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PRECLINICAL STUDIES

A New Intra-Arterial DeliveryPlatform for Pro-Arteriogenic Compounds to Stimulate Collateral Artery Growth Via Transforming Growth Factor-ß1 Release

Sebastian Grundmann, MD^_*,_*, Niels van Royen, MDPhD^_*, Gerard Pasterkamp, MDPhD, Nieves Gonzalez, PhD, Edze J. Tijsma, PhD, Jan J. Piek, MDPhD^_* and Imo E. Hoefer, MDPhD^_*,

^_* Department of Cardiology, AMC, University of Amsterdam, Amsterdam, the Netherlands
Laboratory of Experimental Cardiology, UMC, University of Utrecht, Utrecht, the Netherlands
Medtronic Bakken Research Center, Maastricht, the Netherlands

Manuscript received February 6, 2007; revised manuscript received March 26, 2007, accepted March 28, 2007.

^_* Reprint requests and correspondence: Dr. Imo E. Hoefer, Laboratory of Experimental Cardiology, Room G02.523, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands (Email: i.hoefer{at}umcutrecht.nl).

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)-ß1 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-ß1–eluting stents (TGF) in the iliac artery, or bolus infusion of TGF-ß1 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-ß1–loaded coating based on poly(D,L-lactide) released up to 2.4 µg active TGF-ß1 over a period of 24 h. Perfusion measurements revealed a significant increase in collateral conductance after TGF-ß1 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-ß1 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.

Abbreviations and Acronyms   BMS = bare-metal stent(s)   ELISA = enzyme linked immunosorbent assay   FGF = fibroblast growth factor   HE = hematoxyline and eosine   HUVECS = human umbilical endothelial cells   MMA = methyl-methacrylate   MW = molecular weight   PBMA = poly(n-butyl methacrylate)   PBS = phosphate buffered saline   PDLLA = poly(D,L-lactide)   PEVA = poly(ethylene-co-vinyl acetate)   rhTGF-ß1 = recombinant human transforming growth factor ß1   VEGF = vascular endothelial growth factor   VSMC = vascular smooth muscle cells

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