A new intra-arterial delivery platform for pro-arteriogenic compounds to stimulate collateral artery growth via transforming growth factor-beta1 release.

摘要

OBJECTIVES: The purpose of this study was to develop a cytokine-eluting stent to stimulate collateral artery growth (arteriogenesis) in the peripheral circulation of the rabbit via local transforming growth factor (TGF)-beta1 release. BACKGROUND: The stimulation of arteriogenesis with cytokines is a potential new treatment option for patients suffering from vascular occlusive diseases. However, the lack of a delivery platform for continuous intra-arterial application of pro-arteriogenic compounds has hampered the clinical implementation of this promising therapeutic strategy. METHODS: Different polymer coatings were tested regarding their suitability for cytokine release. Fifty-four rabbits underwent implantation of bare-metal stents (BMS), polymer-only coated stents (PDLLA), polymer-coated TGF-beta1-eluting stents (TGF) in the iliac artery, or bolus infusion of TGF-beta1 and subsequent femoral artery ligation. Collateral artery growth was assessed with fluorescent microspheres, angiography, and histological quantification of the proliferation marker Ki67. In-stent neointima formation was measured in histological sections of plastic-embedded stents. RESULTS: A TGF-beta1-loaded coating based on poly(D,L-lactide) released up to 2.4 microg active TGF-beta1 over a period of 24 h. Perfusion measurements revealed a significant increase in collateral conductance after TGF-beta1 stent implantation compared with the control groups ([ml/min/100 mm Hg] BMS: 47.8 +/- 2.5; PDLLA: 44.1 +/- 3.9; TGF: 91.3 +/- 32.6). Bolus infusion of TGF-beta1 had no effect. Collateral arteries showed a higher proliferation activity in the TGF-treated group. At 7 days, no significant difference in in-stent neointima formation was observed. CONCLUSIONS: We first describe the use of a cytokine-releasing stent to stimulate collateral artery growth. These results show that intra-arterial cytokine-releasing devices might serve as a novel platform for the delivery of compounds affecting biological processes downstream of the site of implantation.