Trans-iliac rat aorta stenting: a novel high throughput preclinical stent model for restenosis and thrombosis

Abstract

Background: Currently, preclinical stent development requires elaborate large animal models, which are time consuming and expensive. We herein report a high throughput rat aorta stenting model which could provide a rapid and low-cost platform for preclinical stent development.

Methods: A total of 86 metal stents (316L stainless steel 13 mm, VasoTech, Inc.) coated with poly (D, L-lactide-co-glycolide)/amorphous calcium phosphate (PLGA/ACP) copolymer were pre-mounted on 1.5 mm × 15 mm balloon catheters and were implanted into aspirin treated Sprague-Dawley rats (500-700 g) initially using either direct placement in the abdominal aorta (group A, n = 7) or a trans-iliac approach (cut-down, group B, n = 79). The surviving rats were sacrificed at 1, 2, 4, and 12 wk post-implantation and the stented arteries were analyzed histopathologically.

Results: Four rats died in group A and nine rats died in group B within 48 h post-stent implantation (mortality: 57% versus 11%, P < 0.05). All animals that died had stent thrombosis/paralysis with visible thrombus on necropsy. Histologically, neointimal growth peaked at approximately 4 wk post-implantation.

Conclusion: This result suggests that human-sized stents can be successfully implanted into the rat aorta via iliac artery insertion with a significantly higher survival rate than trans-aorta implantation. The model system allows rapid (4-12 wk) assessment of stent biocompatibility with mortality/paralysis used as an indicator of stent thrombosis.

Fig. 1

Animal mortality of two surgical methods: Trans-abdomial aorta (Group A, n = 7) and Trans-iliac artery (Group B, n = 79)

Fig. 2

Schematic pictures of A. Trans-abdominal aorta and B. Trans-iliac artery. Arrows indicate the aortic/arterial incisions.

Fig. 3

Operative photographs of rat abdominal aorta stenting through left iliac artery: A. The stent implanted in the rat aorta after surgery. B. The stent implanted in the rat aorta after 4 weeks. Arrows indicate the arterial incisions.

Fig. 4

In-stent restenosis at different time points. Please note all comparisons between each two groups were significant different (P<0.05) other than 1 week vs. 2 weeks (P>0.05) and 4 weeks vs. 12 weeks (P>0.05).

Fig. 5

The representative images of stents at different time points post rat aorta implantation. Upper panel: 4x; Lower panel: 20x of boxed area in upper panel. A: 1 week, B: 2 weeks, C: 4 weeks, D: 12weeks. Please note no significant change in neointimal thickness between 4weeks (C) and 12 weeks (D) post implantation (arrows in C and D, low panel, and the “healed” scar “tissue at 12 weeks (D, arrow, low panel).