E. K. Gregory4, A. R. Webb2,3, J. M. Vercammen4, M. E. Flynn4, W. Jiang4, R. van Lith2, G. A. Ameer2,4, M. R. Kibbe4 2Northwestern University,Biomedical Engineering/ McCormickSchool Of Engineering,Chicago, IL, USA 3University Of Florida,Department Of Materials And Science Engineering,Gainesville, FL, USA 4Feinberg School Of Medicine – Northwestern University,Surgery/ Vascular,Chicago, IL, USA
Introduction: The poor performance of expanded polytetrafluoroethylene (ePTFE) vascular grafts demonstrates the need for alternative prosthetic graft materials. All-trans retinoic acid (atRA) has many beneficial effects on the vasculature, including inhibition of proliferation. We previously demonstrated that localized delivery of atRA through a poly (1,8) octamethylene citrate (POC) periadventitial membrane significantly reduced neointimal hyperplasia after carotid balloon injury in rats. The objective of this study was to develop an atRA-POC coated ePTFE graft and evaluate the biocompatibility and efficacy of this graft in the vasculature. We hypothesize that atRA-POC ePTFE grafts will be biocompatible and inhibit intimal formation after aortic interposition grafting in rats as compared to standard ePTFE grafts.
Methods: To evaluate biocompatibility ex vivo, compliance was evaluated via compression testing, platelet aggregation was evaluated using plasma from Sprague Dawley rats (n=3), and complement activation was assessed using human serum (n=3). To establish efficacy and biocompatibility in vivo, an aortic interposition bypass was performed on 12-week-old Sprague Dawley rats. Treatment groups included ePTFE (n=6), POC ePTFE (n=7), atRA ePTFE (n=6) and atRA-POC ePTFE (n=6). At 28 days the grafts with 1 cm of native aorta and blood were collected. Morphometric analysis was performed on H&E stained cross sections using ImageJ software. Analysis was performed on collected blood samples to evaluate renal and liver function.
Results: All 3 grafts (POC, atRA, and atRA-POC) ePTFE exhibited similar compliance as compared to standard ePTFE grafts. There were no differences in platelet aggregation or complement activation between the treatment groups. Rats who received the atRA-POC ePTFE grafts were found to have 40% less intimal formation at the proximal graft anastomosis and 56% less intimal formation at the distal graft anastomosis compared to control ePTFE grafts (P<0.03). atRA ePTFE grafts resulted in a 53% decrease in intimal formation at the distal graft anastomosis compared to ePTFE control (P< 0.01); however, atRA ePTFE grafts did not reduce intimal formation at the proximal graft anastomosis. There were no clinically significant differences in the liver function tests and renal chemistries between treatment groups.
Conclusion: atRA-POC ePTFE grafts resulted in less intimal formation at both the proximal and distal graft anastomoses compared to ePTFE grafts. Assessment of biocompatibility revealed no alteration of graft compliance, platelet aggregation, complement activation, or hepatic or renal toxicity. This novel drug-eluting prosthetic vascular graft has great potential to impact prosthetic graft patency rates. Further study in a large animal model is warranted.