The Feasibility Studies Of New Types Of Cobalt Alloy Biodegradable Polymer Coating Sirolimus-eluting Stents And Magnesium Alloy Biodegradable Polymer Coating Sirolimus-eluting Stent

The Feasibility Studies of New Types of Cobalt Alloy Biodegradable Polymer Coating Sirolimus-eluting Stents And Magnesium Alloy Biodegradable Polymer Coating Sirolimus-eluting StentBackgroundThe treatment of coronary artery disease has been revolutionized by drug-eluting stents(DES).Unlike the Bare metal stents(BMS),DES containing sirolimus or paclitaxel reduce the rate of restenosis to less than 10%due to their antiproliferative effect on the vascular neointima in the coronary artery.But Permanent polymers used in first generation of DES may trigger chronic inflammation and hypersensitivity reactions,which may contribute to the increased risk of late thrombosis and rebound restenosis.Some of new generation DES use bioabsorbable or biodegradable polymer coating on the metallic stent struts to minimize these risks,such as the Excel stent,BioMATRIX^TM stent and the Nobori^TM stent.Moreover,totally biodegradable stents including magnesium alloy stent,which will be completely absorbed in the arterial wall after doing their jobs to prevent recoil and elute drugs,are being developed to avoid the long-term stimulation to the vessel wall caused by the durable stent struts. ObjectivesIn order to research and develop new types of biodegradable polymer coating DES in China,the safety and efficacy of polylactic acid-co-polyglycolic acid(PLGA) coating SES and poly-L-lactic acid (PLLA) coating SES on inhibiting the neointimal proliferation in miniswine coronary model were investigated,and compared with that of durable polymer coating SES.The feasibility of a magnesium biodegradable polymer coating SES was also studied.MethodsTo evaluate a biodegradable PLGA coating SES,4 types of stents were implanted in minipig coronary arteries using coronary angiography to optimize stent apposition:316L stainless steel bare metal stents(316L); L605 cobalt chromium bare metal stents(L605);PLGA polymer coated L605 stents(PLGA);and L605 stents coated with PLGA containing sirolimus(PLGA SES).The dose density of sirolimus was 120μg/cm². The stents were manufactured by TianJian Medical(Suzhou) Co.,Ltd. Vitro studies demonstrated that the drug was completely eluted in 70 days and polymer degradation was completed in 80-90 days.Animals underwent angiographic restudy and were then sacrificed at 4 weeks,12 weeks and 26 weeks,respectively,for histopathologic and histomorphometric examinations including neointimal thickness over the struts,neointimal thickness between the struts,neointimal area and percentage area stenosis.The endothelialization was assessed by scanning electron microscope(SEM).The correlation between inflammation and neointimal area was also analyzed.To evaluate a biodegradable PLLA coating SES,4 types of stents were implanted in minipig coronary arteries:316L stainless steel bare metal stents(316L);L605 cobalt chromium bare metal stents(L605(2)); PLLA polymer coated L605 stents(PLLA);and L605 stents coated with PLLA containing sirolimus(PLLA SES).The dose density of sirolimus was 140±20μg/cm².The stents were manufactured by WanRuiFeiHong Medical(Beijing) Co.,Ltd.Vitro studies demonstrated that the drug was completely eluted and polymer was completely degradated in 60 days. Animals were sacrificed following angiographic restudy at 4 weeks for histopathologic and histomorphometric examinations.The endothelialization was assessed by SEM.The 2 biodegradable polymer coating SESs were also compared with Firebird(MicroPort Medical(Shanghai) Co.,Ltd.),which was a durable EVAC coating SES.For the preliminary observation of a biodegradable magnesium alloy PLA coating SES,2 AZ31B magnesium alloy stents,2 magnesium alloy stents coated with PLA and 2 magnesium PLA coating SESs were implanted in minipig coronary arteries.The stents were offered by Metal Institute,Chinese Academy of Sciences.And histopathologic examination was conducted at 4 weeks after implantation.ResultsAt 4 weeks after implantation,SEM observation found that the luminal surface is about 75%to 100%endothelialised in PLGA SES group.As compared with 316L,L605 and PLGA groups,PLGA SES had significantly lower neointimal thickness over the struts(0.06mm vs. 0.32mm,0.30mm and 0.21mm,respectively,P＜0.05),neointimal thickness between the struts(0.06mm vs.0.24mm,0.28mm and 0.29mm, respectively,P＜0.05),neointimal area(0.59mm² vs.2.04 mm²,1.91 mm² and 1.54 mm²,respectively,P＜0.05) and percentage area stenosis (13.85%vs.42.41%,45.63%and 33.79%,respectively,P＜0.05), while there were no statistical differences among the 3 controls.No in-stent stenosis was found in PLGA SES group.Bivariate correlations analysis showed there was statistically positive correlation between inflammatory area and neointimal area(p＜0.001,correlation coefficient=0.719).When stent type,mean injury score and EEL area were controlled,partial correlations analysis showed there was still statistically positive correlation between inflammatory area and neointimal area(p=0.01,correlation coefficient=0.498).In the segments of PLGA SES implantation,no inflammatory reaction was noted,and no abnormal changes in histopathologic examinations of cardiac muscle, liver,spleen,lung and kidney tissues and in blood sample tests were observed in PLGA SES group.At 12 weeks after PLGA SES implantation,the luminal surface is fully endothelialised.As compared with the results of 4 weeks,neointimal thickness between the struts was significantly increased(0.10mm vs. 0.06mm,P=0.036),while there were no significant differences statistically between neointimal thickness over the struts(0.15mm vs. 0.06mm,P=0.304),neointimal area(0.91mm² vs.0.64mm²,P=0.054) and percentage area stenosis(30.01%vs.13.85%,P=0.076),respectively.At 26 weeks after PLGA SES implantation,the luminal surface is fully endothelialised and the neointimal proliferation was similar to the result of 4 weeks in 2 vessels without inflammation,while in-stent stenosis was found in the other 2 vessels with obvious inflammation.At 4 weeks after implantation,SEM observation found that the luminal surface is about 50%to 80%endothelialised in PLLA SES group. As compared with 316L group,PLLA SES had 76%reduction of neointimal thickness over the struts(0.10mm vs.0.41mm,P=0.004),72% reduction of neointimal thickness between the struts(0.08mm vs.0.29mm, P=0.002),62%reduction of neointimal area(0.79mm² vs.2.09mm², P=0.001)and significant reduction of percentage area stenosis(21.22%vs. 47.27%,P=0.008),respectively.There were no significant differences statistically between PLLA SES and L605(2),and no in-stent stenosis was found in both groups.In the segments of stents implantation,no inflammatory reaction was noted in L605(2) and PLLA SES groups, while moderate inflammatory reaction was observed in 2 arteries in PLLA group.No abnormal changes in histopathologic examinations of cardiac muscle,liver,spleen,lung and kidney tissues and in blood sample tests were found in the PLLA SES group.At 4 weeks after implantation,as compared with Firebird stent, PLGA SES had a tendency to have lower neointimal thickness over the struts(0.06mm vs.0.12mm,P=0.146),neointimal thickness between the struts(0.06mm vs.0.16mm,P=0.075) and percentage area stenosis (13.85%vs.22.81%,P=0.274),however,there were no significant differences statistically.The neointimal area was significantly reduced in PLGA SES than in Firebird stent group(0.64mm2 vs.1.38mm2,P= 0.011) There were no significant differences between PLLA SES and Firebird stent in neointimal thickness over the struts(0.10mm vs.0.12mm, P=0.234),neointimal thickness between the struts(0.08mm vs.0.16mm, P=0.115),neointimal area(0.79mm² vs.1.38mm²,P=0.052) and percentage area stenosis(21.22%vs.22.81%,P=0.756).No in-stent stenosis was found in any group and neointimal healing was similar in the 3 SES groups.Inflammatory response in the PLGA SES and PLLA SES groups were significantly reduced,as compared with Firebird group. In the preliminary study on the biodegradable magnesium alloy PLA coating SES,stent disintegration was observed even at 1 week after implantation.At 4 weeks,only stent debris remained in the arterial wall in some samples,and complete degradation was found in 2 stents.Serious inflammatory response and in-stent stenosis were observed in both PLA and SES groups.ConclusionsIn the present study,we found that:1.The biodegradable PLGA coating SES had good biocompatibility and could significantly inhibit the neointimal proliferation 4 and 12 weeks after stent implantation in porcine coronary artery model.At 4 weeks,the luminal surface is 75%to 100%endothelialised in most vessels,and endothelialization was completed at 12 weeks.2.Our study was the first pathologic observation in China to find that there was statistically positive correlation between inflammatory area and neointimal area.Inflammation might promote neointimal proliferation after coronary stent implantation.3.The biodegradable PLLA coating SES had good biocompatibility and could significantly inhibit the neointimal proliferation 4 weeks after stent implantation in porcine coronary artery model.At 4 weeks,the luminal surface is 50%to 80%endothelialised. 4.We conducted the first study in China to compare the inflammatory reaction and the inhibition of neointimal proliferation between biodegradable polymer coating SES and permanent polymer coating SES in animal model.The results showed that the efficacy on inhibiting neointimal hyperplasia of PLGA coating SES and PLLA coating SES was at least similar to that of Firebird stent,and inflammatory reaction in arterial wall was significantly reduced in the 2 biodegradable polymer coating SES groups.5.We conducted the first study to explore the feasibility of magnesium alloy drug-eluting stent,and found that the biodegradable magnesium PLA coating SES in this study couldn't satisfy the clinical need yet due to its fast degradation,poor mechanical strength and inacceptable biocompatibility.Further studies to improve its mechanical and chemical features are needed.