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A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues.

ABSTRACT: Drug-eluting stent implantation suppresses the excessive proliferation of smooth muscle cells to reduce in-stent restenosis. However, the efficacy of drug-eluting stents remains limited due to delayed reendothelialization, impaired intimal remodeling, and potentially increased late restenosis. Here, we show that a drug-free coating formulation functionalized with tailored recombinant humanized type III collagen exerts one-produces-multi effects in response to injured tissue following stent implantation. We demonstrate that the one-produces-multi coating possesses anticoagulation, anti-inflammatory, and intimal hyperplasia suppression properties. We perform transcriptome analysis to indicate that the drug-free coating favors the endothelialization process and induces the conversion of smooth muscle cells to a contractile phenotype. We find that compared to drug-eluting stents, our drug-free stent reduces in-stent restenosis in rabbit and porcine models and improves vascular neointimal healing in a rabbit model. Collectively, the one-produces-multi drug-free system represents a promising strategy for the next-generation of stents.

SUBMITTER: Wu H

PROVIDER: S-EPMC10810808 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues.

Wu Haoshuang H Yang Li L Luo Rifang R Li Li L Zheng Tiantian T Huang Kaiyang K Qin Yumei Y Yang Xia X Zhang Xingdong X Wang Yunbing Y

Nature communications 20240125 1

Drug-eluting stent implantation suppresses the excessive proliferation of smooth muscle cells to reduce in-stent restenosis. However, the efficacy of drug-eluting stents remains limited due to delayed reendothelialization, impaired intimal remodeling, and potentially increased late restenosis. Here, we show that a drug-free coating formulation functionalized with tailored recombinant humanized type III collagen exerts one-produces-multi effects in response to injured tissue following stent impla ...[more]

PMID: 38272886

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Project description:IntroductionPatients undergoing coronary stent implantation incur a 2% annual rate of adverse events, largely driven by in-stent restenosis (ISR) due to neointimal (NI) tissue proliferation, a process in which smooth muscle cell (SMC) biology may play a central role. Dipyridamole (DP) is an approved therapeutic agent with data supporting improved vascular patency rates. Pre-clinical data supports that DP may enact its vasculoprotective effects via adenosine receptor-A2B (ADOR-A2B). We sought to evaluate the efficacy of DP to mitigate ISR in a pre-clinical rabbit stent model.Methods & results24 New Zealand White Rabbits were divided into two cohorts-non-atherosclerosis and atherosclerosis (n = 12/cohort, 6 male and 6 female). Following stent implantation, rabbits were randomized 1:1 to control or oral dipyridamole therapy for 6 weeks followed by optical coherence tomography (OCT) and histology assessment of NI burden and stent strut healing. Compared to control, DP demonstrated a 16.6% relative reduction in NI volume (14.7 ± 0.8% vs. 12.5 ± 0.4%, p = 0.03) and a 36.2% relative increase in optimally healed stent struts (37.8 ± 2.8% vs. 54.6 ± 2.5%, p < 0.0001). Atherosclerosis demonstrated attenuated effect with no difference in NI burden (15.2 ± 1.0% vs. 16.9 ± 0.8%, p = 0.22) and only a 14.2% relative increase in strut healing (68.3 ± 4.1% vs. 78.7 ± 2.5%, p = 0.02). DP treated rabbits had a 44.6% (p = 0.045) relative reduction in NI SMC content. In vitro assessment of DP and coronary artery SMCs yielded dose-dependent reduction in SMC migration and proliferation. Selective small molecule antagonism of ADOR-A2B abrogated the effects of DP on SMC proliferation. DP modulated SMC phenotypic switching with ADOR-A2B siRNA knockdown supporting its role in the observed effects.ConclusionDipyridamole reduces NI proliferation and improves stent healing in a preclinical model of stent implantation with conventional antiplatelets. Atherosclerosis attenuates the observed effect. Clinical trials of DP as an adjunctive agent may be warranted to evaluate for clinical efficacy in stent outcomes.

Project description:BackgroundThe objective of the present study was to evaluate the bioresorption rate of collagen coating (CC) sealed on textile vascular grafts (VGs) and their healing in humans using histologic analysis of explanted VGs.MethodsA total of 27 polyester textile VGs had been removed during surgery from 2012 to 2020. The segments underwent histologic assessment. The CC bioresorption rate was assessed using morphometric analysis to determine the internal and external capsule thickness, inflammatory reaction degree, presence of neovessels, and endothelial cell layer.ResultsA total of 27 VGs were explanted from 25 patients because of infection (n = 5; 18.5%), thrombosis (n = 7; 25.9%), stenosis (n = 2; 7.4%), rupture (n = 4; 14.8%), aneurysmal degeneration (n = 3; 11.1%), revascularization (n = 4; 14.8%), or another cause (n = 2; 7.4%), with a median implantation duration of 291 days (interquartile range [IQR], 48-911 days). VGs with remaining CC (n = 7; 26%) had been explanted earlier than had those without (n = 20; 74%; 1 day [IQR, 1-45 days] vs 516 days [IQR, 79-2018 days]; P = .001). After 1 year, no remaining CC was detected on the analyzed VG sections. VGs implanted for <90 days had had a greater CC maximal thickness (63.90 μm [IQR, 0-83.25 μm] vs 0 μm [IQR, 0-0 μm]; P = .006) and a greater CC surface coverage (180° [IQR, 0°-360°] vs 0° [IQR, 0°-0°]; P = .002) than those implanted for >90 days. VGs implanted for >90 days had a greater external capsule thickness (889.2 μm [IQR, 39.6-1317 μm] vs 0 μm [IQR, 0-0 μm]; P = .002), a higher number of inflammatory mononuclear cells and giant cells (168 cells [IQR, 110-310 cells] vs 0 cells [IQR, 0-94 cells]; P < .0001) and a higher number of neovessels (4 [IQR, 0-5] vs 0 [IQR, 0-0]; P = .001) than those implanted for <90 days.ConclusionsCC had a slow bioresorption rate in humans. Complete healing was never achieved, with no endothelial coverage observed. This finding implies that CC might not help graft healing.

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A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues.

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A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues.

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