Perivenous Application of Fibrin Glue as External Support Enhanced Adventitial Adenovirus Transfection in Rabbit Model

Abstract

Placement of an external support has been reported to prevent intimal hyperplasia of vein grafts. However, it's application limited by potential complications. Peri-adventitial gene delivery is a promising alternative therapy to reduce intimal hyperplasia, but it is limited by low and transient levels of gene transfection. To get more effective inhibition of intimal hyperplasia and to avoid the limitations associated with these two approaches, a study was undertaken to investigate whether mixing adenovirus with fibrin glue may increase the level and prolong the time period of gene expression. Right jugular vein to common carotid artery interposition grafting was performed in 36 male New Zealand white rabbits (2.5-3.0 kg) and the animals were divided into four groups: control group (n = 6); fibrin glue group (n = 6); Ad-GAL group (n = 12); fibrin glue/Ad-GAL group (n = 12). Commercially available fibrin glue and adenovirus expressing the gene for beta-galactosidase (Ad-GAL) was applied separately or in mixing around vein grafts. At 7th day and 14th day after implantation, the grafts were harvested to evaluate transfection rate. At 28th day the grafts were harvested for morphometric analysis. Compared with weak staining in 2.1 +/- 0.5% in Ad-GAL alone grafts, a high level of beta-Galactosidase staining was evident in 13.2 +/- 4.6% in fibrin glue/Ad-GAL grafts at 7th day (P < 0.001). At 14th day, almost no staining (0%) was detected in Ad-GAL alone grafts. However, there was still a relative high level staining (6.3 +/- 3.8%) in fibrin glue/Ad-GAL grafts (P < 0.001 versus Ad-GAL alone group). At 28th day, a statistically significantly decrease in neointimal area (0.68 +/- 0.06 mm(2)versus 1.00 +/- 0.08 mm(2), P < 0.05) was shown in fibrin glue grafts compared with unsupported vein grafts (control group). The same statistically significantly difference was also existed in fibrin glue/Ad-GAL group and unsupported group in neointimal area (0.66 +/- 0.07 mm(2), P < 0.05). A novel method of adventitial gene delivery using fibrin glue as external support is proposed. Fibrin glue may be an ideal candidate for controlled release delivery that would facilitate adventitial gene transfer.