Influence And Mechanism Of Bioabsorbable PLLA Stent On Intimal Repair And Vascular Remodeling

Percutaneous coronary intervention is a major therapy for cardiovascular disease.Bioresorbable scaffold could provide temporary support for blood vessels,availably prevent acute vascular shut-off after stent implantation and reduce the incidence of restenosis.The stent is gradually degraded and absorbed by the vascular tissue after stent implantation,and local mechanical stimulation disappears correspondingly.This complex process may cause vascular response differed from traditional metal drug-eluting stents,affect the phenotype and function of vascular cells.The evaluation of the bioresorbable scaffold should be different from drug-eluting stents,too.At present,few studies have put forward new evaluation indexes combined with the characteristics of bioresorbable scaffold itself and focused on in vivo degradation process of stent implantation and its effects on phenotypic transformation,extracellular matrix changes.These matters are also the key points for bioresorbable scaffold to effectively solve the problems of stent restenosis,thrombosis,and local inflammation in clinical applications.Therefore,this research focused on the vascular repair process after Poly-L-lactic acid?PLLA?stent implantation and to explore its mechanism,which to provide a new referential evaluation for the clinical study of BRS.We used the abdominal aorta of SD rats as an animal model and analyzed the endothelial function mainly for the recovery of endothelial function,the vascular reconstruction after PLLA stents implantation and the stents'degradation characteristics combined with the phenotypic changes of vascular cells during degradation,and explored the influence of lactic acid,one of the degradation product of PLLA stents,on the osteogenic phenotype transformation of smooth muscle cells.The main work includes the following sections:?1?Re-endothelialization and endothelial function recovery after PLLA stent implantation.4 weeks after the implantation of PLLA stent into the abdominal aorta of SD rats,the re-endothelialization was essentially complete,and stable expression of CD31 in lumen cells occurred,the neointima obtained had better endothelial barrier function.In the early stage after PLLA stent implantation,the endothelial CD31^hiEMCN^hi subtype occurred with the process of intimal hyperplasia,and then gradually weakened with the vascular repair.The inflammatory reaction which blood vessels experienced raised first and then decreased.In conclusion,neointimal repair after PLLA stent implantation was a changing process,and the neointima with well repair and better barrier function had been obtained.?2?Time-dependent intimal hyperplasia and vascular reconstruction after PLLA endovascular stent implantation.The lumen diameter decreased first and then increased.The degree of intimal hyperplasia increased at first and then decreased,accompanied by the changes of cellular phenotypes in the neointima after PLLA stent implantation.Similarly,collagen fibers increased first and then decreased,while elastic fibers decreased first and then increased,the two showed a turning point of change at 24weeks,the vessel underwent a positive reconstruction process at this time point,the vessel was closer to the normal blood vessel after 48 weeks.In conclusion,the degree of neointimal hyperplasia increased and then decreased after PLLA stent implantation,the vascular remodeling began at 24 weeks and gradually tended to return to normal physiological function after 48 weeks.?3?Degradation of PLLA endovascular stents in vivo and associated changes of vascular cell phenotypes.At 24 weeks,the significant degradation appeared,the outline of the scaffold filament became smaller,and the degradation fragments appeared near the vascular site at the same time.The expression changes of mechanical response factor MGF and BMP2 accompanied by the degradation of scaffolds increased first and then decreased.The phenotypes of neointimal cells changed,the expression of RUNX2increased and expressed mainly in the nucleus,and then the expression reduced with the increase of time.In conclusion,significant degradation of PLLA scaffold began at 24weeks after implantation,and vascular cells underwent a process from normal to osteogenic transformation and then decreased in the degree of transformation.?4?Lactic acid,a degradation product of PLLA,could promote osteogenic phenotype transformation of vascular smooth muscle cells.Lactic acid could stimulate the response of cells to the mechanical environment and increase the expression of the mechanical response factor MGF and the response to substrate stiffness.Lactic acid could promote the cell transformation from smooth muscle phenotype to osteogenic phenotype,and infiltrate into the adventitia to promote the expression and distribution of RUNX2 in the media near the intima and the adventitia.Lactic acid could enter into the cell through monocarboxylic acid transporter 1,increase intracellular lactate dehydrogenase B and promoted the increase of lysosome number.While in the presence of vascular injury,the vessel first responds to the injury.It was worth noting that the vascular reaction after stent implantation was complex,and lactic acid did not necessarily possess the main position.In conclusion,lactic acid could promote the osteogenic phenotype transformation of vascular smooth muscle cells and increases the potential risk of calcification.In conclusion,vascular repair and reconstruction after PLLA stent implantation matched the degradation progress of the stent,1 week after PLLA stent implantation,inflammation was the main reaction of vessels,the intimal hyperplasia was severe in 4weeks,and the re-endothelialization was complete at 12 weeks.In this process,neointima with good endothelialization and better barrier function was obtained.After PLLA stent implantation,the degree of vascular hyperplasia first increased and then decreased.PLLA stent degraded significantly at 24 weeks,and began to reconstruct positively,the vessels showed positive repair at 48 weeks,the phenotypic transformation of vascular cells occurred during the entire repair process.Lactic acid,a PLLA degradation product,could stimulate osteogenic phenotypic transformation and poses a risk of vascular calcification in the very late stage after stent implantation.Our study evaluated the process of intimal repair and vascular reconstruction after PLLA stent implantation in detail via the animal model,provided more reference indexes for the clinical evaluation and theoretical basis for the design of drug coating of bioresorbable scaffold.