transvaginal cholecystectomy, marked a turning point that demonstrated the feasibility of a completely incisionless surgical concept. Over time, major barriers such as safe access, reliable closure, and effective hemostasis have been steadily addressed through advances in endoscopic tunneling, suturing platforms, hemostatic materials, and flexible endoscopic systems. The evolution of third space endoscopy, endobariatric procedures, and organ preserving transluminal interventions has further strengthened the translational foundation of NOTES. Robotic are now providing greater stability, precision, and triangulation, bringing NOTES closer to daily clinical use. Now more than two decades since its conception, NOTES stands on the verge of redefining minimally invasive therapy. This review revisits its journey, summarizes the present achievements, and highlights the innovations and global collaboration needed to guide the next era of scarless surgery. Recent advances in magnetic-assisted platforms have also played an important role in improving exposure, traction, and anastomosis creation within NOTES.

Key Words: Natural orifice transluminal endoscopic surgery; Minimally invasive surgery; Third space endoscopy; Robotic endoscopy; Interventional endoscopy; Magnetic surgery

Core Tip: Natural orifice transluminal endoscopic surgery (NOTES) represents a major frontier in gastrointestinal endoscopy by extending minimally invasive therapy toward truly incisionless intervention. Although early clinical translation was limited by concerns regarding access, closure, infection, hemostasis, spatial orientation, and training, many of these barriers have been progressively addressed through advances in third-space endoscopy, endoscopic suturing, closure devices, hemostatic materials, robotic systems, and magnetic platforms. This opinion review highlights the evolution of NOTES, its current clinical and experimental applications, and the collaborative innovation needed to transform NOTES from a pioneering concept into a safe and practical therapeutic platform.

INTRODUCTION

In 2000, Kalloo et al[1] performed the first natural orifice transluminal endoscopic surgery (NOTES) experiment in an animal model. In 2003, Rao et al[2] reported the first human application, a transgastric appendectomy. In 2005, the Society of American Gastrointestinal and Endoscopic Surgeons and the American Society for Gastrointestinal Endoscopy established the Natural Orifice Surgery Consortium for Assessment and Research, with the goal of guiding NOTES toward safe clinical adoption and identifying the barriers to its progress[3].

Despite significant enthusiasm, early translation of NOTES was slow. The development of sophisticated endoscopic tools lagged behind surgical needs, and concerns about infection, closure, and safety limited broader adoption[4]. The lack of standardized training and the uncertainty about managing potential adverse events further delayed clinical progress. Nonetheless, researchers across the world continued to explore NOTES independently, each contributing incremental advances that gradually shaped the field.

A decade after its inception, Liu et al[5] performed the first pure NOTES transrectal gallbladder preserving cholecystolithotomy, marking a key milestone in human NOTES. This was soon followed by reports of pure NOTES transgastric ovarian cystectomy, transcecal appendectomy, and gastroenterostomy[6-9]. Parallel advances in magnetic-assisted transluminal surgery further expanded the feasibility of incisionless anastomosis, including early work by Jamshidi et al[10], and Ryou et al[11,12], which demonstrated the potential of magnetic compression techniques for safe and controlled tissue apposition. These achievements reflected not only technical innovation but also the persistence of investigators who believed in the future of scarless surgery.

Today, NOTES represents the convergence of surgery and advanced endoscopy. The boundaries between the two fields continue to dissolve as innovations in flexible robotics, magnetic platforms, stent and endoclip design, endoscopic suturing platforms, and artificial intelligence-assisted spatial orientation transform what was once an experimental concept into a realistic clinical option[12-15]. The path forward will depend on global collaboration among endoscopists, surgeons, and engineers, along with well-structured training and standardized procedural frameworks. The historical trajectory of NOTES, from early animal experiments to modern transluminal applications, is summarized in Table 1[1-3,5-13,15,16].

Table 1 Evolution and key milestones in natural orifice transluminal endoscopic surgery.

Ref.	Date	Model or setting	Access route	Procedure/innovation	Key contribution/outcomes
Kalloo et al[1]	2000	Porcine model	Trans-gastric	Diagnostic peritoneoscopy	First proof-of-concept of transluminal endoscopic access to the peritoneal cavity
Rao et al[2]	2008	Human	Trans-gastric	Appendectomy	First human NOTES procedure
Rattner et al[3]	2006	Consensus group	-	Established safety framework	Laid research and training foundations for clinical NOTES
Jamshidi et al[10]	2009	Human	Trans-gastric	Human magnetic compression gastroenterostomy	First human magnetic-assisted transluminal anastomosis
Liu et al[7]	2013-2014	Human	Trans-gastric	Ovarian cystectomy	First pure transgastric human NOTES
Liu et al[5]	2015	Human	Trans-rectal	Gallbladder preserving cholecystolithotomy	First pure organ-preserving NOTES procedure
Liu et al[6], Liu et al[7], Liu et al[8], Wang et al[9]	2018-2020	Clinical	Trans-rectal, trans-gastric, trans-vaginal	Appendectomy, gastroenterostomy	Expansion to transluminal therapeutic applications
Zhao et al[16]	2021-2023	Human	Trans-rectal	Balloon-assisted access and closure	Development of detachable balloon system reducing peritoneal contamination risk
Jamshidi et al[10], Ryou et al[11], Ryou et al[12], Thigpen et al[13], Simsek et al[15]	2023-2025	Clinical and Experimental	Trans-rectal, trans-gastric, trans-vaginal	Gallbladder, liver, pancreas, mediastinal interventions	Integration of robotics, magnetic platforms, and AI-assisted navigation into NOTES

NOTES: Natural orifice transluminal endoscopic surgery; AI: Artificial intelligence.

This review aims to provide an updated overview of the current landscape of NOTES, the progress made in overcoming its original challenges, and the potential directions that may define its next decade of growth.

FUNDAMENTAL CHALLENGES TO SAFE DEVELOPMENT OF NOTES

Early development of NOTES was defined by a series of technical and safety obstacles that shaped its research trajectory. These challenges included: (1) Safe and reliable access to the peritoneal cavity; (2) Safe closure of the luminal incision/entry site; (3) Prevention of infections in the peritoneum and submucosal tunnel (the risk of fecal contamination and peritoneal infection); (4) Development of suturing and anastomosis devices; (5) Patient spatial orientation; (6) Development of multitasking platform(s) to accomplish NOTES; and (7) Control of adverse events.

Management of iatrogenic complications, physiological untoward events, and compression syndrome(s).

Training-related obstacles

Safe peritoneal access is a cornerstone for NOTES feasibility. Sumiyma and colleagues developed endoscopic submucosal tunnelling with a mucosal flap safety valve technique, where the endoscope enters the submucosal space, traverses it a short distance facilitated by submucosal disseciton, following which an incision is made to access the peritoneal cavity in a safe and time efficient manner[17-19]. Upon withdrawal of the endoscope, the access site collapses, preventing spillage of gastric contents into the peritoneum; healthy submucosal tissue is noted to spontaneously close thereafter. This technique gave rise to what is now known as the field of third space endoscopy, the most notable of which is peroral endoscopic myotomy (POEM).

Natural orifice access to the peritoneal cavity can be accomplished via transvaginal, transgastric, or transrectal routes. Initial NOTES experiments employed the transgastric route. Transvaginal access is commonly used but is limited to females, whereas transrectal access is not limited by patients’ sex. The transvaginal route carries specific contraindications that must be respected irrespective of technological progress. Patients with a history of endometriosis, prior pelvic inflammatory disease, or significant pelvic adhesions are unsuitable candidates due to distorted anatomy and increased risk of complications. In addition, transvaginal access is not recommended for nulliparous women because of concerns regarding endomyometrial trauma and perceived risk of placental pathologies and complications related to conception and childbirth and long-term pelvic floor integrity. These limitations reinforce the need for individualized access-route selection in NOTES. In addition to anatomical contraindications, long-term functional concerns remain a major limitation of the transvaginal route. Evidence regarding postoperative dyspareunia, pelvic floor dysfunction, and impacts on sexual health is limited and heterogeneous, but these risks cannot be excluded. Until high-quality long-term data are available, these potential sequelae of transvaginal NOTES must be discussed with patients as part of informed consent, and the transvaginal approach should be reserved for individuals who fully understand and accept these considerations.

There are benefits and pitfalls to transgastric and transrectal access for NOTES. Transrectal access provides an excellent spatial and operational field for the upper abdomen while allowing for early resumption of oral intake (generally within six hours), reduced post-operative pain and consequently, less need for analgesia. Transrectal NOTES is performed with patient in the supine position which allows one to perform effective peritoneal washout, thereby reducing the risk of peritonitis. The major drawback of transrectal access is the requirement of bowel preparation and disinfection before the procedure. Concerns regarding peritoneal contamination by proctocolonic contents with transcolonic or transrectal access to the peritoneum remain a matter of debate to this day. The risk of distal colonic contamination may be reduced by use of a detachable obstructive colonic balloon, although this approach requires further validation before broad adoption[16].

Transgastric access obviates the need for a preoperative bowel cleansing, though it is not without its own set of challenges. With the transgastric approach, it is more difficult to access the gallbladder and stabilize the endoscope for interventions. Patients are placed in a left lateral position for transgastric NOTES, which makes it difficult to perform effective peritoneal washout. Time to resumption of oral intake is delayed with transgastric access compared to transrectal access. Lastly, closing the gastric mucosotomy is more difficult than a rectal mucosotomy due to thickness of the gastric wall. These nuances highlight that there is no single ideal access for NOTES; one should consider the technicalities of the procedure to be performed and patient-associated factors when deciding on the appropriate approach for peritoneal access[20].

It was crucial to have devices capable of performing sutures whose quality would be on par with surgical sutures. Kalloo et al[1] demonstrated endoscopic suturing with a prototype device, The Eagle Claw, in 2005; a jejunal loop was pulled into the stomach through a luminal wall defect created by endoscopy, and then secured in the stomach by stitches placed by a curved needle[21]. The jejunal limb was subsequently incised with a needle knife to create a gastrojejunostomy. Over the years, the Eagle Claw evolved into the OverStitch device (Boston Scientific, Marlborough, MA, United States) which allows full thickness capture of the gastrointestinal lumen and enables suturing that is on par with surgical suturing[22]. Availability of OverStitch also fueled the development of endobariatrics, and clinical development of endoscopic sleeve gastroplasty (ESG) and endoscopic transoral outlet reduction[23]. In addition to ESG and transoral outlet reduction, several emerging technologies have further broadened the therapeutic impact of NOTES-adjacent innovation. Duodenal mucosal resurfacing using the Fractyl system, and more recently duodenal mucosal electroporation platforms, have demonstrated promise as minimally invasive metabolic interventions. Likewise, endoscopic suturing is now widely used in the management of bariatric surgery complications, including closure of leaks, reinforcement of marginal ulcer repairs, and restoration of anastomotic integrity. These advances highlight how the pursuit of NOTES has accelerated the development of flexible endoscopic platforms with broad clinical utility.

Endoscopic suturing also enabled closure of complex luminal defects. Even in the absence of suturing devices, tissue approximation and closure of most luminal defects can be achieved with standard endoclips; with advancements in endoscopic submucosal dissection (ESD), a robust amount of evidence has emerged using endoclips for luminal defect closures in various configurations, sometimes assisted with endoloop or suture thread for apposition[24]. For larger or full-thickness incisions, advanced closure modalities such as over-the-scope clip, and flexible staplers have broadened the therapeutic possibilities and improved safety[25,26]. The development of cinching devices has extended closure capability to relatively larger defects, while new mechanical and magnetic cinching systems show promise in experimental and early clinical settings. However, their availability and cost currently limit widespread use to specialized centers.

Achieving hemostasis during NOTES remains one of the most demanding technical challenges. The endoscopic application of TC-325 hemostatic powder, now known as Hemospray, was an early attempt to address this issue. Clinical studies have demonstrated the use of TC-325 in variceal hemorrhage and peptic ulcer-related bleeding[27,28]. However, the powder often obscured the operative field and provided only temporary hemostasis, making it a useful but nondefinitive solution. More recently, newer agents such as polysaccharide-based powders and self-assembling peptide hydrogels have emerged as notable advances, offering improved safety, biocompatibility, and durability[29]. Comparative studies and registry data now suggest that these modern hemostatic agents achieve success rates exceeding 90 percent with favorable safety profiles, although their effectiveness in the constrained NOTES environment continues to be evaluated[30,31].

Despite these advances, several challenges persist. Safe, reproducible access must be paired with reliable closure and hemostasis methods that do not compromise visualization. Development of integrated platforms combining these capabilities, alongside improved spatial navigation, tactile feedback, and training models, will be essential for widespread adoption of NOTES.

ONCOLOGIC SAFETY AND CURRENT LIMITATIONS

Applications of NOTES in malignant disease remain contraindicated at present. The risks of tumor disruption, peritoneal contamination, loss of oncologic integrity, and potential tumor seeding make NOTES unsuitable for neoplastic conditions with current technology. Current flexible platforms do not reliably ensure en bloc resection, adequate oncologic margins, or safe specimen retrieval. For these reasons, NOTES should remain restricted to benign disease until future technologies and clinical data can demonstrate oncologic safety.

NOTES AND THIRD SPACE ENDOSCOPY

Our pursuit towards NOTES gave rise to third space endoscopy, a field that has matured into one of the most significant advances in interventional gastroenterology. Although popularity of the former stalled over time, third space endoscopy has grown robustly. Under the umbrella of third space endoscopy, ESD, POEM, and submucosal tunnelling-endoscopic resection have matured with established clinical applications.

POEM was among the first techniques to arise from the pursuit for NOTES, first described in animal experiments by Pham et al[21] and subsequently in humans by Inoue et al[32] for the treatment of achalasia. It was the understanding that the submucosal space could be used to access the muscular layer of the esophagus that led to the development of a submucosal tunneling technique, which comprised of four main steps: (1) Mucosal incision; (2) Tunnelling in the submucosal space; (3) Selective myotomy of circular muscle or full thickness myotomy; and (4) Closure of the mucosotomy. POEM has become the first-line treatment for achalasia. Liu et al[33] modified this technique by combining tunneling and myotomy in one step; widespread adoption of this technique is currently limited. Endoscopic Zenker’s diverticulotomy has also become a standard of care in select patients, replacing invasive surgical myotomy[34]. The extension of POEM to the pylorus has become an established standard of care for select patients with gastroparesis[35]. Furthermore, endoscopic myotomy at the antrum has recently been introduced as an adjunct to ESG as a treatment option for obesity[36]. As the comfort of luminal endoscopists’ with extra-luminal encounters grows, third space endoscopy is poised to become a common technique, supplanting multiple traditional surgical interventions of the gastrointestinal tract. Recent preliminary data has emerged demonstrating the feasibility of endoscopic fundoplication in conjunction with myotomy (peroral endoscopic myotomy with fundoplication) to prevent gastroesophageal reflux disease in patients with achalasia[37]. Long-term outcomes of POEM have also been summarized in recent systematic reviews and meta-analyses[38,39].

Progress in training and clinical application of ESD has culminated in it being the standard of care for esophageal, gastric, duodenal, colonic, and rectal lesions, including early malignancies without locoregional spread[40]. The development of ESD also gave rise to innovative endoluminal surgical techniques, the most notable of which are endoscopic traction techniques that allow safe and efficient submucosal dissection. Innovation on devices for submucosal dissection and devices to stabilize the endoluminal operative field have also been introduced to the commercial market because of widespread adoption of ESD[41,42]. These examples represent the progress made in the pursuit of NOTES, giving rise to ever-expansive endoscopic interventions which are allowing patients to forego invasive surgical interventions.

The natural convergence of NOTES and third space endoscopy has also inspired new transluminal procedures beyond the traditional lumen. For example, endoscopic antral myotomy, when combined with ESG, has shown potential as a hybrid treatment for obesity[36]. Submucosal tunneling and traction-assisted approaches are now being evaluated for selective resection of subepithelial lesions and complex endoluminal disease[41,42]. As experience grows and cross-disciplinary training expands, the line between third space and transluminal interventions continues to blur, bringing NOTES closer to routine clinical practice.

Although NOTES was initially promoted as a strategy to eliminate trocar-related morbidity, the tangible clinical benefits of avoiding small abdominal incisions are limited in many routine scenarios. In contrast, some of the most impactful advances arising from NOTES have been the development of parallel technologies that facilitate dissection, partial or full thickness resection, and defect closure. These tools are now widely used in mainstream endoscopy and often carry clearer patient benefit than many early NOTES applications. The revised landscape therefore reflects that the pursuit of NOTES not only pushed the boundaries of incisionless intervention, but also accelerated the development of technologies that have improved outcomes across multiple gastrointestinal diseases.

NOTES AND THE GALLBLADDER

NOTES of the gallbladder has evolved from a hybrid procedure, which required laparoscopic assistance, to pure NOTES cholecystectomy, and finally to gallbladder preserving cholecystolithotomy[5]. Transrectal cholecystectomy was developed to mitigate the shortcomings of a transvaginal approach; an incision is created on the right anterior wall of the rectum, and an endoscope with a transparent cap is introduced into the pelvic cavity and advanced upwards into the peritoneal cavity. After the liver and gallbladder are localized, dissection and resection of the gallbladder is pursued in standard fashion as would be done in a transvaginal cholecystectomy. Transrectal cholecystolithotomy evolved from transrectal cholecystectomy and is the first interventional, organ sparing approach to management of cholelithiasis[17]. An incision is made in the gallbladder; gallstones are retrieved using a biliary stone extractor and removed through the rectal incision. Upon exit, the incisions of the gallbladder and rectum are closed using endoclips.

With growing experience, pure transgastric access has also been explored for gallbladder interventions, using a submucosal tunneling technique to reach the peritoneal cavity safely. Transgastric gallbladder-preserving cholecystolithotomy has shown favorable outcomes in selected patients, offering an incisionless alternative for symptomatic gallstones while maintaining gallbladder function. Recent reports and reviews suggest that pure NOTES gallbladder-preserving cholecystolithotomy is technically feasible in selected patients, with favorable short-term outcomes reported; however, long-term recurrence, gallbladder function preservation, and comparative effectiveness require further validation[43].

Although NOTES gallbladder-preserving cholecystolithotomy offers an incisionless and organ-sparing alternative, patient selection remains essential. Gallstone formation is commonly linked to impaired gallbladder motility, and long-term recurrence remains a possibility in patients with chronic cholecystopathy. Reports of acute abdomen due to gallbladder perforation further highlight the need for structured follow-up and careful preoperative evaluation[44]. As highlighted above, the transrectal and transgastric routes also carry inherent risks, such as peritoneal contamination and technical challenges in closure. For these reasons, NOTES gallbladder procedures should be performed in centers with dedicated experience, established infection-control protocols, and operators who have completed an appropriate learning curve, ideally under a dedicated research protocol. Patients should be fully informed of these considerations during preoperative counseling.

Despite these encouraging developments, challenges remain before NOTES gallbladder procedures can enter mainstream practice. These include standardization of patient selection, optimization of access and closure methods, and long-term evaluation of outcomes compared with conventional laparoscopic surgery. Future research should also assess patient preference, as the demand for organ-preserving and scarless options continues to rise in minimally invasive surgery.

NOTES FOR THE LIVER

Early experiments in NOTES for hepatic intervention marked an important milestone in transluminal access to solid organs. Kalloo et al[1] first reported transgastric peritoneoscopy with hepatic tissue acquisition in a porcine model, demonstrating the feasibility of flexible endoscopic access to the liver through a natural orifice. Subsequent studies successfully reproduced this technique in animals, confirming both its safety and technical reproducibility[45,46].

These encouraging findings eventually led to human translation. Hazey et al[46] performed transgastric liver biopsy in ten patients, successfully obtaining tissue samples from both the right and left hepatic lobes using endoscopic biopsy forceps. Hemostasis was achieved with electrocautery when necessary, and the mean procedural time was only a few minutes. All patients had uneventful recoveries, highlighting the potential of NOTES as a minimally invasive alternative to percutaneous or laparoscopic liver biopsy.

Beyond diagnostic applications, NOTES has also been explored for therapeutic hepatic interventions, particularly in the management of hepatic cysts. Early reports of trans-sigmoid NOTES sclerotherapy, transgastric cyst deroofing, and transgastric cyst fenestration suggest that these approaches are technically feasible in selected cases[47-49]. However, the available evidence remains limited, and these early reports should not be interpreted as sufficient to support generalized success-rate claims.

Recent progress (2023-2025) has expanded the experimental and early clinical application of pure NOTES liver interventions. Endoscopic transgastric fenestration for large hepatic cysts has now been validated in small human cohorts, with outcomes comparable to conventional laparoscopic deroofing and advantages in postoperative pain and cosmesis[49]. Experimental studies have also described hybrid NOTES approaches combining magnetic-assisted retraction and flexible robotic platforms, offering improved visualization and control during parenchymal dissection[50].

Despite these advances, NOTES for the liver remains in its early clinical phase. Challenges include maintaining a stable operative field in solid organ surgery, achieving durable hemostasis, and optimizing closure after transgastric access. Nevertheless, the accumulated data from both animal and early human studies continue to support the feasibility, safety, and translational potential of NOTES for hepatic interventions. With ongoing technological innovation and careful patient selection, NOTES could eventually provide an incisionless alternative for both diagnostic and therapeutic liver procedures.

NOTES FOR THE PANCREAS

NOTES for pancreatic diseases carries diagnostic and therapeutic potential. Transgastric endoscopic partial or total resection of the pancreatic tail was demonstrated in 15 healthy pigs by Wang et al[51]; the technical success rate and survival rate was 100%. Pancreatic leaks were reported in 16% of cases with total pancreas tail resection. There were no adverse events in the immediate postoperative period; the pancreatic leak manifested one week after surgery and continued for two weeks postoperatively. Possible explanations for the leak include the clipping method (metal clips) used in their closure technique; damage to the main pancreatic duct could lead to a pancreatic leakage. However, placement of metal clips may obscure a leak in the initial stages and may pave way for encapsulation of the leak within weeks. Such a leak may not manifest as overt pancreatic ascites.

A less invasive and potentially organ sparing application of pancreatic NOTES that may be more appealing for widespread adoption is tumor enucleation, which has been studied in animal models[52]. After creation of distal pancreatic tumor by injection of a polymer under endoscopic ultrasound guidance, transgastric tumor enucleation was successfully performed in seventeen porcine models. Two animals developed esophageal dissection related to overtube insertion, while two small splenic lacerations occurred and were managed endoscopically with successful hemostasis before closure of the transgastric defect. Further exploration of this technique will require the development of more sophisticated endoscopic instruments. In addition to its interventional applications, NOTES combined with endoscopic ultrasound may serve as a minimally invasive diagnostic approach for pancreatic cancer staging. Moreover, application of the self-assembling peptide hydrogel SPG-178 to the pancreatic stump reduced biochemical markers of pancreatic fistula in a rat model, suggesting its potential role as an agent for preventing postoperative pancreatic fistula[53].

NOTES of the pancreas is in its infancy and has a long journey ahead of it before it can be considered for widespread exploration outside of controlled, experimental settings. The ultimate goal of pursuing NOTES of the pancreas may well be to deconstruct the critical steps involved in a pancreaticoduodenoectomy, assess feasibility and devise tools that allow safe execution of each step, and attempt pure NOTES pancreaticoduodenectomy, graduating from animal models, eventually to humans. The idea of endoscopic pancreaticoduodenectomy may not sit well with practitioners of the current era, who would be right to critique the concept and highlight the multiple obstacles in way of successful execution of such a procedure. Such criticisms also highlight the need for aggressive, innovative research in the field of NOTES; only through well-funded, multi-specialty research efforts can the field of NOTES make any tangible progress if it is to establish its place as an accepted endoscopic surgical modality. A summary of representative NOTES procedures across organ systems, their developmental stages, and corresponding outcomes are presented in Table 2[5,6,8,14,20-23,32,33,37-43,45-49,51,52].

Table 2 Current and emerging clinical and experimental applications of natural orifice transluminal endoscopic surgery across organ systems.

Ref.	Organ system/application area	Representative procedures	Preferred access route	Stage of development	Key technical features	Outcomes/technical success
Liu et al[5], Hao et al[14], Dubcenco et al[20], Shang et al[43]	Gallbladder	Gallbladder-preserving cholecystolithotomy; cholecystectomy	Transrectal, transgastric	Early clinical to selected clinical application	Transparent cap assistance; transrectal or transgastric access; endoscopic gallstone retrieval; endoscopic closure using clips or OTSC when needed	Reported as feasible in selected patients; long-term recurrence, gallbladder function, and comparative outcomes require further study
Steele et al[45], Hazey et al[46], Chen et al[47], Liu et al[48], Chen et al[49]	Liver	Transgastric peritoneoscopy and liver biopsy; hepatic cyst deroofing or sclerotherapy	Transgastric, trans-sigmoid	Experimental to early clinical	Transluminal access to the peritoneal cavity; biopsy forceps or cyst intervention; electrocautery or endoscopic hemostasis when needed	Liver biopsy and hepatic cyst interventions have been reported as feasible in early human experience and selected cases; evidence remains limited
Wang et al[51], Matthes et al[52]	Pancreas	Pancreatic tail resection; pancreatic tumor enucleation	Transgastric	Experimental, animal models	Transgastric access; endoscopic dissection; clip closure; endoscopic management of minor bleeding or injury	Demonstrated technical feasibility in porcine models; pancreatic leak and adjacent organ injury remain important safety concerns
Liu et al[8]	Appendix/cecum	Transcecal appendectomy for appendiceal polyps	Transcecal	Limited clinical experience	Direct cecal access; flexible endoscopic resection; endoscopic closure of the cecal defect	Reported as feasible in selected clinical cases; broader safety and reproducibility require further evaluation
Liu et al[6], Pham et al[21], Ge and Thompson[22], Jin et al[23]	Stomach/small bowel	Pure NOTES gastroenterostomy; endoscopic suturing or defect closure related to transluminal intervention	Transgastric	Early clinical and device-development stage	Submucosal tunneling or transluminal access; endoscopic suturing; OTSC or clip-assisted closure	Early reports support feasibility, but outcomes vary by indication, technique, and available closure platform
Inoue et al[32], Liu et al[33], Inoue et al[37], Vespa et al[38], Nabi et al[39], Draganov et al[40], Harlow et al[41], Grimaldi et al[42]	Third-space endoscopy/esophagus	POEM; modified POEM; POEM-F; ESD and traction-assisted ESD	Transoral	Established for selected indications; evolving for expanded applications	Submucosal tunneling; selective or full-thickness myotomy; endoscopic fundoplication; traction-assisted submucosal dissection	Established for selected luminal and third-space indications such as achalasia and early gastrointestinal neoplasia; reflux and long-term outcomes remain procedure-dependent

NOTES: Natural orifice transluminal endoscopic surgery; OTSC: Over-the-scope clip; POEM: Peroral endoscopic myotomy; POEM-F: Peroral endoscopic myotomy with fundoplication; ESD: Endoscopic submucosal dissection.

TRAINING FOR NOTES

Training is one of the most essential components for bringing NOTES from an experimental concept into safe clinical reality. Because NOTES combines the principles of flexible endoscopy with those of minimally invasive surgery, it requires an entirely new skill set that bridges two traditionally separate disciplines. The ideal operator must possess the delicate maneuvering and fine motor control of an endoscopist while also understanding the spatial awareness, dissection strategy, and anatomic orientation of a surgeon.

During early development of NOTES, most practitioners came from either a surgical or endoscopic background, and training was often self-directed. The absence of a structured educational pathway made it difficult to standardize outcomes and limited early clinical expansion. It is now entirely clear that the ideal clinical and research vehicle for NOTES is a collaborative program with dedicated surgeons and advanced endoscopists at the helm.

The long-term success of NOTES relies heavily on a collaborative model in which surgeons and endoscopists train together and share complementary skill sets. Multidisciplinary education improves communication, procedural planning, and management of intraoperative challenges, and it represents a cornerstone for safe expansion of NOTES into clinical practice.

Modern training programs now follow a structured, stepwise approach. Trainees begin with ex vivo tissue models to learn instrument handling and closure techniques, followed by animal laboratory sessions that simulate realistic peritoneal access and transluminal procedures. These sessions allow repetitive practice under controlled conditions and provide immediate feedback on safety, efficiency, and complication management. With growing experience, trainees progress to supervised human cases, where precision, decision-making, and teamwork become central to mastery.

Simulation-based education has further transformed training. Advanced platforms that integrate tactile feedback and virtual imaging now allow practice of submucosal tunneling, suturing, and hemostasis in a lifelike setting. These tools help shorten the learning curve and build confidence before live application. Equally important is the shift toward collaborative training, where surgeons and endoscopists work together in shared programs, learning each other’s techniques and communication patterns. This multidisciplinary model not only enhances safety but also fosters mutual respect and shared responsibility during procedures.

As NOTES continues to evolve toward complex therapeutic interventions and organ-preserving surgery, the training model must adapt as well. The future will likely involve robotic control systems, artificial intelligence-assisted navigation, and remote mentoring technologies that allow international collaboration and continuous feedback. Ultimately, the widespread and safe adoption of NOTES will depend on a unified, structured, and team-oriented training framework that brings together the strengths of both endoscopy and surgery.

THE FUTURE OF NOTES

Despite a dampened interest over the past two decades, with persistence and through a series of incremental gains, NOTES has demonstrated the potential to transform the future of interventional medicine. NOTES may establish clinical utility in the thoracic esophagus, distal colon and rectum, or other anatomic locations where laparoscopic approaches are currently challenging or where there is still significant morbidity with traditional approaches. However, NOTES should not be viewed as a universally applicable or inherently superior approach. Its potential advantages must be balanced against procedure-specific risks, technical complexity, and the possibility that an attempted NOTES procedure may fail to achieve the intended therapeutic goal. Therefore, NOTES should be applied in carefully selected patients, appropriate anatomical settings, and experienced centers with access to multidisciplinary expertise. Future progress should be guided by patient safety, standardized training, appropriate indications, and evidence-based comparison with conventional approaches, rather than by technological enthusiasm alone.

There is a need to transform the design of flexible endoscopes; current gastrointestinal endoscopes offer small instrument channels, which makes retraction and dissection of tissues difficult. Currently, there are various endoscopic operative platforms under investigation. These can be classified into three different types: (1) Mechanical platforms such as the EndoSamurai (Olympus, Tokyo, Japan), the Anubis (Karl Storz, Tuttlingen, Germany), the Direct Drive System (Boston Scientific, Natick, MA, United States) and the Endosurgical Operating System (EOS, USGI Medical, San Clemente, CA, United States), which allows passage of additional larger-caliber endoscopic instruments, without possibility of triangulation; (2) Computer-assisted platforms such as the master and slave transluminal endoscopic robot (University of Singapore) or the da Vinci system (Intuitive Surgical, Sunnyvale, CA, United States); and (3) Non-tethered systems such as mechanical or magnetic capsules.

Flexible robotic endoscopes with articulated arms now permit controlled traction, triangulation, and suturing through natural orifices, improving stability and precision. Magnetically anchored platforms offer a way to achieve exposure and retraction without abdominal incisions, while artificial intelligence-assisted imaging and navigation are beginning to enhance spatial orientation, lesion detection, and procedural safety. These emerging technologies mark a transition from feasibility toward practical clinical application, signaling that the evolution of NOTES is once again gaining momentum.

The Appollo program succeeded in spaceflight, allowing mankind to walk on the moon. As an offshoot of the Appollo program, however, multiple industries flourished and improved the quality of life of humans on earth. NOTES is undoubtedly the Appollo program of gastrointestinal endoscopy, as is evident by the advances made due to our pursuit for realization of NOTES (Figure 1). Interventions that were previously thought to be highly unlikely without invasive abdominal surgery are now being performed with flexible endoscopy. Endoscopic closure of perforations is now commonplace, as is full thickness endoscopic tissue acquisition and lesion resection, endoscopic gastrojejunostomy, and endoscopic drainage of intra-abdominal fluid collections. The advent of endobariatrics is poised to evolve the interventional management of obesity. In the quest to advance NOTES, the armamentarium of endoscopy continues to grow, as does our ability to push the envelope of interventional endoscopy with the rigor, durability and safety of laparoscopic or open surgery. The journey of realizing NOTES will undoubtedly continue to put innovators to the test, whereas the destination of NOTES is a way away. Only through sheer determination, open collaboration, and economic support will the endeavor of advancing flexible endoscopy to natural orifice surgery come to fruition.

Figure 1 Innovations in gastrointestinal endoscopy as a consequence of natural orifice transluminal endoscopic surgery. NOTES: Natural orifice transluminal endoscopic surgery; ESD: Endoscopic submucosal dissection; POEM: Peroral endoscopic myotomy; G-POEM: Peroral endoscopic myotomy to the pylorus; POEM-F: Peroral endoscopic myotomy with fundoplication; Z-POEM: Zenker’s peroral endoscopic myotomy; E-POEM: Esophageal peroral endoscopic myotomy; C-POEM: Cricopharyngeal peroral endoscopic myotomy.

CONCLUSION

NOTES has evolved from an experimental concept into an important driver of innovation in gastrointestinal endoscopy and minimally invasive therapy. Although its widespread clinical adoption remains limited by challenges related to access, closure, hemostasis, instrumentation, training, and patient selection, the pursuit of NOTES has already accelerated major advances in third-space endoscopy, endoscopic suturing, defect closure, organ-preserving interventions, robotic endoscopy, and magnetic-assisted platforms. Current evidence supports the continued development of NOTES in carefully selected benign conditions and experienced centers, with patient safety and evidence-based indications as the primary priorities. Future progress will depend on multidisciplinary collaboration among endoscopists, surgeons, engineers, and industry partners, together with standardized training and high-quality clinical studies to define the appropriate role of NOTES in modern gastrointestinal care.