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Significance Statement
A new device contains a form of vitamin A that controls inflammatory responses, preventing scar tissue formation and promoting wound healing. The soft, porous, and thin elastic material contains an acid form of vitamin A, called a retinoid. This material has potential application in open cardiovascular surgeries.
AJP: Heart and Circulatory Physiology, 2014; 307 (10): H1419.
Gregory EK1, Webb AR2, Vercammen JM1, Flynn ME1, Ameer GA3, Kibbe MR4.
1Division of Vascular Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois;
2Biomedical Engineering Department, McCormick School of Engineering, Northwestern University, Evanston, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois; VesselTek Biomedical, Chicago, Illinois; University of Florida, Gainesville, Florida.
3Biomedical Engineering Department, McCormick School of Engineering, Northwestern University, Evanston, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois;
4Division of Vascular Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois; [email protected].
ABSTRACT
Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within acitrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimalhyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POCmembranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 μg of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 μmol/l) inhibited [(3)H]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POCmembranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P < 0.003) in animals treated with atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P < 0.001). In conclusion, perivascular delivery of atRA inhibitedneointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit neointimal hyperplasia following open cardiovascular procedures.
Copyright © 2014 the American Physiological Society.
