Research Of The Degradation Of Biodegradable Magnesium Alloy Stent-MPM Implanted In The Abdominal Aorta Of Experimental Rabbits

BackgroudIn the past several decades,with the acceleration of aging process, the number of cases of patients with obstructive vascular disease increased year by year,which had a serious threat to people’s standard of living, health, and even life.The endovascular treatment by stents has the epochmaking significance and has solved many clinical problems. But with the enlargement of the indications of endovascular treatment by stents, possible complications caused by the nondegradable intervention equipment are focus on by more and more medical staff. According to the data analysis, the pro-bability of restenosis is up to 15%～50% after stent implantation in patients needing PCI intervention again. Several main kinds of stents:1,permanent vascular stents, which were made of cobalt chromium alloy, stainless steel, nickel titanium alloy and so on.This kind of bracket is representative.After implanted in the body and perman-ent remained in the body,they stimulate the peripheral tissue in different degrees, wh-ich leads to different levels of inflammation, vascular intimal hyperplasia and resteno-sis.Related experiments show that the 6-12 months of stent restenosis rate was 15%-20%.2:Drug-eluting stents(DES), as the name suggests, which surface were coated with drugs.At present most of the stent surface coating is antiproliferative drugs, such as taxol, etc.Application of this kind of stent significantly reduced the restenosis after carotid stenting.But recent research reports DES may delay vascular endothelium etc,which may lead to increased risk of late stent thrombosis.Compared with permanent stents and DES, biodegradable endovascular stents can overcome their shortcomings.Because of this, the study about their gradually become hotspot.Biodegradable stent materials are mostly high polymer material. At present, there are the following classification:natural biodegradable polymer materials,microbial synthesisof polymeric materials,biodegradable macromolecule polymer material and biodegradable metal material. Most of the natural biodegradable polymer material are sugar.The kind of stent composed of this material has good biological compa-tibility,but poor mechanical property.At present,there are little research on microbial synthesis of polymeric stents but a lot of research on biodegradable macromolecule polymer stents and biodegradable metal stents.But most of the strength of the polymer is low,about a quarter of the metal,and the low plasticity which leads to the rebound rate> 20%(the rebound rate of metal<5%).So the biodegradable metal stenthave the characteristics of small volume and strong mechanical property as the metal.what’s more,the metal material could be corroded in the body and be rapidly decomposed in a few months,which can effectively prevent stent restenosis brought bypermanent stents.Because of good properties of magnesium alloy stent,research and development of biodegradable magnesium alloy stent gradually become hotspot.The people of the world is concerned with biodegradable medical magnesium alloy known as "revolutionary" metal biomaterialls.Heublein etc firstly researched with magnesium AE21 (2% aluminum and 2% of rare earth elements) as absorbable metal stent materials.They implanted magnesium alloy stent into the pig.Although there are significant vascular intimal hyperplasia at first,the blood vessels are remodeling after 1-2 months and the quality of the stent has a 50%loss and the blood vessels has fewer thrombosis and mild inflammationJn clinical practice,Bosiers etc whocooperated with multiple centers researched by collecting 117 patients with 149 lower limb vascular occlusion from the Netherlands, Australia and Germany.They were randomly divided into 2 groups.60 patients were treated with using biodegradable magnesium alloy stent.other 57 patients were treated with angioplasty.the vascular stenosis rate of absorbable magnesium alloy stents group (31.8%) is significantly lower than the angioplasty group(58.0%),p=0.013. Erbel etc reported the world’s first prospective, randomized, multicenter clinical trial (PROG-RESS-AMS) about application of biodegradable magnesium alloy stents in coronary artery at the American college of cardiology annual meeting.The results showed that a good mechanical properties of biodegradable magnesium alloy stents and no myocardial infarction, subacute or late thrombosis and death caused by heart disease.In addition,they also found stents degradation products did not cause embolization, and its application is safe and feasible in the human body.To sum up, the strength and biocompatibility of biodegradable magnesium alloy stents in basic research and clinical practice has been confirmed that the advantage compared with permanent stents.Although the advantages of biodegradable magnesi-um alloy stents is significant, there are still the following problems:first,Lack of sten-t’seffective action time,second,metal materials of stents are not completely non-toxi c,third,stent’s low plasticity andbrittleness. Therefore, it needs more basic and clinical researches to further explore.Aiming at the shortcomings of biodegradable magnesium alloy stent, we and the research and development department of Shanghai minimally invasive medical equip-ment co., LTDdeveloped a new kind of biodegradeable magnesium alloy metal stents-MPM.In vitro test,the various parameters of MPM stents were superior to the existing some biodegra-dable magnesium alloy stents.ObjectiveOn the basis of literature about the biodegradeable metal stent at home and abroad,we observe the degradation properties of biodegradable magnesium alloy stent-MPM including the degradation time, characteristiccs of vascular intimal hyperplasia and the change of the serum magnesium ions concentration after the stent was implanted into rabbit abdomenal aorta.Materials and methods1. object of study24 biodegradable magnesium alloy stents-MPM.2. MethodsDifferent gender,healthy twenty-four New Zealand white rabbits whom weight were 2.2±0.2 Kg were divided into four groups(Marked as 1,2,3,4 groupsrespecti-vely) randomly and equally in our experiment.We get the rabbit taking aspirin (10m-g/kg) and clopidogrel(10mg/kg). After disinfected local skin of rabbit ears,We extrac-ted the venous blood to detect serum magnesium ion concentration.After fixed the anesthetic rabbits, we separated the right femoral artery under direct vision.After retrograde punctured the right femoral artery with the improved Seldinger technology/we implanted and fixed the vascular sheath(4F).Under DSA imaging, we observe aorta and bilateral renal artery. We implanted the stent MPM (balloonexpandable stent,the size of 3x23mm, the stent which was carved with laser was reticular and its surface was processed with polishing and chemical protection)into the abdominal artery one centimeter below the left renal artery.Under DSA,after found no abnormalities,we pulled out the vascular sheath and ligated the femoral artery and sutured incision. We continued to give the rabbit taking aspirin and clopidogrel as same as before for 28 days after the surgery.After 28 days,we get the rabbit taking aspirin(5mg/kg) until dissecting the rabbit.We extracted the venous blood of all rabbits in the 30d,60d,90d,180d after the operation,respectively.We disinfected and anesthetized and fixed and separated left the femoral artery the corresponding each group of rabbits at that time. We retrograde punctured the left femoral artery with the improved Seldinger technology and fixed the vascular sheath(4F).After assessed of vascular conditions,we made the rabbit death.We removed the vessel segment with stents.The Specimen was fixed,dehydrated and embedded.The near,middle and far 5um segment of each blood vessel with stent were underwent HE staining and immunehistochemistry.We observed with microscope and recorded the number of empty hole after stent degradation.We observed the neointimal hyperplasia, vascular lumen and PCNA positive cells.We detected serum magnesium ion concentration of all rabbit’s Venous blood.3. Statistical methodAll the data were expressed as mean plus or minus standard deviation.We esti- mated the degradation time of stent by analyzing the data with the linear regression of SPSS20.0.Compared the differences in the neointimal hyperplasia area,the residual lumen area and the average optical density value of immunohistochemical PCNA positive cells among groups by the ONE-WAY ANOVA,we get the characteristics of the vascular intima. Analyzed various stages of the serum magnesium ion concentration with ONE-WAY ANOVA and repteated measurement data analysis of variance,we get the characteristics of the serum magnesium ions in the process of stent degradation.4. ResultsAll four groups of experimental animals survived.Four groups of preoperative and postoperative serum magnesium concentrations had no significant statistical dif-ferences.The DSA imaging showed unblocked abdominal aorta and no obvious sten-osis during the follow-up period.Pathological results showed endovascular stent’s the area of degradation was gradually increased.The number of faulted struts of stent was gradually increased.The support of stent was gradually diminished.It was not until t-he fourth group(the 180th day) that stent was degraded completely.What’s more,stent was completely absorbed,with a small amount of residual fragments of the stent. l,2,3,4groups of neointimal hyperplasia area respectively were 0.96±0.54 mm2、 0.80±0.42 mm2,1.52±0.54 mm2.1,2,,3,4groups of residual luminal area were 2.32±0.52 mm2,2.12±0.48 mm2,1.58±0.42 mm2,2.06±0.45 mm2, respectively.After the stent was implanted,we observed the waveform changes of intimal hyperplasia and lumen residual area gradually increased vascular intim and gradually reduced r-esidual lumen area. On the 90th day (the third group),neointimal hyperplasia was most significant,with the smallest residual luminal area.Comparing the group and other groups respectively, there were significant statistical differences(Compared with other groups, P> 0.05).Similarly, the average optical density value of immunohist-ochemical PCNA positive cells was gradually increased and reached the maximum in the ninetieth day. Comparing the group and other groups respectively, there were significant statistical differences(Compared with other groups, P> 0.05).The indicators further confirmed neointimal hyperplasia gradually and gradually narrow the lumen after stent was implanted. On the ninetieth day, the index reached maximu-m.After that,the blood vessels gradually appeared positive remodeling.hyperplasia of endometrium area was smaller.In addition,the residual lumen area also increased gradually. Four groups of preoperative and postoperative serum magnesium ions concentration had no obvious statistical differences by the statistical analysis.ConclusionsOn 182th day,the support of biodegradable magnesium alloy stent was disappeared. Neointimal hyperplasia was most significant on the 90th day.At the same time,lumen stenosis was the most obvious. After this time,the blood vessels appeared a positive remodeling. According to the characteristic of vascular intimal changes,this kind of stent could prevent the late vascular restenosis.In the process of magnesium alloy stents degradation, serum magnesium ions concentration had no obvious difference compared with the preoperative,which did not have obvious toxic effects on rabbits.