A new intra-arterial delivery platform for pro-arteriogenic compounds to stimulate collateral artery growth via transforming growth factor-beta1 release.
OBJECTIVE
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.
Grundmann
Sebastian
S
Department of Cardiology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
van Royen
Niels
N
Pasterkamp
Gerard
G
Gonzalez
Nieves
N
Tijsma
Edze J
EJ
Piek
Jan J
JJ
Hoefer
Imo E
IE
D020341:Absorbable Implants; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000503:physiopathology; D003097:Collateral Circulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011108:Polymers; D011817:Rabbits; D015607:Stents; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage* / Q000378:metabolism*; D016896:Treatment Outcome
D043925:Angiogenesis Inducing Agents; D011108:Polymers; D053773:Transforming Growth Factor beta1