Particle debris from a nanoporous stent coating obscures potential antiproliferative effects of tacrolimus-eluting stents in a porcine model of restenosis

Abstract

Polymer stent coatings may not be suitable for drug elution because of inherent proinflammatory effects. A previous study suggested a beneficial effect of a stent eluting tacrolimus from a nanoporous ceramic aluminum oxide coating in a rabbit restenosis model. We investigated whether this stent is effective in preventing in-stent restenosis in a porcine restenosis model. Thirty-four juvenile swine underwent balloon overstretch injury and were subjected to implantation of either stainless steel (bare) stents, bare stents coated with nanoporous aluminum oxide alone, and coated stents eluting 50 and 180 mug of tacrolimus (FK506). In-stent restenosis was quantified at 1 and 3 months after stent placement by histomorphometry. A significant increase of neointimal hyperplasia was noted with the stents coated with aluminum oxide alone compared with bare stents (2.92 +/- 1.02 and 1.38 +/- 0.51 mm(2), respectively; P < 0.02). In all arteries containing coated stents, particle debris was found in the media and neointima, resulting in augmented vascular inflammation. In the group of stents coated with aluminum oxide, FK506 elution at a dose 180 mug reduced neointimal hyperplasia vs. no drug elution (1.66 +/- 0.49 vs. 2.92 +/- 1.02 mm(2); 180 mug vs. ceramic alone; P < 0.03). At a dose of 50 mug stent-based delivery of FK506, no reduction of neointimal hyperplasia was found (2.88 +/- 1.31 and 2.92 +/- 1.02 mm(2), respectively; P = NS; FK506 vs. ceramic alone). In summary, particle debris shed from a drug-eluting aluminum oxide coating of a stainless steel stent counteracts potential antiproliferative effects of stent-based tacrolimus delivery in a porcine model of restenosis. We propose that stent coatings eluting drugs need to be routinely tested for being tightly anchored into the stent surface. Alternatively, omission of any coating used as a drug reservoir may eliminate inflammatory particle debris after placement of drug-eluting stents.

Coronary stents: A materials perspective

“…Though the surface modification by ceramic coating did not show significant effect in reducing the neointima in a rabbit model, the release of tacrolimus reduced neointimal thickness in a dose dependent (52% and 56% reduction for 60 and 120 mg, respectively) manner [146]. Recently, it was reported that this kind of ceramic coating may liberate particle debris which in turn affects the antiproliferative effect of tacrolimus and results in a significant increase in the neointima as compared to the control uncoated stents [147].…”

TiO₂ nanotube platforms for smart drug delivery: a review

“…Recent in vivo studies have demonstrated that the shedding of particle debris released from the nanoporous coatings produces a great increment of neointimal hyperplasia. 124 Fine et al reported that drug-releasing coronary stents based on Ti promote better interactions with ECs. 125 In this study, a new material called rosette nanotubes without drugs was coated on Ti stent surfaces, aiming to enhance the EC adhesion and proliferation.…”

Enhancing Stent Effectiveness with Nanofeatures

“…However, preclinical studies have shown variability regarding the effectiveness of stents coated with nanoporous materials. 34,35 Although biocompatibility has been documented, nanoparticle debris ejected from the stent surface has been observed. This debris could provoke inflammation and subsequent restenosis.…”