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      A comparative study of the effects of vitamin C, sirolimus, and paclitaxel on the growth of endothelial and smooth muscle cells for cardiovascular medical device applications

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          Abstract

          Antiproliferative drugs such as sirolimus (SIR) and paclitaxel (PAT) are currently released from stents and vascular grafts to inhibit the growth of smooth muscle cells (SMCs), thereby preventing neointimal hyperplasia. However, these drugs delay or impair the growth of endothelial cells (ECs) on implant surfaces causing late thrombosis. Hence, there is a need to use alternative drugs in these implants to encourage the growth of ECs and to inhibit the growth of SMCs. Vitamin C (L-ascorbic acid [L-AA]) is one such drug which has been shown to encourage EC growth and inhibit SMC growth when orally administered or added directly to the cell cultures. In this research, four sets of in vitro cell culture experiments were carried out to compare the effects of L-AA, SIR, and PAT on the growth of ECs and SMCs under similar conditions, and to compare the effects of different doses of L-AA to determine the optimal dose for promoting maximum EC growth and inhibiting SMC growth. The ECs and SMCs treated with different drugs were characterized for their viability and proliferation, and morphology using the quantitative resazurin assay (as well as qualitative fluorescence microscopy characterization) and phase contrast microscopy, respectively, for up to 7 days. Also, the phenotype of ECs was characterized using immunofluorescence microscopy. Both SIR and PAT significantly inhibited the EC growth while L-AA significantly encouraged EC growth even more than that of the controls with no drugs. Also, L-AA significantly inhibited SMC growth although the inhibitory effect was inferior to that of SIR and PAT. The L-AA dosage study demonstrated that 100 μg and 300 μg of L-AA showed maximum EC growth after 7 days when compared to other dosages (1 μg, 500 μg, and 1000 μg) of L-AA and controls investigated in this study. Also, the 100 μg and 300 μg L-AA doses significantly inhibited the SMC growth. Thus, this study demonstrates that L-AA is a promising drug for potential use in stents and vascular grafts, to promote their endothelialization and inhibit neointimal hyperplasia.

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          Most cited references 35

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          Vascular responses to drug eluting stents: importance of delayed healing.

          Polymer-based sirolimus- (Cypher) and paclitaxel-eluting (Taxus) drug eluting stents have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI). Although these stents reduce rates of restenosis compared with bare metal stents (BMS), late thrombosis, a life threatening complication, has emerged as a major safety concern. Our understanding of the pathophysiology of late DES thrombosis is derived from animal and human pathologic samples taken after implantation of these devices. These data indicate that both DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared with BMS. This delayed healing is the primary substrate underlying all cases of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis such as penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions represent additional barriers to healing and should be avoided if DES are to be used to minimize the risk of late thrombosis. Because the time course of complete healing with DES in man is unknown, the optimal duration of antiplatelet treatment remains to be determined.
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            Endothelial cell recovery between comparator polymer-based drug-eluting stents.

            The purpose of this study was to assess trends in endothelial coverage and recovery among leading polymer-based drug-eluting stents (DES). Autopsy studies of human U.S. Food and Drug Administration (FDA)-approved DES implanted coronary arteries suggest that complications of late stent thrombosis are associated with incomplete endothelial coverage of struts. Rabbits received sirolimus-eluting stents (SES), paclitaxel-eluting stents (PES), zotarolimus-eluting stents (ZES), and everolimus-eluting stents (EES) for 14 or 28 days along with MULTI-LINK (ML) Vision control stents. Endothelial coverage above and between struts was measured by morphometric analysis of images acquired through en face scanning electron microscopy. Dual fluorescent immunolabeling was performed for platelet-endothelial cell adhesion molecule (PECAM)-1 and thrombomodulin (TM), factors involved in cell-to-cell contact and thrombogenicity, respectively. In a separate analysis, the endothelial mitogen, vascular endothelial growth factor (VEGF), was also assessed. Varying rates of endothelialization among comparator DES were most notable at 14 days, where coverage above struts remained poor in SES, PES, and ZES ( or=70%), whereas no significant differences were observed at 28 days. Select DES with poor endothelialization showed a further reduced expression of PECAM-1. All DES showed an absence or weak expression of the antithrombotic cofactor TM. Incomplete endothelialization in select DES was further associated with increased VEGF secretion and messenger ribonucleic acid levels at 14 days, providing evidence of a transitional healing surface. The present study marks the first comparator analysis of endothelial coverage in leading polymeric DES, supporting disparities in arterial healing based on endothelial regrowth and recovery, favoring newer designs over the current generation of FDA-approved stents.
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              Coronary stents: a materials perspective.

              The objective of this review is to describe the suitability of different biomaterials as coronary stents. This review focuses on the following topics: (1) different materials used for stents, (2) surface characteristics that influence stent-biology interactions, (3) the use of polymers in stents, and (4) drug-eluting stents, especially those that are commercially available.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2013
                24 June 2013
                : 7
                : 529-544
                Affiliations
                Biomedical Engineering Program, The University of South Dakota, Sioux Falls, SD, USA
                Author notes
                Correspondence: Gopinath Mani Biomedical Engineering Program, The University of South Dakota, 4800 N Career Avenue, Sioux Falls, SD 57107, USA, Tel +1 605 367 7773, Email gopinath.mani@ 123456usd.edu
                Article
                dddt-7-529
                10.2147/DDDT.S45162
                3699137
                23836963
                © 2013 Kakade and Mani, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

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