Biodegradable Polymeric Esophagus Stents - ACS Symposium Series

Chapter 12

Biodegradable Polymeric Esophagus Stents

Downloaded by UNIV OF FLORIDA on October 26, 2017 | http://pubs.acs.org Publication Date (Web): October 25, 2017 | doi: 10.1021/bk-2017-1253.ch012

Divia Hobson,1 Arvind Dhinakar,1 Nianyuan Shi,2 Le Zhang,3 Wenjing Wu,1 Lifeng Hou,4 and Wenguo Cui1,* 1Department of Orthopedics, the First Affiliated Hospital of Soochow University, Orthopedic Institute, Soochow University, 708 Renmin Road, Suzhou, Jiangsu 215006, China 2School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shanxi 710049, P. R. China 3Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi’an, Shaanxi 710069, China 4Physics Department and Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai, Shanghai 200241 *E-mail: [email protected]

Esophagus stents are a common and effective treatment for esophageal strictures. Esophageal stricture can cause dysphagia, weight loss, malnutrition, respiratory failure and aspiration. Limitations of current self-expanding metal and plastic stents include ingrowth of tissue and stent restenosis. Partially covered self-expanding metal stents (SEMS) tend to become embedded in tissue and difficult to remove. Self-expanding plastic stents (SEPS) as well as fully covered SEMS have a high migration rate. The major benefit of polymeric biodegradable stents (BDS) is that do not require to be removed as a result of decomposition into non-toxic chemical species. Patient concerns regarding implant permanence in addition to long-term risks like thrombosis are reduced. Furthermore, BDSs are able to carry and release drugs as they degrade. Limitations of these devices are the mechanical strength and lower radial force that diminish effectiveness of the stent in stricture dilation and leak closure. This chapter reviews recent clinical evidence of BDS.

© 2017 American Chemical Society Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Introduction Esophageal strictures often occur as a result of disease that can be either benign or malignant in nature. Treatment of the stricture can be categorized as operative or non-operative based on the approach. Conditions such as esophageal reflux and sclerotherapy, advanced cancer, caustic ingestions, and external beam radiation act as reasons to opt for non-operative treatment. Similarly, operative treatment is selected in cases where patients experience surgical anastomosis, have undergone endoscopic submucosal dissection (ESD), or endoscopic mucosal resection (EMR) for early esophageal neoplasms (1). Common problems that stem from esophageal strictures are dysphagia, weight loss, malnutrition, respiratory failure and aspiration. In order to address these complications and obstructive symptoms, balloon dilation alone or in combination with stent insertion is used to improve the patient’s quality of life. Stents in esophageal stricture applications have developed significantly in the past three decades from stiff plastic tubes to bendable self-expanding metal and plastic stents (SEMS, SEPS). SEMS can be classified into two types depending on the implantation time: permanent and retrievable temporary stents. Similarly, SEMS can be designed to be partially or fully covered metal stents. While present-day SEMS and SEPS insertion are a favourable treatment alternative for esophageal disease, patients widely experience difficulties that include the ingrowth of tissue, restenosis, migration and a need for continual procedures. More specificially, partially covered SEMS become firmly secured, inhibiting stent migration, while stent restenosis occurs from hyperplastic tissue reaction that impedes removal. Reactive hyperplasia is decreased in fully covered SEMS and SEPS designs; however, these stent have a high migration rate. Advancements of polymeric biocompatible and biodegradable materials have in the last twenty years have led to the fabrication of polymeric biodegradable stents (BDSs) to overcome the drawbacks experienced with the SEMS and SEPS (1). The main motivation for the research and development of BDSs is the cardiovascular stent market as BDSs have been preferred to SEMS and SEPS since 1997 due to the frequency of adverse occurrences associated with their usage. BDSs are beginning to be used to treat esophageal strictures as they relieve dysphagia and do not necessitate endoscopic removal (2, 3). Moreover, the insertion of BDSs or biodegradable drug-eluting stents (DES) can be taken as an intermediate step before surgery or a palliative treatment method to ameliorate enteral nutrition up until neo-adjuvant treatment is concluded. In this chapter, we will discuss types of esophagus stents including SEMS and SEPS leading to the development of BDS and DES in addition to relevant clinical evidence.

Esopahgus Structure The structure of the esophagus is tubular and can vary in length from roughly 18 to 26 cm in length in adults (4). As part of the gastrointesiontal tract, the esophageal wall is made up of the mucosa, submucosa and muscularis propria (4). 238 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Unlike other parts of the gastrointestional tract, there is no serosal covering in the esophageal body. The mucosa is composed of stratified squamous epithelium that can be looked at as three sublayers (mucous membrane, lamina propria, and muscularis mucosae). Glands of the esophagus are found in the submuscosa. The functions of the esophagus are to move ingested food and fluid to the stomach and avert gastroesophageal reflux. Motor functions of the esophagus are enabled through complex voluntary and involuntary mechanisms (5). Three functional areas that exist within the esophasgus are the upper and lower esophageal sphincters as well as the esophageal body (depicted in Figure 1).

Figure 1. Anatomy of the Esophagus.

Types of Esophagus Stents Esophageal strictures are a very common medical condition encountered in gastroenterological practice today and can be either malignant or benign. An esophageal stricture is the gradual narrowing of the esophagus that might lead to swallowing problems in patients as known as dysphagia (1). These strictures arise due to various causes that can be categorized as operative or non-operative. Non-operative causes include gastric reflux disease (GERD), cancer and external beam radiation whereas operative causes might include endoscopic sub mucosal dissection and mucosal resection (ESD, EMR) (6). Mechanical dilation of the esophagus and stent insertions (Figure 1) have been playing a vital role in alleviating the symptoms of esophageal dysphagia and improving the quality of life for the patient (7). 239 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 2. Stent used for esophagus insertion. Adapted with permission from reference (6). Copyright 2016 Multidisciplinary Digital Publishing Institute. Esophageal stents are playing a major role in the treatment of esophageal strictures and consequential symptoms of dysphagia (6–8). Historically rigid polyvinyl plastic stents were used to treat patients with esophageal obstructions. However, using these plastic stents has increased the number of complications and morbidity rates amongst patients. In a study by Conigliaro et al, sixty patients with obstructions due to adenocarcinoma, lung cancer, squamous cell carcinoma and thyroid tumor were treated with stent insertions (9). It was seen that early minor complications arose in 19 patients and major complications in 13 (9). Death occurred in three patients due to pulmonary embolism and massive hemorrhage (9). In order to overcome this issue, most stents currently are made from metal alloy compounds and durable polymers and are used to treat a variety of benign and malignant esophageal conditions (10). With the advancement in medical technology and research, the development of SEPS, SEMS is seen to be very cost effective and safe (10). These stents are available in three types: fully covered, partially covered and uncovered (11). The type of coverage represents the presence of material covering the metallic or plastic mesh (11). Due to various complications caused by uncovered stents a variety of covering materials including polytetraflouroethylene have been developed (11). Clinical evidence suggests that the partially covered SEMS are superior to uncovered SEMS in the palliation of obstructive esophageal cancer due to the recurrence in tumor ingrowth through uncovered stents (11). Although the use of self-expandable stents proved to be very cost effective and safer than the rigid plastic counterparts, the long term implantation of these stents proved chronic inflammatory reactions and lead to medical atrophy with aneurysm formation (10). However, recent studies have shown that fully covered SEMS may be able to overcome the problems of partially or completely uncovered SEMS (10). Yang et al. used the biodegradable polymer mixed of poly(ε-caprolactone) (PCL) and poly (trimethylene carbonate) (PTMC) as the coated material to cover the magnesium alloy stents for fabricating a new type of esophageal stent (Figure 240 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

2) (6). This kind of stent showed great ability to delay the degradation time and long term mechanical performance mainteace. The in vivo experiment results also proved that the stent insertion was feasible and provided reliable support for more than 4 weeks without any collagen deposition. A study by Eloubedi et al, suggested that dysphagia improved in patients who underwent stent placement (12). In addition 31% of the patients had successful long-term outcomes without the need for reinterventions (12). Thus FCSEMS may represent an attractive alternative for the treatment of esophageal conditions (12). A list of current stent types used today in the medical field is shown in Table 1 (1).


Self-Expandable Metallic and Plastic Stents (SEMS, SEPS) Various other stents such as SEMS and SEPS are being used extensively for stricture treatment (13). Although these stents have advantages, recurrent dysphagia due to stent migration is seen to be a common complication of these stents (13). The Ultraflex stent (Microvasive Boston Scientific Coporation) is made of a single strand of Nitinol wire exerting radial pressure while minimizing traumatic tissue compression (14). These self expendable metallic stents are designed to be placed through a narrow stricture in a collapsed state (14). As the stent expands progressively, the complications that occur are found to be lower than that of latex prosthesis (14). This makes it easier for patients to swallow as they now have a much larger lumen in comparison to the latex prosthesis. Although these stents are useful in palliative treatment of esophageal strictures, tumor ingrowth and stent migration seems to be a very common complication in many cases. In a study, 125 patients with dysphagia were treated with the Polyflex, Ultraflex or the Niti-S stents (15). The initial improvement of dysphagia in all three stents groups was similar (15). However, recurrent dysphagia due to migrations and tissue growth was significantly different between the Ultraflex and the other groups (15). It was noted that stent migration occurred more frequently with Polyflex stents as opposed to other groups (15). Similarly, in a study by Conigliaro et al, 60 patients were treated with the self-expendable plastic Polyflex stent for unresectable esophageal cancer (9). Early minor to major complications were seen in almost 50% of the patients, followed by delayed stent migration and tumor overgrowth (9). This can suggest that the Polyflex stents have similar efficacy but has a higher chance to migrate post treatment (9). Moreover, the overhead cost and technicality of placement make it difficult for treatments (9). Despite the various types of self-expandable stents available there is no apparent superiority among different stents with regards of dysphagia relief. Sabharwal et al. performed a prospective randomized controlled trial comparing the rate of early and late complications in 53 patients diagnosed with inoperable lower third esophageal carcinoma randomized to receive either a flamingo covered wallstent (Boston Scientific Inc., Watertown, Mass, USA) or an Ultraflex covered stent (Boston Scientific Inc.) for palliation (16). In both stent groups, there was a significant improvement in dysphagia but no significant difference was seen between the two groups (16). The frequency of complications among the groups was similar (16). In a study by Conio et al., one hundred patients with unresectable esophageal carcinoma were randomly treated with Polyflex and 241 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


partially covered Ultraflex stents (17). Results showed major complications in almost 48% of the polyflex group and around 33% of the Ultraflex group (17). A multivariate analysis performed on the results showed a significantly higher complication rate with a Polyflex stent in comparison to the Ultraflex stent (17). From the above studies performed, it can be conferred that self-expandable metallic or plastic stenting does provide relief from esophageal strictures and tumors but can also lead to a variety of early minor or late major complications. Improving the quality of available stents types and promoting the use of BDS or radioactive coated stents can control complications and enhance the quality of life of the patients. The use of SEMS is successful in the palliative treatment of malignant strictures while not implemented for routine use due to shortfalls of this device (9–11). Stent removal of the SEMS is frequently hampered by tissue embedment following placement which can become highly difficult and tramaumatic for the patient. Complications associated with uncovered SEMS were bleeding, fistulae, erosion, tissue embedment, reoccuring or new formed strictures (9–11). Although researchers have found that fully covered SEMS may reduce the complications experienced with uncovered SEMS, the major benefit of BDS over all types of SEMS is that they do not necessitate removal. Moreover, the need for repeated stent insertion is decreased with BDS. Biodegradable Polymeric Stents With the advancements in polymer science and technology, resorbable and nonresorbable polymeric stents have been recently fabricated (18). These biodegradable polymeric stents have shown to greatly decrease the need for reinterventions and prevent complications of tissue ingrowth and stent migration (18). Most of the biomaterials used in polymeric stents are synthetic polymers including poly-glycolic–acid (PGA), poly-lactic-acid (PLA) and poly-caprolactone (PCL) (19). Given these characteristics the main advantage in using synthetic polymers are: (1) adequate biocompatibility, (2) low friction coefficients, (3) pose alternatives for surface chemical and physical changes, (4) ability to immobilize cells and biomaterials on the surface. Thus biodegradable stents (BDS) can be designed using various synthetic polymers or various co-polymers with hydrolytic degradation and speed of degradation influenced by size, structure, and type of tissue, pH and temperature (20). Currently there are a variety of BDS used in the medical field. A very prominent example is the use of the Ella Stent (ELLA-CS, s.r.o, Hradec Kralove, Czech Republic) (19). The Ella Stent is a biodegradable stent that is manufactured from polydioxanone (PDX) absorbable surgical suture (11). Polydioxanone occurs as a semi crystalline biodegradable polymer part of the polyester family. The degeneration of this polymer is accelerated by low pH (11). The stent structure consists of radiopaque markers at both the proximal and the distal ends as seen in Figure 3 (19). The diameter of the stent is approximately 25 mm with lengths ranging from 60-135 mm (19). As observed, the stent integrity and radial force is completely maintained for a 6-week period following implantation. The reported degradation occurs at the 11-12 week period (19). Clinical success of the stent varies from 242 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


0-100% with a mean of 74.68% (6). In a study by Hirdes et al., stent placement procedure in 28 patients with refractory benign esophageal strictures saw a 25% success rate with a long term follow up from the initial stent placement (21). The major drawback of BDS is stent migration (21). There are not many follow up studies in the use of the ELLA-BDS, however the based on the studies mentioned above the initial placement of the stent showed great progress in alleviating the symptoms of esophageal strictures with only minor complications and recurrence (22). Thus ELLA-BDS can be considered as an effective alternative for severe RBES symptoms and can avoid frequent serial dilations. BDSs are derived from various synthetic polymers and their copolymers. The degradation is hydrolytic and the speed is determined by factors like the polymer size and structure as well as the temperature, pH and kind of body tissue or fluid the stent is exposed to (5). The main advantage of polymeric BDS is the natural decomposition into non-toxic chemical species reduing patient concerns regarding implant permenance as well as decreasing future risks of thrombosis or dual antiplatelet therapy (5). As BDSs have the ability to carry and release drugs, the release profile can be manipulated through the BDS composition. Adjusting composition on the abluminal and luminal sides can result in further benefits (5). Moreover, BDSs have a comparatively low cost for manufacturing. One challenge of BDSs is that they do not have the same strength of metallic stents. Consequently, BDSs may recoil soon after placement. Furthermore, as a result of the dimishned radial force, effectiveness in stricture dilation and leak closure are weakened (5). The lower radial force also influences stent migration in addition to the continual loss of support force and mechanical strength through biodegradation (5). This degradation process ultimately leads to a stent that is unable to combat the force of the stricture. BDSs are associated with notable local inflammation (5). Moreover, restenosis may occur based on the slow bioaborption rate. BDS stents are also radioluscent which poses a challenge in placing them easily and accurately without fluoroscopic guidance (5). Recently many researchers have begun using these polymeric stents as carriers for a variety of drugs including paclitaxel, gemcitabine and carboplatin (23). GEM, PTX and curcumin are some other important drugs used today in drug eluting stents (4). PTX is a lipophilic molecule with a diterpenoid derivative that is essential for microtubule function and as a result cells division (23). PTX in the biological system leads to cell death by inhibiting the cell division and migration (23). GEM, an analog of deoxucytinide, on the contrary is a hydrophilic drug that inhibits DNA synthesis (23). This can be a very useful drug in treating solid tumors in the biological system. Finally, Curcumin is a chemical compound with low intrinsic toxicity, and poses a wide variety of pharmacological activity from anti-thrombus, anti-oxidation and even anti-proliferation (23). It is therefore very crucial to choose the right drug as well as the right polymer when designing drug-eluting stents for palliative treatment of esophageal strictures and other complications. In a study by Suk et al., a metallic polyurethane stent was used to carry paclitaxel to palliate 21 patients with unresectable malignant biliary obstruction. The results conferred that the drug eluting stents provided a greater opportunity for patient survival and healing in comparison with conventional stents (24). 243 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Stent

Material

Covering

Length (cm)

Diameter Shaft/flare (mm)

Anti-Reflux Valve

Manufacturer

Ultraflex

Nitinol

NC/PC

10/12/15

18/23

No

Boston Scientific

Wallflex

Nitinol

PC/covered

12/12/15

12/28

No

Boston Scientific

Esophageal-Z

Stainless Steel

PC

8/10/12/14

18/25

Yes

Cook

Evolution

Nitinol

PC

8/10/12.5/15

20/25

No

Cook

Niti-S

Nitinol

Covered

8/10/12/14

16/20

No

TaeWoong Medical Boston Scientific Alveolus

Polyflex

Polyester

Covered

9/12/15

16/20

No

Alimaxx-E

Nitinol

Covered

7/10/12

18/22

No

244


Table 1. FDA-approved Stents currently marketed in the United States

Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 3. Samples of various stents used in the medical field. From left to right, Polyflex by Boston Scientific, Esophageal NG Stent System by UltraFlex, Fully Covered Esophageal stent by WallFlex , and Partially Covered Esophageal Stent by WallFlex. Reproduced with permission from reference (11). Copyright 2012 Millennium Medical Publishing, Inc.

Clinical Applications Benign Stricture An encouraging potential treatment alternative are BDSs that were initially designed to address esophageal strictures. It is not necessary to remove the BDS after insertion and in the event that it migrates, gastric acid is able to dissolve and accelerate degradation of the stent through hydrolysis. This safeguard mechanism mitigates injury as well as potential fatality to the patient. PLC-BDSs have been developed as a treatment for patients suffering from benign stenosis (25–27). Goldin et al. (28) reported the first use of a PLLA-BDS (InStent, Eden, MN, USA) in the treatment of benign esophageal strictures in 1996. The PLLA is known to have expansion properties and exert radial force and biodegrade within a period of 3-6 months. The stent is a coil wrapped onto a catheter and held at a diameter of 10 mm with a thin wire securing both ends. The released stent expanded spontaneously to take its design diameter of 14-16 mm with a length of 6-10 mm over the course of a few minutes following endoscopic placement. The 245 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


BDS collapsed in three patients within 3 weeks of use and resulted in recurrent dysphagia. In two patients, patency of the stent was ameliorated with a better stent design. Fry and Fleischer first used PLLA-BDS (EsophaCoil; InStent, Eden Prairie, MN, USA) in the USA as a course of treatment for benign esophageal stricture stemming from radiation injury in 1997. Balloon dilatation must be carried out after stent insertion to allow further expansion as the radial force of BDSs is less than that of typical metal stents. These applications were developed while biodegradable stents were in the investigative stage. In the following decade, BDSs were established. Tanaka et al. (29), in 2006, reported on modified PLLA stents that had an adequate radial force for treatment and it was consequently named the Tanaka-Marui stent. These stents demonstrated a radial force in a similar range to clinically applied esophageal stents. The results of two sets of patients who were treated with Tanaka-Marui stents (Marui Textile Machinery, Osaka, Japan) (Figure 4) were reported on by Saito et al. (30, 31) The larger cohort of 13 patients required stents for varying reasons (six BES, two caustic, four anastomotic, seven RBES, and seven esophageal cancers following endoscopic mucosal dissection). Within this cohort, 10 of the 13 patients experienced spontaneous migration of the stent 10-21 days following insertion. Entire relief of dysphagia was considered clinical success. This was observed in all patients in a 7-24 month follow-up period. Continued studies demonstrated that the PLLA-BD stent had a low rate of complication pertaining to the stent. Given that a high early stent migration rate was found in the three studies, history of degradation in the esophagus and tolerability of the process over time were not adequately assessed. An additional novel stent fabricated from the biodegradable polymer PDX was developed in 2009 (EllA esophageal stent, EllA-SX, s.r.o., Hradec Kralove, Czech Republic) (32). At present, the stent is able to be amassed onto a 9.4 mm (28 F) delivery system that allows it to expand gradually following release. Stents are made in four diameters (18, 20, 23 and 25 mm) with lengths from 60 to 135 mm. The preformed diameter is achieved 24-48 h succeeding release. While the stent then proceeds to slowly degrade via random hydrolysis of molecular ester bonds, the integrity and radial force remain consistent for roughly six weeks after implantation. At the seven to nine week point, two-thirds of the integrity and radial force remain. After nine weeks, one-third of the integrity and radial force remain. On average, total degradation is found to occur between 11 and 12 weeks. Acidsuppressing therapy carried out by proton-pump inhibitors is suggested to extend integrity of the stent as a low pH accelerates the degradation process. A small number of cohort studies have been produced that detail the application of ELLABDS in treatment of benign esophageal disease. This classification of disease can include conditions like benign esophageal strictures (BES), refractory benign esophageal stricture (RBES) (21, 33–44) and achalasia (45). While insertion of the stent did not pose any difficulties, clinical success had a mean of 74.68% and fluctuated from 0 to 100%. Furthermore, a limited number of studies had ten patients or more. Dysphagia was found to be entirely relieved in 43% of patients with RBES following EllA-BDS placement after a median follow-up of 53 weeks (range: 25–88 weeks); eight (26%) patients had recurrent dysphagia in a study by Repici et al. (46). Similarly, Van Boeckel et al. (22) found that dysphagia 246 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


was fully alleviated in 33% of patients following a median of 166 days (range: 21–559 days); main complications take place in 22% of patients. In another study containing 20 patients with an ELLA-BDS, Ibrahim et al. (47) concluded that 50% of the patients needed another stent insertion, or multiple, six months later. Moreover, an EllA-BDS insertion was determined to be a successful one-step management technique in 60% patients by for an esophagogastric anastomotic stricture by Van Hooft et al. while obstruction was found to recur in 40% of patients and 30% required endoscopic dilation after six months. Hair et al. (45) evaluated the successive ELLA-BDS insertion of 59 stents in 28 RBES patients in order to assess safety and efficacy. Following placement of the initial stent, the mean duration without dysphagia was 90 days (range: 14–618 days) and 25% of patient experienced clinical success (dysphagia-free for ≥6 months). Following the insertion of a second BD sent, 15% of patients found clinical success and the mean period without dysphagia was 55 days (range: 25–700 days). After the third BD stent insertion, the mean period without dysphagia increased to 106 days (range: 90–150 days); however, none of the patients were considered clinically successfully. These studies demonstrate that for the majority of patients, a solitary ELLA-BDS placement is only viable in the short term. The main complications from this procedure were vomiting and retrosternal pain and following one, two and three insertions, 29%, 8% and 28% of patients experienced these problems, respectively (42). A viable alternative for severe RBES is sequential ELLA-BDS insertion in order to prevent recurring serial dilations.

Figure 4. The PLLA esophageal stent (Tanaka–Marui stent; Marui Textile Machinery Co., Ltd., Osaka, Japan) (a);the mucosal defect after ESD (b); the released PLLA stent(c); fixation of the rostral side by endoscopic clips (d); and the view at six-month follow-up (e). Reproduced with permission from reference (30). Copyright 2007 Baishideng Publishing Group Inc. 247 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Unlike PLLA-BDS, ELLA-BDS have demonstrated encouraging results. A low rate of migration, from 0% to 22%, and suitable rate of clinical success, from 33% to 60%, have been demonstrated in a preliminary case series treating esophageal strictures with ELLA-BDS (22, 47–50). Ongoing research has exhibited that embedding of the stent into the esophageal wall occurs with uncovered ELLA-BDS and results is a considerably diminished rate of migration although substantial hyperplastic tissue responses can be prompted (45, 49, 51–53). A review of 157 patients suffering from benign esophageal strictures was conducted in nine studies. This review found that the technical success rate was 96%, clinical success rate was 54.67% while 13.98% of cases experienced early stent migration and 14.54% hyperplasia (22, 29–31, 44). Malignant Stricture In treating resectable esophageal malignancy, a novel recent concept is placing the stent prior to neoadjuvant therapy as independently, neoadjuvant chemoradiotherapy is applied to extend survival post-surgery. This course of treatment has the potential to improve nutritional status of the patient through solid oral intake as well as way toward surgery during the chemotherapy stage. In typical circumstances, an esophagectomy is conduced soon after neoadjuvant therapy is completed. This strategy in treatment has been reviewed in a number of studies that utilize various types of stents and differing neaoadjuvant therapies. A thorough examination of 57 patients suffering from malignant esophageal stricture from four studies demonstrate a technical success rate of 96%, clinical success rate of 91%, and early stent migration rate of 8.8%. These studies are effective in ameliorating dysphagia and the sustentation of patient nutrition. Moreover, the relief of dysphagia rate was determined to be 79.5% and tissue hyperplasia rate was 14.5% although complications would still manifest. Immediate surgery is necessary is cases of esophageal puncture or stent migration. Stent migration has been found to give way to small bowel damage through perforation or obstruction. Leak or Perforations Of late, implementation of modified ELLA-BDSs with a polyurethane covering were applied postoperatively to anastomotic leaks (n = 4) as well as to benign perforations of the esophagus (n =1) with an original technical success rate of 100%. The clinical success rate was determined to be 80% while the rate of stent migration was also 60%. Use of a biodegradable material to cover the stents in this type of treatment was found to be viable and safe. Nonaka et al. developed a novel biodegradable covered stent fabricated from a 1:1 copolymer of PLA and PCL, reinforced with PGA fibers. The stent was endoscopically inserted into the esophagus in order to repair the perforation being treated. In this case, four pigs were treated for repair of emergent esophageal perforation. One week following implantation, the stent was able to be observed and then completely undetectable at the two week mark. No stenosis or infection was encountered at the site of repair. There are currently two clinically available BD stents: an ELLA-BD stent composed of polydioxanone (ELLA-CS, Hradec Kralove, Czech Republic), 248 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

and a PLLA-BD stent made from knitted PLLA monofilaments (Marui Textile Machinery, Osaka, Japan).


Conclusion and Future Prospects The uncovered design of the BDS has resulted in reduced migration rates and excellent performance compared to SEMS and SEPS. While both SEPs and BDSs decrease tissue hyperplasia and avert stent removal, common complications of thoracic pain, hyperplastic tissue reactions and migration are encountered and reported as a major problem to be addressed going forward. In considering BDS implantation as a course of treatment, severity of tissue response and the time period for full degradation of the BDS are still unfamiliar elements that pose difficulty. Furthermore, the selection of the type of BS stent that should be used in each case for effective treatment of esophageal diseases remains uncertain. Consequently, this selection for endoscopic management requires an individualized approach. Progress in this technology has resulted in increased patency and radial force of BD stents and lessened complications stemming from their implantation. Continual design improvement is seen in esophageal BDSs that resolve deficiencies and help to improve the quality of life for patients. One significant difference from the design of vascular and colorectal stents is the acidic environment for the esophageal BD stent. Additional technical refinements and study are necessary to establish as well as improve the efficacy of these stents.

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