Periluminal expression of a secreted transforming growth factor-ß type II receptor inhibits in-stent neointima formation following adenovirus-mediated stent-based intracoronary gene transfer.

Transforming growth factor-ß1 (TGF-ß1) has been shown unequivocally to enhance neointima formation in carotid and ileo-femoral arteries. In our previous studies, however, TGF-ß1 expression in coronary arteries actually reduced neointima formation without affecting luminal loss postangioplasty, while expression of a TGF-ß1 antagonist (RIIs) in balloon-injured coronary arteries reduced luminal loss without affecting neointima formation. These observed effects may be a consequence of the mode of coronary artery gene transfer employed, but they may also represent differences in the modes of healing of coronary, carotid, and ileo-femoral arteries after endoluminal injury. To help clarify whether a gene therapy strategy to antagonize TGF-ß might have application within the coronary vasculature, we have investigated the effect of high-level periluminal expression of RIIs using stent-based adenovirus-mediated intracoronary gene transfer. Porcine coronary arteries were randomized to receive a custom-made CoverStent preloaded with saline only, or with 1×10(9) infectious units of adenovirus expressing RIIs or ß-galactosidase (lacZ). Vessels were analyzed 28 days poststenting, at which time angiographic in-stent diameter was significantly greater in RIIs-treated arteries, and in-stent luminal loss significantly reduced. Computerized morphometric minimum in-stent lumen area was ~300% greater in RIIs-exposed vessels than in lacZ or saline-only groups. This was because of significantly reduced neointima formation in the RIIs group. RIIs had no demonstrable effect on cellular proliferation or apoptosis, but greater normalized neointimal/medial collagen content was observed in RIIs-exposed arteries. These data highlight the qualitatively similar effect of TGF-ß antagonism on neointima formation in injured coronary and noncoronary arteries, and suggest that since cellular proliferation is unaffected, TGF-ß1 antagonism might prevent in-stent restenosis without the delayed healing that is associated with drug-eluting stents in current clinical use.

Pilot study using doxycycline-releasing stents to ameliorate postoperative healing quality after sinus surgery.

Poor postoperative healing after sinus surgery is associated with high concentrations of matrix metalloproteinase-9 (MMP-9). The frontal recess is especially vulnerable to restenosis, and frontal sinus stents have been used to overcome this problem. However, the long-term success rate is still controversial and may be poor. In this perspective, we developed doxycycline (DC)-releasing stents, delivering the MMP-9 synthesis-suppressing agent locally to the frontal recess area. We evaluated postoperative MMP-9 levels, bacterial colonization, healing quality, and symptom scores in patients suffering from chronic rhinosinusitis with (CRSwNP) and without nasal polyposis (CRSsNP) (n=10) who underwent functional endoscopic sinus surgery during which the DC-releasing and placebo stents were placed. We found that MMP-9 concentrations were significantly lower at the side of the DC-releasing stent (3,414+/-582 ng/mL) compared with the contralateral placebo stent (9,172+/-2,564 ng/mL) (p<0.05) at month 3 postsurgery. DC stents adequately suppressed bacterial growth compared with placebo stents. Furthermore, the visual analog scale (VAS) for the frontal region was significantly better (mean value 75.1 vs. 52.8, p<0.001) compared with its placebo counterpart. We conclude that compared with placebo stents, DC-releasing stents significantly lowered MMP-9 concentrations and bacterial colonization locally, and improved postoperative healing quality after functional endoscopic sinus surgery, as demonstrated by visual analog scale and ostial closure.

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

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.