Degradation And Biocompatibility Of Biodegradable Poly-L-lactic Acid Atrial Septal Defect Occluder

Atrial septal defect(ASD)is a common noncyanotic congenital heart disease,and there are about 240,000-400,000 ASD patients in China,causing a serious social and economic burden.Percutaneous transcatheter closure has gradually replaced surgery as the preferred treatment for ASD patients with appropriate anatomical conditions due to its advantages of less trauma and rapid recovery.At present,the occluder uses metal materials that must be permanently retained in the body,and there is a certain degree of metal material-related complication rate,so the development of biodegradable ASD occluder has become the focus of cardiovascular research.Objective:In this study,biodegradable poly-L-lactic acid(PLLA)monofilament was used to product double-disc occlusion umbrella,and PLLA non-woven fabrics flow blocking membrane was used to independently develop a new biodegradable ASD occluder.The feasibility and safety of PLLA monofilament and non-woven fabrics material in the development of degradable ASD occluder were evaluated from the perspective of clinical medicine and materials interdisciplinary discipline.Methods:1.Material characterization of occluder:The interfacial properties of PLLA were observed by scanning electron microscope,and the microstructure,molecular weight,thermal properties,mechanical properties and hydrophilic/hydrophobic properties of PLLA were observed by Gel permeation chromatography,Differential scanning calorimetry,X-ray diffraction analysis,Mechanical properties test and Contact angle measurement.2.In vitro degradation study of occluder materials:To observe whether the changes of microstructure,pH value,weight loss rate,water absorption rate,molecular weight loss,thermal properties,mechanical properties and contact angle of PLLA materials in in vitro degradation are suitable for the development of atrial septal defect occluder.3.Biocompatibility evaluation of occluder materials:Cultured porcine atrial septal primary fibroblasts were used to evaluate the cytocompatibility of PLLA materials by Cytotoxicity test,Wound Healing and Apoptosis detection,the hemocompatibility of materials was evaluated by Hemolysis rate test,Prothrombin time,Activated partial thromboplastin time,and Dynamic coagulation time.Materials were implanted into rabbit muscle and blood vessels,and the porcine ASD model was established and occluders were implanted to observe the histocompatibility of the materials,and the systemic toxicity test was performed by oral perfusion and intravenous injection of material extracts in mice.Results:1.Material characterization of occluder:Scanning electron microscope magnified to 20 μm observation,the material is smooth and uniform,with blood compatibility and degradation consistency.The average molecular weight(Mn)of monofilaments was 98 kDa,elastic modulus was 7.153±0.621 Gpa,fracture strength was 286.72 ±26.11 Mpa,and elongation at break was 33.92± 4.79%,which met the requirements for plugging disc application.The glass transition temperature was 65.2 ℃,Melting point(Tm)was 159.6 ℃,and Endothermic enthalpy of fusion(ΔHm)was 51.4 J/g,which maintained reliable thermal properties at body temperature changes.The diffraction peak was 16.3°,the crystallinity χc was 55.27%,the crystalline phase intensity was high,and the shape memory ability was good.Non-woven fabrics has a static contact angle of 112.80 ± 6.12°,is hydrophobic,its porous structure has a"Wicking effect ",and the liquid can rapidly penetrate into the pores.2.In vitro degradation study of occluder materials:In vitro degradation experiments showed that within 180 days of observation,the surface of the materials was smooth and homogeneous,and the release of hydrogen ions during degradation did not cause a significant decrease in pH(decrease<0.13),monofilament Mn decreased to 61 kDa(degradation rate of 192.74 Da/d),the weight loss rate slightly increased(<2%),ΔHm increased to 57.31±0.73 J/g,and the fracture strength decreased to 193.86±13.70 Mpa.Within 120 days,Tm first increased to 162.46 ± 1.37 ℃,decreased to 154.77 ± 1.39 ℃ at 180 days,and the elongation at break increased to 51.63 ± 2.47%and decreased to 22.48 ± 2.00%at 180 days,elastic modulus remained essentially unchanged after a slow rise and decreased to 6.73 GPa at 180 days.The contact angle of the non-woven fabric gradually decreased to 99.87±1.74 ° in the first 90 days and then gradually slowed down(P>0.05).3.Biocompatibility evaluation of plugging device materials:The results of material biocompatibility test showed no cytotoxicity,no triggering apoptotic mechanism,and no effect on cell migration and repair compared with the negative control group(P>0.05).The material hemolysis rate ranged from 2.62 ± 0.071%to 2.58 ± 0.063%,which is lower than the medical requirement of 5%hemolysis rate.Compared with the clinical application of mature nitinol materials,there was no significant effect on the coagulation system(PT32.70±2.22 vs.33.65±0.98,APTT 13.16±0.92 vs.13.58±0.52,P>0.05).Degradation products during in vivo degradation did not cause severe chronic inflammatory reactions in tissues,no thrombosis and maj or organ damage were found,the endothelialization process on the occluder surface met the requirements of clinical application,and there was no acute systemic toxicity.Conclusions:The physical and chemical properties of PLLA monofilament and non-woven fabrics materials meet the requirements for the use of ASD occluder.Within 180d observed in vitro degradation,the interface characteristics,thermal properties and mechanical properties of the material surface are stable,the degradation rate meets the clinical requirements,and the materials have good biosafety.PLLA monofilament and non-woven fabrics have the feasibility and safety of biodegradable ASD occluder development.