Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats

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 a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia 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-POC membranes 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-POC membranes 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 inhibited neointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit neointimal hyperplasia following open cardiovascular procedures.

A polymer–extracellular matrix composite with improved thromboresistance and recellularization properties

“…[29] Therefore, the use of POC on the ECM of decellularized tissues or organs could potentially decrease inflammatory responses in vivo by masking any residual antigen and/or attenuate oxidative stress in tissues.…”

Citrate-Based Biomaterials and Their Applications in Regenerative Engineering

“…In addition to NO, all- trans retinoic acid has been loaded into POC perivascular membranes to prevent neointimal hyperplasia following arterial injury. Histomorphometry analysis showed that all- trans retinoic acid–POC membranes inhibit neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, I/M area ratio, and percent stenosis, respectively (72). …”

Biodegradable Elastomers with Antioxidant and Retinoid-like Properties

“…18–20 Our lab has reported cell proliferation effects of atRA consistent with antioxidant properties at micromolar concentrations. 19 Reported inconsistencies could partially be explained by cell-specific effects. For example, reports of micromolar pro-oxidant effects of atRA were measured in Sertoli cells, cells that are known to have macrophage-type effects and therefore may be more prone to rapid ROS generation as part of their phenotypical tendencies.…”