Newly Designed Biodegradable And Self-expandable Metallic "Pieced" Esophageal Stent In The Fundamental And Animal Experiment Study

Background and aimsEsophageal strictures including malignant or benign esophageal strictures are a common clinical problem for gastroenterological doctors. The malignant strictures are usually caused by tumors and the benign strictures are often caused by acid or alkali corrosive injury, Schatzki’s rings, esophageal surgery, radiation injury, after ablative therapies and achalasia. The management of incurable malignant strictures commonly requires permanent stent placement for the palliation of dysphagia and avoid complications of esophageal obstruction. For the patient with benign strictures,1-3 consecutive sessions of bougies or balloons dilatations are primary therapies for centuries. However, for those patients with refractory benign esophageal strictures who failed in several dilatations, temporary implantation of stent was considered to be a good choice, comparing with other alternative management.At present, the most commonly used esophageal stents can be categorized according to different materials, that is, metallic stents, plastic stents and other material stents. Metallic stents usually were made from stainless or titanium-nickel and were initially succeeded in the treatment of malignant stricture. However, due to its rigid shape, the complications including adjacent tissue imbedding, granulation, necrosis, ulceration and new strictures formation suggested frustrating results in their applications of temporary implantation for benign esophageal stricture. Plastic stents covered by silicon had a lower rate of tissue imbedding than metallic stent. However, it is associated with high migration rate compared with metal stent. With the invention and development of biodegradable materials and organizational engineering, biodegradable stent were introduced to the treatment of benign esophageal strictures recently in order to solve the problems in stent removal, such as tissue overgrowth and migration. The stent were composed of polydioxanone which can be degraded by hydrolysis of molecule ester bonds. However, the radial force of biodegradable stent is not enough, comparing with conventional stent and it cannot sustain dilation effect to some extent.It would be ideal if the temporary placement of an esophageal stent could remold the esophagus in the strictured area through a long-term dilation effect and maintain luminal patency while simultaneously stretching the stenosis, and then be easily extracted. In clinic, the stent is forced to be pull out of the esophagus during removal procedure. So far, no stent can completely change its radial force during removal procedure. The main problem prevented stent removal is its existed radial force. Sometimes, the stent removal is painful and difficult. According to the urgent problems mentioned above, we designed a group of esophageal stent with unique characteristic. In this study, we designed and manufactured the self-expandable metallic detachable "pieced" esophageal stent which possess well radial force as conventional metallic stent and had no radial force during retraction. Moreover, the biodegradable "pieced" stent can be degraded into pieced in a certain period and avoid endoscopic removal procedure. We investigated the effect and feasibility the stent in the fundamental and animal experiment.Part I The Design and Manufacture of Biodegradable and Self-expandable Metallic "Pieced" Esophageal StentObjectives1. To draw the blueprint of this "pieced" esophageal stent with effectively sustained dilatation effect and feasibility of easy removal.2. To prepare the biodegradable thread and test it degradable property.3. To manufacture the biodegradable and self-expandable metallic "pieced" esophageal stent.Contents and Methods1. The characteristics of the stent is mentioned below: ①the stent contained two or more pieces of curved nickel-titanium mesh;②all the nickel-titanium pieces were connected by thread;③one type of this stent applied non-absorbable surgical suture lines, and the thread of the other type used biodegradable materials;④the degradation period which can be controlled according to the proportion of the ingredients were suitable for benign esophageal stricture; ⑤the stent is a fully covered self-expandable metal stent.2. Stent manufacture:the nickel-titanium memory alloy were braided on metal mould and put into high temperature cabinet-type electric furnace for patterning the braided metallic mesh pieces. The pieces were immersed for coating in the coupling reagent which was prepared by silicon solution made from medical grade silicon rubber with solute of petroleum ether. The fully covered pieces were connected by two ways; one is a detachable suture way by weighted adjustment, the other is connection of biodegradable thread.3. Synthesis of biodegradable thread:the raw materials for synthesis of L-lactide contained L-lactic acid, D, L-lactic acid and glycolic acid; preparation of poly(L-lactide) (PLLA)and poly(lactic-co-glycolic acid) (PLGA) were synthesized by ring-opening polymerization. Granulation and fibre-drawing of the synthesized biodegradable thread.4. The synthetic product was characterized by Infra-Red (IR) and Nuclear Magnetic Resonance(NMR) spectrum, Gel-Permeation Chromatograph(GPC) and Differential Scanning Calorimeter (DSC).5. The appearance and morphology of biodegradable thread were observed during 0-8 weeks and pH value and mass-loss were measured. We calculated intrinsic viscosity and measured tensile strength, thermal behavior and degree of crystallinity and orientation.Results1. Self-expandable metallic "pieced" stent:this stent were manufactured and its appearance was smooth without burrs, sharp edges and pits.2. Synthesizing biodegradable materials:the IR and NMR spectrum suggested that the compounds contained methyl, methylene, methine, ester and et al. The melting point of PLLA was 183.9℃, PLGA was 199.7℃, which suggested that PLLA and PLGA were both at crystalline state. Fusion and granulation process did not influence the molecular weight of the polymer. The PLLA and PLGA compounds were conduced fibre-drawing and achieved optimum mechanic efficiency when the temperature of drawbench was 125℃ with the speed of 5m/min and 4 times stretch ratio.3. Degradable property of the biodegradable thread:the appearance of PLLA thread from 1 to 8 weeks showed no obvious different, comparing with the beginning time. Sample of PLGA thread degraded from 5-7 weeks and the appearance turned rough and loss. The sample lost former fibrous structure and turned to be fragments and powder on 8 weeks.4. The braided mesh pieces were connected by surgical suture lines or PLGA thread. The nickel-titanium thread is φ0.13mm; and diameter of the stent was 10mm±0.5mm with the 30mm±5mm length. For the braided mesh pieces, the thermal treatment temperature is 55℃ and period is 25min.The silicon coating temperature is 120℃ and dry time is 1 hour. Physical property showed that the flexibility, radial compression ratio and radial force of stent meet design requirements.Part II The Effect and Feasibility of Biodegradable and Self-expandable Metallic "Pieced" Esophageal Stent in Animal ModelObjectives1. To compare the application and retrieval condition between the conventional self-expandable metallic stent and self-expandable metallic "pieced" esophageal stent in animal model of benign esophageal stricture.2. To evaluate the degradation condition and radial force of self-expandable metallic "pieced" esophageal stent connected with biodegradable thread (biodegradable stent) in vitro.3. To investigate the application and degradation condition of the biodegradable stent in animal model of benign esophageal stricture.Methods1. Establishing an animal model of benign esophageal stricture.2. Implanting the esophageal stent under endoscopy.3. Extracting the esophageal stent under endoscopy.4. Measuring the radial force, intrinsic viscosity, melting point, crystallinity, appearance and morphology of biodegradable stent.5. Observing the detachment of biodegradable "pieced" stent in vivo.6. Evaluating the rate of extraction, procedure time and complications.Results1. In the comparison of conventional stent and "pieced" stent, the control group and study group both involved 15 rabbits. By the end of the observation period,11 stents in study group and 10 in control group remained in situ.11 stent were extracted successfully without severe complications, such as bleeding, perforation and death, in study group at the end of observation period.9 of these were collapsed by pulling forward the threads; 2 cases came across thread broken. The debris of thread was pulled by forceps and then the stent were collapsed and extracted.6 stent were extracted in control group, while 4 failed (1 case had severe bleeding,2 had tissue overgrowth and 1 was dead). The removal rate of test group was 100%, while control group was 60%. The comparison between the two groups was statistically significant (P=0.035). The time of stent removal procedure in study group was significantly faster than the time in control group (9.18±4.22min vs.7.17±6.55min, P=0.009). The stent removal-related complications in study group were significantly lower than control group (0% vs.40%, P=0.026)2. The stent with PLLA thread had no obvious degradation in PBS or simulated gastric fluid. PLGA thread stent began to degradation at 6 weeks in PBS and 9 weeks in simulated gastric fluid. The radial force decreased to zero and its intrinsic viscosity decreased with time linearly.3. In animal model study of biodegradable stent, there were 15 rabbits in each groups. The conventional stents were placed in control group and biodegradable "pieced" stent were placed in study group. The dilatation and degradation condition were observed for 8 weeks. By the end of the observation period,8 stent in study group were degraded of itself and 6 stent in control group remained in situ.3 cases failed to retrieval in control group (2 had tissue tearing and 1 had severe bleeding).Conclusions1. Biodegradable and self-expandable metallic "pieced" esophageal stents possessed proprietary intellectual property and are the products with original technological innovation.2. The self-expandable metallic "pieced" esophageal stent which contains covered nickel-titanium mesh and surgical suture lines can be collapsed by pulling forward the suture lines during removal. The radial force will be disappeared during endoscopic removal. Its removal rate and related injuries are superior to conventional stent.3. The biodegradable "pieced" esophageal stent which contains covered nickel-titanium mesh and PLGA threads. The PLGA threads can be degraded in 8 weeks and then the stent will be collapsed and expel from digestive tract.SignificationsBenign esophageal stricture is one of the most common digestive diseases and it can badly influence the life quality of patient. For the patient with refractory benign esophageal strictures failed in several consecutive dilatations, short-term stent implantation treatment can palliate dysphagia and discomfort caused by obstruction by sustained dilatation. However, stent removal turns out to be a great problem for endoscopists. Although stent radial force can help remold the esophageal tract and maintain the luminal patency, it prevent stent removal. No esophageal stent can completely change its shape and be taken out with no radial force by far. In this study, the self-expandable metallic "pieced" stent possesses the properties of not only strong radial force for sustaining dilatation but also easy removal with no radial force. The biodegradable stent cannot provide sufficient radial force for dilatation now. The other newly designed self-expandable metallic "pieced" stent connected with biodegradable thread has the same sustained force as conventional metallic stent and can be degraded in a certain period. The biodegradable and self-expandable metallic "pieced" stent can provide a better alternative management for treatment of refractory benign esophageal stricture (Patent No. ZL201110323099.5).