Structural and temporal dynamics analysis on drug-eluting stents: History, research hotspots and emerging trends

Purpose:This review aims to explore the history,research hotspots,and emerging trends of drug-eluting stents(DES)in the last two decades from the perspective of structural and temporal dynamics.Methods:Publications on DES were retrieved from WoSCC.The bibliometric tools including CiteSpace and HistCite were used to identify the historical features,the evolution of active topics,and emerging trends on the DES field.Results:In the last 20 years,the field of DES is still in the hot phase and there is a wide range of extensive scientific collaborations.In addition,active topics emerge in different periods,as evidenced by a total of 41 disciplines,511 keywords,and 1377 papers with citation bursts.Keyword clustering anchored five emerging research subfields,namely#0 dual antiplatelet therapy,#3 drug-coated balloon,#4 bifurcation,5#rotational atherectomy,and 6#quantitative flow ratio.The keyword alluvial map shows that the most persistent research concepts in this field are thrombosis,restenosis,etc.,and the emerging keywords are paclitaxel eluting balloon,coated balloon,drug-eluting balloon,etc.There are 7 recent research subfields anchored by reference clustering,namely#2 dual antiplatelet therapy,#4 drug-coated balloon,#5 peripheral artery disease,#8 fractional flow reserve,#10 bioresorbable vascular scaffold,#13 intravascular ultrasound,#14 biodegradable polymer.Conclusion:The findings based on the bibliometric studies provide the current status and trends in DES research and may help researchers to identify hot topics and explore new research directions in this field.

The Janus-faced role of Piezo1 in cardiovascular health under mechanical stimulation

In recent years,cardiovascular health problems are becoming more and more serious.At the same time,mechanical stimulation closely relates to cardiovascular health.In this context,Piezo1,which is very sensitive to mechanical stimulation,has attracted our attention.Here,we review the critical significance of Piezo1 in mechanical stimulation of endothelial cells,NO production,lipid metabolism,DNA damage protection,the development of new blood vessels and maturation,narrowing of blood vessels,blood pressure regulation,vascular permeability,insulin sensitivity,and maintenance of red blood cell function.Besides,Piezo1 may participate in the occurrence and development of atherosclerosis,diabetes,hypertension,and other cardiovascular diseases.It is worth noting that Piezo1 has dual effects on maintaining cardiovascular health.On the one hand,the function of Piezo1 is necessary to maintain cardiovascular health;on the other hand,under some extreme mechanical stimulation,the overexpression of Piezo1 may bring adverse factors such as inflammation.Therefore,this review discusses the Janus-faced role of Piezo1 in maintaining cardiovascular health and puts forward new ideas to provide references for gene therapy or nanoagents targeting Piezo1.

A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent: Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway

Objective:Arsenic trioxide(ATO or As2O3)has beneficial effects on suppressing neointimal hyperplasia and restenosis,but the mechanism is still unclear.The goal of this study is to further understand the mechanism of ATO's inhibitory effect on vascular smooth muscle cells(VSMCs).Methods and results:Through in vitro cell culture and in vivo stent implanting into the carotid arteries of rabbit,a synthetic-to-contractile phenotypic transition was induced and the proliferation of VSMCs was inhibited by ATO.F-actin filaments were clustered and the elasticity modulus was increased within the phenotypic modulation of VSMCs induced by ATO in vitro.Meanwhile,Yes-associated protein(YAP)nuclear translocation was inhibited by ATO both in vivo and in vitro.It was found that ROCK inhibitor or YAP inactivator could partially mask the phenotype modulation of ATO on VSMCs.Conclusions:The interaction of YAP with the ROCK pathway through ATO seems to mediate the contractile phenotype of VSMCs.This provides an indication of the clinical therapeutic mechanism for the beneficial bioactive effect of ATO-drug eluting stent(AES)on in-stent restenosis(ISR).

Effect of intraplaque angiogenesis to atherosclerotic rupture-prone plaque induced by high shear stress in rabbit model

Atherosclerotic prone-rupture plaque is mainly localized in the region of the entrance to the stenosiswith high shear stress and the reasons are largely unknown. Our hypothesis is that such a distributionof cells in atherosclerotic plaque may depend on the angiogenesis. Silastic collars inducedregions of high shear stress (20.6865.27 dynes/cm2) in the upstream flow and low shear stress(12.2561.28 dynes/cm2) in the downstream flow in carotid arteries. Compared with the low shearstress region, plaques in the high shear stress region showed more intraplaque haemorrhaging,less collagen and higher apoptotic rates of vascular smooth muscle cells;endothelial cells (ECs) inthe high shear stress region were characterized with integrity and high endothelial nitric oxidesynthase (eNOS) expression (1570.36345.5% vs 172.9649.9%). The number of intraplaque microvesselsis very high in the high shear stress region (1561.8 n/mm2 vs 3.560.4 n/mm2), and themicrovessels in the plaque show ECs were abnormal, with membrane blebs, intracytoplasmic vacuolesand leukocyte infiltration. Our current study reveals that the integrity of the endothelium andthe vulnerability of atherosclerotic plaques are simultaneously localized in high shear stress regions,and we provide evidence for the first time that microvessels in the intraplaque maybe responsiblefor rupture-prone plaque formation in the high shear stress region.

Distinctive effects of CD34- and CD133-specific antibody-coated stents on re-endothelialization and in-stent restenosis at the early phase of vascular injury

It is not clear what effects of CD34-and CD133-specific antibody-coated stents have on reendothelialization and in-stent restenosis(ISR)at the early phase of vascular injury.This study aims at determining the capabilities of different coatings on stents(e.g.gelatin,anti-CD133 and anti-CD34 antibodies)to promote adhesion and proliferation of endothelial progenitor cells(EPCs).The in vitro study revealed that the adhesion force enabled the EPCs coated on glass slides to withstand flow-induced shear stress,so that allowing for the growth of the cells on the slides for 48 h.The in vivo experiment using a rabbit model in which the coated stents with different substrates were implanted showed that anti-CD34 and anti-CD133 antibody-coated stents markedly reduced the intima area and restenosis than bare mental stents(BMS)and gelatin-coated stents.Compared with the anti-CD34 antibody-coated stents,the time of cells adhesion was longer and earlier present in the anti-CD133 antibody-coated stents and anti-CD133 antibody-coated stents have superiority in re-endothelialization and inhibition of ISR.In conclusion,this study demonstrated that anti-CD133 antibody as a stent coating for capturing EPCs is better than anti-CD34 antibody in promoting endothelialization and reducing ISR.

Inhibition of in-stent restenosis after graphene oxide double-layer drug coating with good biocompatibility

In this study,we designed a double layer-coated vascular stent of 316L stainless steel using an ultrasonic spray system to achieve both antiproliferation and antithrombosis.The coating included an inner layer of graphene oxide(GO)loaded with docetaxel(DTX)and an outer layer of carboxymethyl chitosan(CMC)loaded with heparin(Hep).The coated surface was uniform without aggregation and shedding phenomena before and after stent expanded.The coating treatment was able to inhibit the adhesion and activation of platelets and the proliferation and migration of smooth muscle cells,indicating the excellent biocompatibility and antiproliferation ability.The toxicity tests showed that the GO/DTX and CMC/Hep coating did not cause deformity and organ abnormalities in zebrafish under stereomicroscope.The stents with GO double-layer coating were safe and could effectively prevent thrombosis and in-stent restenosis after the implantation into rabbit carotid arteries for 4–12 weeks.

Two-stage degradation and novel functional endothelium characteristics of a 3-D printed bioresorbable scaffold

Bioresorbable scaffolds have emerged as a new generation of vascular implants for the treatment of atherosclerosis,and designed to provide a temporary scaffold that is subsequently absorbed by blood vessels over time.Presently,there is insufficient data on the biological and mechanical responses of blood vessels accompanied by bioresorbable scaffolds(BRS)degradation.Therefore,it is necessary to investigate the inflexion point of degradation,the response of blood vessels,and the pathophysiological process of vascular,as results of such studies will be of great value for the design of next generation of BRS.In this study,abdominal aortas of SD rats were received 3-D printed poly-l-actide vascular scaffolds(PLS)for various durations up to 12 months.The response of PLS implanted aorta went through two distinct processes:(1)the neointima with desirable barrier function was obtained in 1 month,accompanied with slow degradation,inflammation,and intimal hyperplasia;(2)significant degradation occurred from 6 months,accompanied with decreasing inflammation and intimal hyperplasia,while the extracellular matrix recovered to normal vessels which indicate the positive remodeling.These in vivo results indicate that 6 months is a key turning point.This“two-stage degradation and vascular characteristics”is proposed to elucidate the long-term effects of PLS on vascular repair and demonstrated the potential of PLS in promoting endothelium function and positive remodeling,which highlights the benefits of PLS and shed some light in the future researches,such as drug combination coatings design.

Corrigendum to“A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent:Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway”[Bioact.Mater.62(February 2021)375-385]

The authors regret the publication of incorrect fund numbers in the acknowledgment section of the article.The number“cstc2019jcyj-zdxm0033”has been updated as“cstc2019jcyj-zdxmX0028”.The corrected acknowledgment section is as follows:This study was supported in part by grants from the National Natural Science Foundation,China(31971242,31701275),the Natural Science Foundation of Chongqing,China(cstc2020jcjy-msxmX0189),the Chongqing Research Program of Basic Research and Frontier Technology,China(cstc2019jcjy-dxmX0028),Open Fund for Key Laboratory of Biorheological Science and Technology,Ministry of Education,China(CQKLBST-2019-010),Innovation Talent Project of 2020 for Chongqing Primary and secondary School,China(CY200405)and the National Key R&D Program,China(2016YFC1102305).The support from the Chongqing Engineering Laboratory in Vascular Implants,China,the Public Experiment Centre of State Bioindustrial Base(Chongqing)and the National“111 Plan”,China(B06023)are gratefully acknowledged.

Cytotoxic effects of docetaxel as a candidate drug of drug-eluting stent on human umbilical vein endothelial cells and the signaling pathway of cell migration inhibition,adhesion delay and shape change

Docetaxel(DTX),a paclitaxel analogue,can efficiently inhibit proliferation of vascular smooth muscle cells and has broadly been used as an antiangiogenesis drug.However,as a candidate drug of drug-eluting stent,the effects of DTX on human umbilical vein endothelial cells(HUVECs)are still not well understood.Herein,we investigated the effects of DTX on proliferation,apoptosis,adhesion,migration and morphology of HUVECs in vitro.We found that DTX had the cytostatic and cytotoxic effects at low and high concentrations,respectively.DTX could inhibit the proliferation and migration of HUVECs,induce HUVECs apoptosis,delay HUVECs adhesion and decrease spreading area and aspect ratio of individual cells.The signaling pathway that DTX led to the migration inhibition,adhesion delay and shape change of HUVECs is the VE-cadherin mediated integrin b1/FAK/ROCK signaling pathway.The study will provide a theoretical basis for the clinical application of DTX.