Combining mathematical modelling with in vitro experiments to predict in vivo drug-eluting stent performance

Drug-eluting stents (DES) have significantly improved restenosis rates as compared to bare metal stents (BMS), however, an increased risk in late stent thrombosis (LST) has been observed due to delayed healing and incomplete endothelialization. These adverse events have been associated to the high level of anti-proliferative drugs eluted from 1st generation DES, as well as non-erodible polymers that remain intact. The purpose of this study was to fist determine optimal surface modification in vitro and to then assess trends in endothelial coverage and recovery of the modified non-polymeric DES in a rabbit iliac stent model.

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Corrigendum to “Paclitaxel/sirolimus combination coated drug-eluting stent: In vitro and in vivo drug release studies” [J. Pharm. Biomed. Anal. 54 (2011) 807–811]

Journal of Pharmaceutical and Biomedical Analysis ◽

10.1016/j.jpba.2011.10.008 ◽

2012 ◽

Vol 59 ◽

pp. 217

Author(s):

Xiaodong Ma ◽

Shizu Oyamada ◽

Fan Gao ◽

Tim Wu ◽

Michael P. Robich ◽

...

Keyword(s):

Drug Release ◽

Drug Eluting Stent ◽

Release Studies ◽

Drug Eluting ◽

Pharm Biomed Anal

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Paclitaxel/sirolimus combination coated drug-eluting stent: In vitro and in vivo drug release studies

Journal of Pharmaceutical and Biomedical Analysis ◽

10.1016/j.jpba.2010.10.027 ◽

2011 ◽

Vol 54 (4) ◽

pp. 807-811 ◽

Cited By ~ 41

Author(s):

Xiaodong Ma ◽

Shizu Oyamada ◽

Fan Gao ◽

Tim Wu ◽

Michael P. Robich ◽

...

Keyword(s):

Drug Release ◽

Drug Eluting Stent ◽

Release Studies ◽

Drug Eluting

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Biosafety and Efficacy Evaluation of a Biodegradable Magnesium based Drug-eluting Stent in Porcine Coronary Artery

10.21203/rs.3.rs-110813/v1 ◽

2020 ◽

Author(s):

Jinzhou Zhu ◽

Xiyuan Zhang ◽

Jialin Niu ◽

Yongjuan Shi ◽

Zhengbin Zhu ◽

...

Keyword(s):

Smooth Muscle ◽

Coronary Artery ◽

Smooth Muscle Cells ◽

Porcine Model ◽

Muscle Cells ◽

Comparable Efficacy ◽

Drug Eluting Stent ◽

Drug Eluting

Abstract Although drug-eluting stent (DES) has become the standard for percutaneous coronary interventions (PCI) based revascularization, stent thrombosis has emerged as a major cause of death and morbidity for those clinical commonly used permanent stents. Drug-eluting bioresorbable stent (BRS) was thus developed as an alternative to DES, which can be completely absorbed after its therapeutic period. Among them, magnesium (Mg) based BRS has attracted great attention due to its suitable mechanical properties, innovative chemical features and well-proven biocompatibility. In the present work, a Mg–Nd–Zn-Zr (JDBM) based drug-eluting BRS loaded with rapamycin was prepared, and its biosafety and efficacy for coronary artery stenosis were evaluated via in vitro and in vivo experiments. The smooth muscle cells adhesion of PDLLA/RAPA coated alloy and the rapamycin pharmacokinetics of JDBM BRS were first assessed in vitro. JDBM BRS and commercial DES Firehawk were then implanted in the coronary arteries of a porcine model. Neointimal hyperplasia was evaluated at 30, 90, and 180 days, and re-endothelialization was evaluated at 30 days. Furthermore, Micro-CT and optical coherence tomography (OCT) analysis were performed to evaluate the technical feasibility and biocompatibility of JDBM alloy based drug-eluting BRS in vivo. The results showed the inhibition ability of PDLLA/RAPA coated JDBM to smooth muscle cells adhesion and moderate drug release rate of JDBM BRS, demonstrating good anti-restenosis ability in vitro. In vivo, low local and systemic risks of JDBM alloy based BRS was demonstrated in the porcine model. We also showed that this novel BRS was associated with a comparable efficacy profile and high anti-restenosis performance. These findings may confer long term advantages for the use of this BRS over a traditional DES.

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Abstract 4461: Rho-kinase Pathway Plays an Important Role in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stent

Circulation ◽

10.1161/circ.118.suppl_18.s_893-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Takashi Shiroto ◽

Satoshi Yasuda ◽

Ryuji Tsuburaya ◽

Yoshitaka Ito ◽

Hatsue Ishibashi-Ueda ◽

...

Keyword(s):

Kinase Inhibitor ◽

Rho Kinase ◽

Bare Metal Stent ◽

Drug Eluting Stent ◽

Rho Kinase Inhibitor ◽

Drug Eluting ◽

Kinase Expression ◽

Kinase Pathway

It has recently been reported that coronary vasoconstricting responses are enhanced at the edge of coronary segment implanted with drug-eluting stent (DES) as compared with bare-metal stent (BMS) in humans. We have previously demonstrated in animal models and humans that activation of Rho-kinase plays a key role in the molecular mechanism of coronary vasospasm. In this study, we thus examined whether Rho-kinase pathway also is involved in the DES-induced coronary hyperconstriction in vitro and in vivo. In cultured human coronary vascular smooth muscle cells, paclitaxel (10 –1000 nM, comparable tissue concentrations in humans, 24 hours) concentration-dependently up-regulated Rho-kinase expression (n=9) and increased Rho-kinase activity (10 nM, n=6). In a porcine model in vivo, DES (Taxus ™ ) and BMS (Express ™ ) were randomly implanted in the left anterior descending and circumflex coronary arteries (n=5). Four weeks after the implantation, coronary vasoconstricting responses to serotonin (5-HT, 50 and 100 μg/kg, IC) were significantly enhanced at the DES site compared with the BMS site (DES −52±4 vs. BMS −31±5%, P<0.01), and the enhanced responses were prevented by hydroxyfasudil (HF, 90 and 300 μg/kg, IC), a selective Rho-kinase inhibitor ( Figure A ). The same in vivo findings also were noted in another comparison between DES (Cypher ™ ) and BMS (Velocity ™ ) (DES −62±3% vs. BMS −41±3%, n=6, P<0.01) ( Figure B ). Histological analysis showed microthrombus formation only at the DES site. These results suggest that Rho-kinase pathway also plays an important pathogenetic role in the DES-induced coronary hyperconstricting responses.

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Carrier free rapamycin loaded drug eluting stent: In vitro and in vivo evaluation

Journal of Controlled Release ◽

10.1016/j.jconrel.2013.02.012 ◽

2013 ◽

Vol 168 (1) ◽

pp. 70-76 ◽

Cited By ~ 25

Author(s):

Wahid Khan ◽

Shady Farah ◽

Abraham Nyska ◽

Abraham J. Domb

Keyword(s):

Drug Eluting Stent ◽

In Vivo Evaluation ◽

Carrier Free ◽

Drug Eluting

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In vitro and in vivo performance of a dual drug-eluting stent (DDES)

Biomaterials ◽

10.1016/j.biomaterials.2010.01.147 ◽

2010 ◽

Vol 31 (15) ◽

pp. 4382-4391 ◽

Cited By ~ 64

Author(s):

Yingying Huang ◽

Subbu S. Venkatraman ◽

Freddy Y.C. Boey ◽

Eeva M. Lahti ◽

P.R. Umashankar ◽

...

Keyword(s):

Drug Eluting Stent ◽

Drug Eluting ◽

Dual Drug

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In vitro and in vivo characterisation of biodegradable polymer-based drug-eluting stent

EuroIntervention ◽

10.4244/eijv7i7a131 ◽

2011 ◽

Vol 7 (7) ◽

pp. 835-843 ◽

Cited By ~ 15

Author(s):

Saami Yazdani ◽

Marc Vorpahl ◽

Masataka Nakano ◽

Shih-Horng Su ◽

Frank Kolodgie ◽

...

Keyword(s):

Biodegradable Polymer ◽

Drug Eluting Stent ◽

Drug Eluting

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Biosafety and efficacy evaluation of a biodegradable magnesium-based drug-eluting stent in porcine coronary artery

Scientific Reports ◽

10.1038/s41598-021-86803-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jinzhou Zhu ◽

Xiyuan Zhang ◽

Jialin Niu ◽

Yongjuan Shi ◽

Zhengbin Zhu ◽

...

Keyword(s):

Smooth Muscle ◽

Cell Adhesion ◽

Coronary Artery ◽

Smooth Muscle Cell ◽

Degradation Rate ◽

Porcine Model ◽

Drug Eluting Stent ◽

Drug Eluting

AbstractAlthough the drug-eluting stent (DES) has become the standard for percutaneous coronary intervention (PCI)-based revascularization, concerns remain regarding the use of DES, mainly due to its permanent rigid constraint to vessels. A drug-eluting bioresorbable stent (BRS) was thus developed as an alternative to DES, which can be absorbed entirely after its therapeutic period. Magnesium (Mg)-based BRSs have attracted a great deal of attention due to their suitable mechanical properties, innovative chemical features, and well-proven biocompatibility. However, the primary disadvantage of Mg-based BRSs is the rapid degradation rate, resulting in the early loss of structural support long before the recovery of vascular function. Recently, a new type of patented Mg–Nd–Zn-Zr alloy (JDBM) was developed at Shanghai Jiao Tong University to reduce the degradation rate compared to commercial Mg alloys. In the present investigation, a poly(d,l-lactic acid)-coated and rapamycin eluting (PDLLA/RAPA) JDBM BRS was prepared, and its biosafety and efficacy for coronary artery stenosis were evaluated via in vitro and in vivo experiments. The degree of smooth muscle cell adhesion to the PDLLA/RAPA coated alloy and the rapamycin pharmacokinetics of JDBM BRS were first assessed in vitro. JDBM BRS and commercial DES FIREHAWK were then implanted in the coronary arteries of a porcine model. Neointimal hyperplasia was evaluated at 30, 90, and 180 days, and re-endothelialization was evaluated at 30 days. Furthermore, Micro-CT and optical coherence tomography (OCT) analyses were performed 180 days after stent implantation to evaluate the technical feasibility, biocompatibility, and degradation characteristics of JDBM BRS in vivo. The results show the ability of a PDLLA/RAPA coated JDBM to inhibit smooth muscle cell adhesion and moderate the drug release rate of JDBM BRS in vitro. In vivo, low local and systemic risks of JDBM BRS were demonstrated in the porcine model, with preserved mechanical integrity after 6 months of implantation. We also showed that this novel BRS was associated with a similar efficacy profile compared with standard DES and high anti-restenosis performance. These findings may confer long term advantages for using this BRS over a traditional DES.

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