Although endoscopic treatment of BBS with FCSEMS or plastic stents is initially effective,8,13 existing surgical, endoscopic, and percutaneous treatments for BBS do not guarantee long-term resolution. BBS recurrence has been observed even using methods with high long-term stricture resolution rates.13 Furthermore, multiple sessions or procedures are required with conventional methods, which is a distinct disadvantage for patients with BBS considering the benign nature of the disease and thus the long life expectancy. Repeated procedures for treating refractory BBS increase medical costs and cause considerable inconvenience to patients. Therefore, new treatment strategies are required. In this animal study, we confirmed that the rate of recurrent stricture in BBS could be reduced by reducing fibrotic wall thickening using steroid-eluting FCSEMS. Safety was also confirmed: no necrosis of the bile duct was observed. The results suggest that steroid-eluting FCSEMS may be effective for minimizing BBS recurrence and thus reducing the need for repeat ERCP procedures for stent insertion
The pathophysiological mechanisms underlying BBS development include an inflammatory response, collagen deposition and fibrosis formation.12 Therefore, corticosteroids, with their well-established anti-inflammatory and anti-fibrotic effects, can be administered. Corticosteroids are widely used to prevent fibrosis. Intralesional corticosteroid injections are used in the treatment of postoperative scars, acting through suppression of proinflammatory mediators to reduce fibroblast proliferation, collagen synthesis, and glycosaminoglycan synthesis.14 Corticosteroid injection of esophageal strictures refractory to conventional treatment can reduce the number of balloon dilations required for treatment, as well as prolong the interval between dilations.21 For colon strictures secondary to Crohn’s disease, a combination of balloon dilation and corticosteroid injection reduces the frequency of re-expansion procedures or surgery compared with balloon dilation alone.22 Oral prednisolone, triamcinolone injections, and polyglycolic acid sheets with triamcinolone injections can prevent the occurrence of strictures after esophageal endoscopic dissection.17,23,24 The combination of triamcinolone injection and shielding with polyglycolic acid sheets and fibrin glue is also effective for preventing and reducing strictures after esophageal endoscopic submucosal dissection.25–28
Previous studies have confirmed the safety and efficacy of directly injecting corticosteroids into areas of gastrointestinal stenosis. However, these methods lead to an uneven distribution of the corticosteroid and require a high degree of control during injection. In addition, the steroid is not released steadily, which reduces the effectiveness of these methods and decreases their ability to consistently prevent the stricture.17 Care must also be taken to avoid injection of steroid into the muscularis propria.17 By contrast, delivering corticosteroids via FCSEMS allows steady release and restricts the steroid to the mucosal layer in direct contact with the stent. In this study, triamcinolone released from steroid-eluting stents diffused evenly over the fibrotic tissue. In addition, only mucosal denudation was observed in the bile duct contacting the stent, and there was no necrosis or perforation
Safety and efficacy have been confirmed for balloon dilation and corticosteroid injection of biliary-biliary stenosis after liver transplantation, as well as for biliary-gastrointestinal stenosis after pancreatic biliary surgery.18,20 Although few studies have been conducted, percutaneous transhepatic corticosteroid injection combined with balloon dilation appears to be safe and effective in the long term for BBS, and could be an alternative treatment for these strictures.18 However, the strategy includes a steroid injection into the stricture site, which can lead to uneven diffusion and stricture enlargement due to balloon dilation, and this to a lack of continuous dilation over a prolonged period. In addition, this method requires the creation of a percutaneous tract and repeated treatments.
Local treatment using drug-eluting stents was first applied to malignant strictures.29,30 Local anti-tumor effects using paclitaxel-eluting stents have been demonstrated in malignant biliary strictures caused by extrahepatic bile duct cancer. Likewise, steroid-eluting stents are expected to have local anti-fibrotic effects in BBS. Metal stenting in biliary stenosis does not require additional procedures, such as percutaneous transhepatic biliary drainage or biliary duct dilation. In addition, it provides constant release of the corticosteroid loaded in the stent, thus producing uniform effects with a small dose. Therefore, based on this animal study, steroid-eluting FCSEMS are expected to serve as a safe and effective treatment for refractory BBS in humans.
In this study, the optimal amount of triamcinolone was 15 mg based on the results of the in vitro drug release test. Drug release was similar after 144 hours for the 15 and 30 mg triamcinolone stents. However, in our pig model, the 30 mg triamcinolone stents were more effective in reducing fibrous wall thickening, and the effectiveness was dose- and time-dependent. This superior effectiveness was likely the result of an increase in the amount of triamcinolone released from the 30 mg stent during the 4-week maintenance period. Considering that the amount of triamcinolone used in previous studies of esophageal strictures was 30 mg,17,18,23,25 the optimal dose may be 30 mg for steroid-eluting FCSEMS. Therefore, this is a limitation of the current study. Additional studies are required to identify the optimal corticosteroid concentration and stent indwelling period, and to assess the long-term drug release pattern.
In this study, RFA was used to create the BBS model. Previous in vivo swine experiments of temperature-controlled EB-RFA reported short- and long-term safety and efficacy of EB-RFA.31,32 At 4 weeks after EB-RFA, histologic examination revealed a fibrous band at the level of the stricture, and gross examination revealed diffuse, reddish mucosal inflammation of the proximal CBD. The bile duct wall was thickened and composed of mucosal ulcerations, reactive myofibroblastic proliferation, dense collagen deposition, fat necrosis, and inflammatory cell infiltration. However, there were no long-term gross or microscopic adverse events, such as perforation or hemorrhage.32 Wound healing is inevitably accompanied by varying degrees of cicatrix formation. Deposition of excessive amounts of collagen in lesion regions can lead to over-proliferation of cicatrix.14 The main manifestations of postoperative BBS are scar contracture and stenosis of the bile duct, but the mechanism underlying stricture formation remains unclear. In a dog model of bile duct trauma repair, the main cause of scar contracture and stricture was myofibroblasts.12 High expression levels of CD68, TGF-β1, and α-SMA are closely related to fibroblast proliferation, extracellular matrix over-deposition, and scar contracture in bile ducts.12 Steroids have anti-inflammatory and anti-fibrotic effects, and are expected to reduce fibrotic wall thickening by inhibiting myofibroblasts. Further studies on the mechanism of steroid-eluting FCSEMS are needed.
One limitation of the current study was that we were unable to determine whether restenosis occurred after stricture resolution. This is an inherent limitation of most animal studies. As long-term stricture resolution without restenosis after stent removal is the ultimate goal of steroid-eluting stents, long-term investigations in humans are required to explore this issue. Another limitation was that our BBS model involved a stricture formed by inducing inflammation, which does not reflect all types of BBS. Clinical studies are required to explore the use of steroid-eluting stents in humans with BBS of various etiologies.
In conclusion, the safety and efficacy of steroid-eluting stents was confirmed in an animal model of BBS induced by EB-RFA. Steroid-eluting stents can exert a mechanical effect that dilates the CBD, and a chemical effect that reduces fibrosis via anti-inflammatory and anti-fibrotic actions. In this animal study, we demonstrated that steroid-eluting stents, through these dual effects, have therapeutic potential for BBS refractory to conventional methods. Clinical trials are required to confirm the safety and effectiveness of this type of stent in humans.