Hierarchical Capillary Coating to Biofunctionlize Drug-Eluting Stent for Improving Endothelium Regeneration - PubMed (original) (raw)

Hierarchical Capillary Coating to Biofunctionlize Drug-Eluting Stent for Improving Endothelium Regeneration

Jing Wang et al. Research (Wash D C). 2020.

Abstract

The drug-eluting stent (DES) has become one of the most successful and important medical devices for coronary heart disease, but yet suffers from insufficient endothelial cell (EC) growth and intima repair, eventually leading to treatment failure. Although biomacromolecules such as vascular endothelial growth factor (VEGF) would be promising to promote the intima regeneration, combining hydrophilic and vulnerable biomacromolecules with hydrophobic drugs as well as preserving the bioactivity after harsh treatments pose a huge challenge. Here, we report on a design of hierarchical capillary coating, which composes a base solid region and a top microporous region for incorporating rapamycin and VEGF, respectively. The top spongy region can guarantee the efficient, safe, and controllable loading of VEGF up to 1 _μ_g/cm2 in 1 minute, providing a distinctive real-time loading capacity for saving the bioactivity. Based on this, we demonstrate that our rapamycin-VEGF hierarchical coating impressively promoted the competitive growth of endothelial cells over smooth muscle cells (ratio of EC/SMC~25) while relieving the adverse impact of rapamycin to ECs. We further conducted the real-time loading of VEGF on stents and demonstrate that the hierarchical combination of rapamycin and VEGF showed remarkable endothelium regeneration while maintaining a very low level of in-stent restenosis. This work paves an avenue for the combination of both hydrophobic and hydrophilic functional molecules, which should benefit the next generation of DES and may extend applications to diversified combination medical devices.

Copyright © 2020 Jing Wang et al.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1

Scheme 1

Schematic illustration of the hierarchical coating on the cardiovascular stent for regulating the intimal regeneration. The capillary-based wicking action could realize the distinctive real-time loading of VEGF during the surgery, which preserved the bioactivity of VEGF and impressively enhanced endothelium recovery while maintaining the inhibition of SMC proliferation after implantation.

Figure 1

Figure 1

Preparation of the hierarchical coating. (a) SEM micrographs of the coating with different top layer spray time. (b) The thickness of the top layer as a function of spray time. Contact angle (c) and X-ray photoelectron spectrums (d) of the coating with different extent of heparinization based on UV irradiation.

Figure 2

Figure 2

The loading and release profile of the hierarchical coating. (a) Rapamycin release profile as a function of time. (b) Comparison of rapamycin release with and without spongy top layer, respectively. (c) The wicking action of rhodamine B. (d) Loading of VEGF as a function of VEGF solution concentration. (e) VEGF release profile as a function of time.

Figure 3

Figure 3

Coculture of ECs with SMCs. Confocal micrographs (a) and corresponding cell density (b) of ECs and SMCs on the hierarchical coatings (n = 5, ∗P < 0.05, ∗∗∗P < 0.001).

Figure 4

Figure 4

Relative expression of endothelial function related genes. Values normalized to control samples (n = 3, ∗P < 0.05).

Figure 5

Figure 5

Regulation of the m-TOR signaling in ECs via the spatial combination of VEGF with rapamycin. (a) Western blot for ERK1/2 and its downstream effector m-TOR. (b) Quantification of Western blot bands. Values normalized to ACTB. (c) Potential signaling pathway related to the regulation of m-TOR by VEGF (n = 3, ∗P < 0.05).

Figure 6

Figure 6

Construction of hierarchical coating onto the stents: SEM micrographs of BSs (a), RESs (b), and VRSs (c). (d) Digital photo of BSs (left) and VRSs (right). Fluorescence micrographs (e) and confocal scanning (f) of VRSs after loading of PLL-FITC.

Figure 7

Figure 7

Histological analysis results at 6 weeks. (a) The digital photos of the stent with a hierarchical coating (left) and the typical wicking process during the surgery (right). (b) The micrographs of the H&E-stained cross-section slices of the arteries with BSs, RESs, and VRSs, respectively. Histological analysis of neointimal thickness (c), and the percentage of neointimal stenosis (d) (n = 3, ∗P < 0.05).

Figure 8

Figure 8

Immunohistochemical analysis of the stented arterial segments for CD31 and Col-I, respectively.

Figure 9

Figure 9

(a) Western blot analysis of arterial segments implanted with BSs, RESs, and VRSs, respectively. Ctrl represents the native arterial segments. (b) Quantification of Western blot bands. Values normalized to GAPDH and then normalized to Ctrl (n = 3, ∗P < 0.05).

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