Designs And Manufactures Of A Totally Bioabsorbable Atrial Septal Defect Occluder And Its Animal Experiment Research

Background:Atrial Septal defect (ASD) account for 30% of congenital cardiovascular malformations. Nickel-titanium ASD closure devices have been widely used in recent years, and transcatheter device closure of ASD has become a optimal treatment of selected patients. Although potential short-and mid-term complications such as residual shunts, thromboembolism, friction lesions, perforations, metal fractures, and rhythm disturbances have been well described, the long-term potential for adverse effects over several decades remains to be determined.However, the device itself may be dispensable once the defect is closed and covered by a complete and firm layer of ingrown, endogenous "repair" tissue. This thought led us to the idea of a totally biodegradable ASD occluder that acts as a temporary guide rail for the ingrowing host tissue from the defect edge to cover the device and thus the defect underneath. The ideal totally bioresorbable occluder scaffold should promote the healthiest and most complete healing response possible while eventually facilitating the full resorption of the material, leaving "native" tissue behind and minimizing the potential for future complications.Therefore, we are in cooperation with relevant manufacturers, developed a totally biodegradable ASD occluder. In this study, the performance of the proposed closure devices will be evaluated, at the same time,by using the matched catheter delivery systems to close ASD in canine model, we can evaluate the feasibility of its clinical application, safety, and biocompatibility. The study was divided into two sections and briefed as follows:Section 1 Designs and manufactures of a totally bioresorbable Atrial septal defect occluder and its evaluationObjective:To evaluate the feasibility of a ASD occluder made of bioabsorbable materials.Methods:A totally bioresorbable ASD occluder consists of a framework filled with two pieces of Poly-L-lactic acid (PLA) fabrics. The framework was woven from polydioxanone (PDO) monofilament and thermoformed into two flat disks with a connecting waist. Mechanical property of the occluder was measured in vitro. For the purpose of degradation in vitro, occluder samples were immersed in phosphate-buffered saline (PBS) (pH 7.4) at 37℃for 12 weeks. The effect of degradation on the mechanical properties, occluder quality loss and morphology of these samples was examined. Occluder disk samples were implanted in SD rats to test histocompatibility. In order to evaluate the feasibility of transcatheter closure, dog isolated heart specimens were used for experiment in vitro by using the matched delivery system.Results:(1).The mechanical properties of the totally bioresorbable ASD occluder:①Compression/elastic recovery performance:the ASD occluder can be smoothly retrieved by 12F and 14F load sheaths.The left disk at least can be compressed to its original size of 26.67%.15 minutes after retention in a 12F delivery sheath in 37℃water, the left and right disc respectively restored to more than 90% of their original diameters immediately after dilivery.②The circular loop in the occluder right disc can withstand the maximum tension averaged 47.5±4.37N.③The left disc support strength:at 37℃environment, support strength of the left disc was 11.68±1.32N,greater than a nickel-titanium ASD occluder of the same specification (P<0.05). (2).Degradation experiment in vitro:①Morphological changes:during the occluders immersed in 37℃PBS buffer, the structure and shape remain unchanged at the 12th week, the color of PDO gradually fades.②Support strength of the left disc changes:1 week after in vitro degradation the support strength did not change significantly,2 weeks later, supporte force, when compared with the initial, increased respectively to 108.9% of the initial support strength, while 6 weeks later, support force decreased significantly (down to 82.3%).③Occluder quality change:lost quality in the first 4 weeks was less than 1%, after 6 to 8 weeks the quality declined significantly. (3). SD rats implantation test in vivo:1-2 weeks after the occluder discs implanted in SD rats, histological examination showed a large amount of fibroblasts and inflammatory cells infiltrated around the PDO and PLA wires. Inflammatory cells were significantly reduced after 4 weeks.Abundant collagen fibers could be found after 6 to 8 weeks. PDO and PLA filament degradation was found at the 12th week. There was neither necrosis nor other rejection reaction after the occluder discs were implanted. (4).In vitro closed experiment:the ASD occluder can be smoothly conveyed by 12F sheath. Occluder restored Immediately a double disk structure and its Waist lied in the atrial septum, Discs fited closely with the atrial septal,did not affect the coronary sinus blood flow and valves opened and closed well.Conclusion:The totally bioresorbable ASD occluder has good mechanical properties,biodegradable properties and excellent biocompatibility,can keep for at least 6 weeks of effective support force,so it can be safely used in animal experiment research.Objective:To evaluate the feasibility, safety, efficacy and biocompatibility of transcatheter closure of ASD with a totally bioresorbable ASD occluder and its delivery system in a canine model.Methods:Under the guidance of fluoroscopy, ASD models were established by transseptal atrial septal puncture via right femoral vein with Brokenbrough needle in healthy anesthesia dogs. The totally bioresorbable ASD occluders were placed by the corresponding delivery cable, while the instantly success rate and complication rate were observed. The location of devices, coronary sinus blood flow and valves were determined by immediately angiography and echocardiography.ECG, echocardiography, and X-ray fluoroscopy was performed at different time points during postoperative follow-up. Dogs were sacrificed in 2,8,12,24 month respectively after device implantation, while tissue samples were obtained for histopathology examination and scanning electron microscopy observation.Results:①In 18 of 20 dogs, ASD models were established successfully. One dog died from pericardial tamponade during the procedure. Another dog was sacrificed because of puncturing into the left ventricle erroneously②The totally bioresorbable ASD occluders were placed by self-made delivery cable in 16 of total 18 dogs.One dog was sacrificed because of persistence third degree A-V block,aother failed case due to gas embolism.No serious procedure related complications were observed in the remaining 16 dogs. Echocardiography after occluder released showed that 15/16 cases (93.75%) had no residual shunt, and 1/16 cases (6.25%) a small residual shunt.③Follow-up:All dogs in good condition. ECG was no conduction block and arrhythmias. Occluders were still clearly visible by transthoracic echocardiography after 4 weeks,there was no significant mitral and tricuspid valves regurgitation. All the particles of tantalum markers were nondisplaced in X ray follow-up.④Gross examinations showed occluders were in stable condition in the atrial septum, the PDO wires of bilateral discs were clearly visible 2 weeks after occluder implantation, and the surface was covered by a thin layer of transparent film wihtout thrombus and vegetation.4 weeks and 8 weeks late, a complete coverage of translucent membrane was found on the discs, the discs were covered by a white membrane at the 12th weeks.24 weeks later, the PDO wires of discs could no longer be identified with a white porcelain dense membrane covered,and the PDO wires of occluder were replaced by the uniform connective tissue. The devices were thoroughly covered by endothelial cells. The various follow-up time points the lungs, liver, spleen, kidney specimens of gross anatomy revealed no abnormalities.⑤Histology (HE staining) examination showed that after 8 weeks we can see a clear fibrous connective tissue hyperplasia. after 12 weeks the inflammatory response has basically subsided, bilateral disk has been continuously covered by flat cells, CD34 immunohistochemical staining confirmed to be endothelial cells.Most of the PDO wires of the disc had degraded at the 24th week with replaced by the fibrous connective tissue. No pathologic changes were found in liver, kidney, lung and spleen.⑥Scanning electron microscope:After 8 weeks occluder appears to be basically endothelialization with covered by "imbricated" endothelial cells.12 weeks, endothelial cells were more compact, occluder appeared as "wavy" surface.Conclusion:Canine ASD model can be prepared by transcatheter atrial sepal puncture, and a totally bioresorbable ASD occluder can be transcatheter placed with high success rate and low procedure related complication. Excellent biocompatibility and efficacy of the occluder indicates that it could be safely used in future clinical trial.