Localized delivery of nitric oxide from hydrogels inhibits neointima formation in a rat carotid balloon injury model.
Using novel nitric oxide (NO)-generating polymeric hydrogels that can be rapidly photopolymerized in situ, we can deliver NO locally at the site of vascular injury. Depending on material design, these poly(ethylene glycol) (PEG)-based hydrogels can generate NO for up to 50 d. This study demonstrates the ability of nitric oxide-generating hydrogels (PEG-Cys-NO) to influence key components of the restenosis cascade both in vitro and in vivo. PEG-Cys-NO hydrogels inhibited smooth muscle cell proliferation, increased endothelial cell proliferation, and inhibited platelet adhesion in vitro. Moreover, in vivo, PEG-Cys-NO hydrogels inhibited intimal thickening in a rat carotid balloon injury model. The perivascular application of NO-generating polymers post-injury reduced neointima formation at 14 d by approximately 80% compared to controls (intimal area/medial area (I/M): PEG-Cys-NO=0.20+/-0.17, control=0.84+/-0.19, p<0.00002; intimal thickness: PEG-Cys-NO=12+/-10 microm, control=60+/-18 microm, p<0.00002). Treatment with the PEG-Cys-NO hydrogels caused a significant decrease in the per cent of proliferating cell nuclear antigen positive medial cells (29+/-5%) at 4 d as compared to treatment with the control hydrogels (51+/-1%, p<0.02). Additionally, vessel re-endothelialization at 14 d was slightly enhanced in the presence of the NO-generating hydrogels. These data indicate that localized delivery of NO from these hydrogels can significantly inhibit neointima formation in a rat carotid balloon injury model and suggest that these materials may be useful in preventing restenosis.
Lipke
Elizabeth A
EA
Department of Chemical Engineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.
West
Jennifer L
JL
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D002340:Carotid Artery Diseases / Q000150:complications / Q000188:drug therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020100:Hydrogels / Q000737:chemistry; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D016896:Treatment Outcome; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology*
D001672:Biocompatible Materials; D020100:Hydrogels; D009569:Nitric Oxide