The Development Of Bioabsorable Atria Septal Defect Occluder Ⅱ

Atrial septal defect(ASD)is the most common congenital heart disease(CHD)secondary to ventricle septal defect and accounts for about 30%of the congenital heart disease.With the development of interventions and cardiac catheterization,the interventional treatment has become the preferred option for ASD patients.Currently,the nickel-titanium-alloy occluder is one of most widely used in clinical treatment.Although the nickel-titanium-alloy has been demonstrated to be safe and effective by a large mount of data now,it is not still perfect.During long term follow-up after the nickel-titanium-alloy occluder implantation,there are many complications involved with it,such as erosion or perforation of the device.delayed endothelialization,thrombus formation,severe valvular damage,hemolytic phenomena,nickel allergy,and even aortic-atrial fistula.Additional,These long-lasting existing devices will potentially obstruct access for future transseptal procedures such as ablation to left atrial tachycardia,mitral valve balloon dilation and so on.As a result,how to avoid these complications has become a research hot spot recently.As of now,the percutaneous devices for septal defect treatment are made of nondegradable metallic and synthetic fabric materials.These devices are not ideal due to risks of future complications.Ideally,occluder material should be completely absorbed by the body as a bridge to achieve the purpose of self-healing defect.The temporary bridge will induce self-tissue ingrowing to cover the device and all parts of the defect.After that,the device will be absorbed and leave the self-tissue alone.In order that,nothing except of selfgrowing tissue can reduce the complications resulted by metal devices and does not obstruct access during future transeptal procedures.There are many abroad bioabsorbable ASD devices have been devised such as BioSTAR,Biodisk occluder,Double-Biodisk occluder,et al.Many animal experiments demonstrated these devices were safe and effective.Especially,The BioStar device was put into use in clinical experiments.However,These biodegradable devices had a common shortcoming.That is those biodegradable devices,a remodeling process of the collagen scaffold and metallic materials frame who can not be degraded,starting after implantion in vivo,resulted in the full replacement of the matrix by host tissue after follow-up.AS a result,the study of the BioStar device has been stoped since 2011.As to domestic noval ASD device study,Dai Ke and Zhu Yufeng respectively developed a biodegradable atrial septal defect occluder made of plydioxanone(PDO)in 2010.Both animal experiments confirmed the effectiveness and biological compatibility of the two devices.Short-and medium-term efficacy was conformed.A remodeling process of complete endothelialization at 8-12 weeks,resulted in the full replacement by host tissue after 24 weeks of follow-up.Due to the reason of the low elastic modulus and low tensile strength and limited shape memory function in PDO,it will cost too long in operating time so that causing deformation of the occluder.As a result,Making a bigger sized occluder may be restricted.Guangdong province cardiovascular institute and ShenZhen lifetech technology company set birth to make our biodegradable ASD devices with PLLA since 2014.PLLA is the majority form of poly-lactic acid(PLA),which offers unique features of biodegradability and biocompatibility.PLA is a biopolymer extracted from corn starch.whose final degradation products are carbon dioxide and water.It can be discharged completely when implanted in the body with circulation.It degrades for about two years in vivo.PLA fiber has no toxicity,especially good biocompatibility and biodegradable absorption function.According to the PLA conformation,It is divided into left and right.Poly-L-lactic acid(PLLA)is a semi crystalline polymer,whose fiber has high tensile strength,good flexibility,heat resistance and good thermal stability.Because of its favorable characteristics,PLA has been utilized as ecological material as well as surgical implant material and drug delivery systems,and also as porous scaffolds for the growth of neo-tissue.Therefore,we designed and developed a kind of novel double-discs PLLA absorbable ASD device and conducted animal experimental study.The animal experiment demonstrated elementally the safety of the PLLA device.However,we found some flaws such as complicated handling,reducing self-expandable ability severely for the second release in vivo and so on.In order to address the above issues,we make some modification to the device and develop the Ⅱ generation novel bioabsorbable device.Objecive:to develop the Ⅱ generation novel bioabsorbable device.Studying the safety,practicability of the novel device in vitro and animal vivo,which will provide data for next-step clinical tests.Methods:1.The PLLA absorbable atrial septal occluder is developed and its development includes:1>PLLA absorbable occluder physical properties and performance testing;PLLA monofilament tensile test;Fatigue resistance;Stability.2>PLLA absorbable occluder chemical and chemical properties;3>PLLA absorbable occluder biological properties and performance tests:PLLA in vitro cytotoxicity assay;sensitization assay;PLLA degradation product toxicity assay.2.The improvement of PLLA atrial septal defect occluder and delivery system,namely the development of PLLA atrial septal defect occluder Ⅱ generation.Specifically include:1>Receivable ASD occluder wire connection change.2>Absorbable ASD occluder head plus developing point.3>Absorbable ASD occluder lock sleeve structure change.4>The structure of the lock is changed.5>Add loader accessories.6>Change the sewing method:the baffle film is reduced from the original 4mm larger than the occluder disk diameter to 2mm.3.PLLA atrial septal occluder implantation in pigs in vivo experiments:1>establish an animal model:using a puncture needle to break the gap between the pigs,the balloon expansion expands the atrial septal puncture point to establish a pig ASD model;2.percutaneous catheter seal Plug device,place 28 PLLA occluder as observation group,place common metal occluder 17 as control group.4.Follow-up:Regular observation and recording of the general status of the observation group and the control group 1 animals:body temperature,hair gloss,mental status,diet,urine,etc.;2 Transthoracic echocardiography to observe the position of the occluder,with or without residual shunt,with or without Affects the surrounding valve function.3Electrocardiographic examination of whether or not arrhythmia occurred.4 Experimental pigs were sacrificed in 1 week,1 month,3 months,6 months,and 12 months after surgery,and gross anatomy,pathological sections,and electron microscopy scans were performed.Result:PLLA occluder development results:1.PLLA physical properties and performance testing:occluder in the 45℃ environment for fatigue experiments.When the fatigue cycle reached 18.66 million cycles(equivalent to a 6-month fatigue cycle),the occluder structure was complete and no parts were missing.In(37±2)℃ environment(gas or water bath),the occluder is fixed in the model hole 2mm smaller than the nominal value of the waist,and the thruster clamp is clamped tightly.The result meets the requirements.2.PLLA chemical properties and want to be able to test:PLLA occluder chemical performance requirements indicators:(1)reducing substances:test solution compared with the same volume of the same batch of blank control solution,potassium permanganate solution[(KMnO4)=0.002 The difference in mol/L consumption should be less than 2.0 mL.(2)Heavy metals:The total content of heavy metals in the test solution should be less than 1μg/mL,and the content of cadmium should not exceed 0.1μg/mL.(3)pH:The pH of the test solution is compared with that of the same batch of blank control solution.The difference between the pH values should be less than 1.5.(4)UV absorbance:The absorbance of the test solution at 250 nm to 320 nm should not exceed 0.1.(5)Evaporation Residue:In the 50 mL test solution,the total non-volatile content should not exceed 2 mg.There was no abnormality in the PLLA in vitro cytotoxicity test.No tissue damage and tissue hyperplasia were found in the PLLA muscle implantation test.2.PLLA interatrial septal occluder improvement:1>changes in the connection method:from multiple strands of nickeltitanium wire connecting cable and occluder to threading occluder and wire rope.2>PLLA ASD occluder heads increase the development point:from the previous 6 development points to 7 development points.3>Change of lock sleeve structure:increase the number of internal threads of the lock sleeve.4>Structure change of the locking member:The structure of the locking member is changed from a straight rod to a double bent structure.5>Add accessories for the import loader.6>Change of the choking method of the choke membrane:The choking membrane is reduced from the original 4mm diameter of the occluder to 2mm.3.In vivo pig experiment with PLLA atrial septum occluder:45 pigs,45 ASD models were successfully created.28 PLLA ASD plugs were successfully implanted and 17 ASD occluders were successfully implanted.Animals taking aspirin 6 months after implanting occluder had no complications and had long-term survival.At 1 week,1,3,6 and 12 months postoperatively,transcatheter and transthoracic echocardiography showed that the occluder was in a good position and had no effect on the surrounding heart valves.There was no abnormal electrocardiogram;red blood cells,platelets and other indicators were within the normal physiological range.After the occluder implantation,the number of white blood cells increased slightly.After 3 months of implantation,the number of leukocytes peaked.There was no significant difference between the other follow-up points and preoperative comparisons.The number of leukocytes at each follow-up point was lower than that of the control group.Significant differences.In the control and experimental group,the occluder can be wrapped in neonatal tissue 1 month after implantation.With the extension of time,the thickness of the intima gradually increases.At the 6month follow-up point,the intimal thickness can reach about 200-300μm.Wrap well and finish the endothelialization.At 3 months,it was completely endothelialized and neonatal small blood vessels were visible.After 6 months of implantation,there was significant nerve production.In the 6month follow-up of the experimental group,the intimal growth rate and the number of endometrium on the PLLA surface were higher than those in the control group,indicating that the PLLA occluder was more rapid than the traditional metal occluder.After 6 months of follow-up,the PLLA occluder disk was still intact and did not degrade.Heart,liver,spleen,lung and kidney have no obvious lesions.Conclusions:1.The occluder for atrial septal defect occluder of the second generation was excellent in operability,and the occlusion effect and flexibility of the atrial septal defect occluder were good.2.Absorbable at 30 days,3 months and 6 months after implantation.The ASD occluder can be covered by endothelial cells in the heart,with well-wrapped tissue,no obvious thrombosis,and mild inflammatory reactions.All indicators are similar to the control group.Pathological results showed that the occluder surface endothelialization of the atrial septal defect occluder was better than that of the control group 6 months after implantation.The biocompatibility and safety of the atrial septal defect occluder device were not significantly different from those of the control group.