Poly(diol-co-citrate)s as novel elastomeric perivascular wraps for the reduction of neointimal hyperplasia

Abstract

The synthesis of poly(diol-co-citrate) elastomers that are biocompatible with vascular cells and can modulate the kinetics of the NO release based on the diol of selection is reported. NO-mediated cytostatic or cytotoxic effects can be controlled depending on the NO dose and the exposure time. When implanted in vivo in a rat carotid artery injury model, these materials demonstrate a significant reduction of neointimal hyperplasia. This is the first report of a NO-releasing polymer fabricated in the form of an elastomeric perivascular wrap for the treatment of neointimal hyperplasia. These elastomers also show promise for other cardiovascular pathologies where NO-based therapies could be beneficial.

Figure 1

Reaction scheme of the synthesis of NO-releasing poly(diol-co-citrate) elastomers.

Figure 2

FT-IR spectra of POCDA₁₀ (A,B) and PDDCDA₁₀ (C,D) elastomers. Pre-polymerized (A,C) and post-polymerized (B,D) materials are shown.

Figure 3

Representative release profile from POCDA₁₀-NO and PDDCDA₁₀-NO elastomers as assessed by Griess reaction.

Figure 4

Morphology of HUVEC and HASMC cultured on amine-containing poly(diol-co-citrate) elastomers. Scale bar: 25 μm.

Figure 5

Proliferation kinetics of HASMC cultured on amine-containing poly(diol-co-citrate) elastomers. Statistical significance: p < 0.05. Differences relative to control samples (*) and between polymers (#) at a similar time point.

Figure 6

Cumulative exposure to NO-releasing poly(diol-co-citrate) elastomers: Effects on HUVEC (A) and HASMC (B) proliferation. Statistical significance among doses: p < 0.05. Differences relative to control samples (*), to low doses (#), and to intermediate doses ($) at a similar time point.

Figure 7

Cumulative exposure to NO-releasing poly(diol-co-citrate) elastomers: Effects on HUVEC and HASMC viability after 48 h exposure to different NO fluxes. The total nitrite released was measured by Griess reaction as: low (0.4–0.7 μmol · cm⁻²), intermediate (3 μmol · cm⁻²) and high dose (7–11 μmol · cm⁻²). Scale bar: 25 μm.

Figure 8

Drawing of the common carotid artery (CCA), internal carotid artery (ICA), and external carotid artery (ECA), with blood flowing from the CCA to the ICA and ECA (first panel). The drawing depicts how the wraps were placed around the artery and secured with a tie. Also shown are photographs of the actual wraps that were placed and secured around the CCA at the time of surgery (second and third panels). Note the close proximity of the wrap to the adventitial surface of the artery. The last panel shows an intact wrap at harvest, 2 weeks following arterial injury and placement of the wrap.

Figure 9

(A) Representative histological haematoxylin and eosin stained sections of the injured carotid arteries with the different treatment groups 14 d after arterial injury (400 ×). Also shown is the morphometric analysis of the (B) intimal area, (C) intima-to-media area ratio, and (D) medial area. ^*p < 0.05 vs. injury (I) alone.