Evaluation of Ultrasonic Spray Method for Application of Sirolimus-Eluting Coating on Bioresorbable Vascular Scaffolds

Abstract

Restenosis is the main cause of failure after stent implantation during angioplasty. The localized, sustained delivery of an antirestenotic drug may reduce smooth muscle cell (SMCs) proliferation and thereby limit neointimal hyperplasia. The aim of this study was to develop degradable sirolimus-eluting polymer coatings that can be applied on bioresorbable polymer-based scaffolds via an ultrasonic coating system. This is a novel approach because the detailed analysis of the coating procedure on bioresorbable polymeric scaffolds with the use of an ultrasonic system has not been reported thus far. It has been observed that the ultrasonic technique facilitates formation of a smooth coating, well-integrated with the scaffold. However, the drug dose is affected by the concentration of the coating solution and the number of layers. Therefore, these parameters can be used for tailoring the drug dose and release process. Although all types of the developed coatings provided sirolimus elution for at least 3 months, a more uniform, diffusion-controlled release profile was observed from coatings obtained from the 1.0% polymeric solution. The released drug showed antiproliferative activity against vascular SMCs, without any hemolytic or thrombogenic effects. The results of the study may be advantageous for further progress in the development and medical translation of polymeric vascular scaffolds with antirestenotic activity.

Keywords: biodegradable vascular scaffolds; restenosis; sirolimus; stent coating; ultrasonic spray coating.

Figure 1

Schematic presentation of bioresorbable scaffolds before (A) and after (B) application of sirolimus-eluting coating. Optical microscope image of scaffold coated with polymer solution containing sirolimus via the ultrasonic technique (C).

Figure 2

SEM images of coating of scaffolds composed of 3 layers of 1.0% polymer solution (A), 5 layers of 1.0% polymer solution (B), 7 layers of 1.0% polymer solution (C), 3 layers of 2.5% polymer solution (D), 5 layers of 2.5% polymer solution (E), and 7 layers of 2.5% polymer solution (F).

Figure 3

Optical microscope image of coating-free vascular scaffold (A) and scaffold coated with 7 layers of 2.5% polymer solution with sirolimus (B).

Figure 4

In vitro release of sirolimus from coatings of the bioresorbable scaffolds composed of 3, 5 or 7 layers and obtained from 1.0% (A) or 2.5% (B) polymer solution (n = 3; ±SD).

Figure 5

The effect of drug-free scaffold on viability of L-929 cells compared to unmodified cell culture (C-). Medium with dimethyl sulfoxide (DMSO) was used as positive control (C+) (±SD, * p < 0.05).

Figure 6

The effect of scaffold coated with 5 layers (1.0%) of coating containing sirolimus, pure drug (sirolimus), and scaffold without coating on viability of HCASMC cells compared to unmodified cell culture (C-). Medium with DMSO was used as positive control (C+) (±SD, * p < 0.05).

Figure 7

Hemolytic effect of scaffolds coated with 5 layers of 1.0% polymeric solution containing sirolimus compared to results for PBS pH~7 (C-) and 10% Triton X-100 (C+), (±SD, n = 3).

Figure 8

Comparison of concentration of thrombin–antithrombin complex (TAT) determined for blood incubated without sample (control), low-density polyethylene (LDPE) (Ref. 1), medical steel (Ref. 2) and scaffold with 5 layers (1.0%) of coating containing sirolimus (±SD, n = 3).