ABBREVIATIONS
CD
Crohn’s disease
DISR
double incision and snare resection
EBD
endoscopic balloon dilation
EMR
endoscopic mucosal resection
ESD
endoscopic submucosal dissection
IBD
inflammatory bowel disease
IT knife
insulated tip knife
TNBS
2,4,6-trinitrobenzenesulfonic acid
TTS
through the scope
INTRODUCTION
Despite advances in medical therapy, up to 75% of patients with Crohn’s disease (CD) require surgery during their lifetime, with up to 50% having to undergo the procedure in the first 10 years of the disease. The prevailing type of surgical procedure is ileocolonic resection. In more than half of the patients who have already undergone surgery, the disease recurs at the site of the anastomosis within 1 year. The leading cause of repeated surgery is the development of a clinically significant (narrow) stricture localized in the constructed ileocolonic anastomosis. Early efficient medical therapy may prevent or delay the development of complications related to the prevailing inflammatory activity but cannot reverse the already existing tight stricture with a predominant fibrotic component at the site of the anastomosis, and is thus ineffective in this case. Given the structural nature of the narrowing, including fibrosis and smooth muscle proliferation, mechanical therapy is the only potentially efficient intervention. Classical surgical approaches, such as resection of the affected area or stricturoplasty, are effective, but their drawbacks include invasive nature, risk of peri- and postoperative complications, and relatively high frequency of either disease recurrence or defective healing due to ischemia. Surgical intervention should therefore represent the choice of last resort when selecting a treatment method for IBD patients.
Technological development and modernization of endoscopic equipment are moving forward rapidly, opening new treatment options with the utilization of less invasive, more effective, and safer methods. One of the nonsurgical methods for the treatment of primary and secondary (i.e., anastomotic) strictures routinely used in clinical practice to avoid further surgical interventions is endoscopic balloon dilation (EBD) with through-the-scope balloons. Although this method is very effective, especially in diaphragm-like and short anastomotic strictures, in more than half of patients this treatment modality has diminishing efficiency in time with the tendency to early restenosis. , This leads to the need for repeated dilatations or even additional surgical interventions including resection of the affected portion of the intestine. In a multicentric retrospective study that has been done on 282 patients with Crohn’s disease and stricture in ileocolonic anastomosis with a total of 615 procedures performed over 6 years between 2013 and 2019, the cumulative probability of redilatation at 6 months, 1 year and 3 years was 20.2% (95% CI: 14.8–26.2%), 31.8% (95% CI: 26.5–37.2%) and 59.4% (95% CI: 55.5–63.0%), respectively. Cumulative probabilities of a need for reoperation were 4.4% (95% CI: 0.5–16.9%), 8.2% (95% CI: 2.3–19.3%), and 14.8% (95% CI: 7.1–25.2%), respectively ( Figs. 8.1 and 8.2 ).
In the past, endoscopic incision of strictures was performed predominantly in the esophagus, stomach, and bile ducts. Recently, Nan Lan and Bo Shen have also described the successful performance of needle-knife endoscopic stricturoplasty in a group of patients; with Crohn’s disease at the site of primary or secondary stricture. One of the anticipated advantages of performing incision instead of balloon dilation includes more control over the process. In addition to limited sustainability of lumen diameter after EBD, deep laceration can appear leading to either immediate or delayed bleeding or occurring in undesirable locations with a high risk of bowel perforation ( Fig. 8.3 ).
The method of submucosal injection of anti-inflammatory agents such as biological drug (infliximab) has also been described suggesting promising effects in small groups of patients; however, no randomized clinical trial or comparison with routinely used method of balloon dilation has been done. ,
Although endoscopic therapy is less invasive compared to surgery, it can be more technically demanding for several reasons. On one hand, this may be due to the presence of the underlying chronic disease and the development of adhesions leading to difficult access with the endoscope to the site of the stricture. Consequently, the unstable position of the device and technical difficulties can hamper performing the procedure. Furthermore, it may be due to changed anatomy after previous surgery and anastomosis design, deformation changes present in the anastomosis, or the fixation of the intestine as a result of the inflammatory process in the surrounding mesentery and fat tissue. It is therefore a legitimate requirement for physicians performing endotherapeutic procedures in IBD patients to have adequate theoretical and practical training, preferably in an experimental animal model, which can help them familiarize themselves with the technique before they start performing the procedures in patients where safety is of utmost priority.
PRINCIPLES
The development of new endoscopic techniques is partially hampered by the safety and ethical issues associated with testing these methods in patients. It is therefore advantageous to utilize various available models that allow training and simulation of real conditions or possible complications. Several different mechanical and virtual simulators could enable the acquisition of basic skills for commonly used endoscopic techniques. Animal models, whether cadaveric or live, offer the greatest benefit in the process of practicing new methods. This is applicable not only for IBD but has been already well established in the case of other advanced endoscopic methods in non-IBD patients.
Training on animal models facilitates the phase of acquiring the basics of the technique and also improves the skills of experienced endoscopists in more complicated methods. The model allows us to try different approaches to solving complications while simulating various scenarios. The greatest advantage of living models is their similarity with real clinical practice. Anatomic dimensions, respiratory movements, peristalsis, and bleeding are not or only hardly substitutable in inanimate or virtual models. For these reasons, the recommendation for the use of the animal model is implemented, for example, in the European Society of Gastrointestinal Endoscopy guidelines for endoscopic submucosal dissection (ESD) in a manner similar to what has already been implemented in laparoscopic and minimally invasive surgery.
Another indisputable advantage of the live animal model is the possibility of modification or innovation of the already existing procedure. This creates an opportunity for adapting the method to the individual ideas of each endoscopist in experimental animal models. However, the use of live animal models for endoscopic training should be preferably limited to more advanced endoscopists, who have sufficient experience to gain maximum benefit from the simulation.
The most common and probably the optimal animal species used for preclinical endoscopic experiments or training of endoscopists is a pig, specifically a minipig that provides the best approximation to humans. The main reason is its highly proportional, morphological, and physiological similarity to the human bowel. The porcine digestive tract is remarkably similar to the one in humans. The only anatomical difference is the spatial arrangement of the large bowel, which consists of a series of centrifugal and centripetal loops so that a complete endoscopic examination of the bottom of the cecum cannot be performed. Minipig is an animal large enough that it allows the use of conventional endoscopic equipment without the need for any modifications. The presence of peristaltic waves and respiratory phenomena is almost identical to humans and thus perfectly mimics real clinical situations. The presence of bleeding during interventions is also an irreplaceable property of any live tissue and a necessity for practicing the resolution of these kinds of complications in routine clinical practice. Despite the undeniable advantage, the living model is unfortunately limited by several factors.
It is necessary to comprehend that animals, like humans, are living creatures capable of feeling pain and suffering to varying degrees, and therefore it is necessary to ensure that they are treated appropriately. Adequate education and legal permission are required to handle laboratory animals. An additional aspect is the financial complexity of running a facility with experimental animals and the availability of a suitable model. Stalls or pens, feeding, comprehensive care, and veterinary treatment must be provided. All services significantly increase the cost of live large animal models.
For routine endoscopic therapeutic methods, such as endoscopic mucosal resection (EMR) or ESD, animal models can be used. For these methods, the model does not need to show endoscopic signs of disease, thus there is no absolute necessity for the presence of a neoplastic or other lesion to practice any of the procedures. Healthy tissue on which the procedure can be performed is sufficient for training. However, in the case of IBD models, the presence of disease signs similar to those that can be seen in patients in clinical practice is an important feature.
TECHNIQUES
The currently existing and available porcine IBD model includes a model of stricture that occurs in anastomosis after ileocolonic resection in Crohn’s disease patients either due to recurrence of the inflammatory activity or ischemic changes resulting from surgical procedure and construction of the anastomosis.
The minipigs that have been used for model creation originate from the Institute of Animal Physiology and Genetics in Libechov, Czech Republic. They were imported in 1967 from the Hormel Institute, University of Minnesota, and from the Institute for Animal Breeding and Genetics of the University of Göttingen in Germany. Survival of parental minipig breeds (Hormel and Göttingen) has been reported to be 12 to 20 years. Females and castrated males are housed in groups of two to three or kept individually. All experiments were carried out according to the guidelines for the care and use of experimental animals and approved by the Resort Professional Commission of the Czech Academy of Sciences for Approval of Projects of Experiments on Animals.
Conformation of the large bowel in minipigs does not allow for a complete colonoscopy to be performed, and it was therefore essential to first overcome the technical issues associated with the endoscopy. The modification of the classic Roux-en-Y procedure was done by surgeons, with the small bowel segment connected to the oral portion of the rectum. This ensures proper reachability during endoscopy and also provides easy bowel preparation before the procedure without the need to empty the whole bowel.
In order to mimic ileo-colonic anastomosis routinely seen in CD patients after ileocecal resection and to enable easy endoscopic reachability in specific porcine anatomy, either side-to-side or end-to-side ileo-sigmoid anastomosis was designed. The anastomosis is handsewn, constructed from an open laparotomy, with an intraoperative diameter of about 20 mm ( Fig. 8.4 ).
A mixture of irritants (liquified phenol (≥89.0%) and 2,4,6-trinitrobenzenesulfonic acid (TNBS) solution (5% w/v)) in a titrated concentration are then applied to the multiple locations of a submucosa at the site of the anastomosis every 2 weeks until the development of the stricture ( Fig. 8.5 ). The model created in this way shows macroscopic (inflammation, ulceration, fibrosis) as well as microscopic (microgranulomas) signs that are characteristic of Crohn’s disease. In a study by Lukas et al. it was confirmed on a cohort of 15 animals that the described model of anastomotic stricture is reproducible with the diameter remaining stable at least for 6 months after the stricture induction. The histopathologic evaluation of the resected specimens revealed the presence of severe submucosal fibrosis with chronic inflammation and lymphoplasmacytic infiltrate and numerous eosinophils. Multiple histiocytic granulomas with multinuclear foreign-body giant cells, occasionally with an abscess in the center, were present, as well as epithelioid microgranulomas similar to those in CD ( Figs. 8.6 and 8.7 ).
CLINICAL APPLICATIONS
Endoscopic dilatation of the stricture using a through-the-scope balloon represents a gold standard and a less invasive alternative to surgery. This technique is reserved for short (up to 50 mm) and uncomplicated (without deep ulcers, severe deformation, or fistula) strictures where the balloon is inserted halfway through the stricture and inflated by a pressure of 1.5 to 5 atmospheres up to a diameter of 20 mm ( Fig. 8.8 ). Although this method is relatively simple and safe, especially in less fibrotic strictures, it fails in 40% to 60% of patients with only temporary effects lasting for a maximum of a few months. Therefore, there is usually a need for either repeated dilatation or surgical resection of the affected bowel. Given these outcomes, research is focused on the development of new endoscopic techniques with longer effects. The balloon dilatation combined with an incision has been previously performed in the esophagus, stomach, and biliary tract.
Over the last 10 years, several cohort studies have been published on small numbers of patients declaring the efficacy and safety of stent placement in primary or secondary stenosis in patients with IBD. Unfortunately, there is no randomized study to confirm the benefit of stent placement over standard and routine procedures used in the treatment of strictures in Crohn’s disease. In human medicine, conducting a study with a higher degree of evidence for interventional methods is complicated, so it is more advantageous to perform at least a proof-of-concept study on animal models. It can be assumed that stents will play an important role in IBD endotherapy shortly, especially in patients with refractory strictures in whom another surgery poses a risk of development of short bowel syndrome. The major obstacle is the absence of a suitable stent specifically designed for the application in Crohn’s disease where the presence of active disease at the site of the ileo-colonic anastomosis is related to a very fast ingrowth of granulomatous tissue through the stent pattern despite the presence of a silicon coating. This limits the maximum duration of stent placement and increases the risk of iatrogenic injury during stent extraction. Stents that have been tested on a porcine model include Niti-S enteral colonic stent (Taewoong Medical, South Korea) ( Fig. 8.9 ), Hot AXIOS apposing stent (Boston Scientific, USA) ( Fig. 8.10 ), and Hanarostent HRC20 (M.I.Tech, South Korea) which is the only commercially available stent dedicated for ileo-colonic localization even in Crohn’s disease.
Related posts:
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Endoscopy-Associated Complications in Colorectal Diseases: Clinical Presentation and Diagnostic Evaluation
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