Journal
BIOMATERIALS
Volume 25, Issue 2, Pages 283-293Publisher
ELSEVIER SCI LTD
DOI: 10.1016/S0142-9612(03)00530-1
Keywords
nitric oxide; catalytic nitrite reduction; lipophilic Cu(II)-complex; nitrite ion pair; biocompatible polymers
Funding
- NIBIB NIH HHS [EB 00783] Funding Source: Medline
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R01EB000783] Funding Source: NIH RePORTER
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A novel approach potentially useful for the development of more thromboresistant polymeric materials is examined. The method is based on the catalytic generation of nitric oxide (NO) via Cu(I) mediated reduction of nitrite ions. Preliminary solution phase studies demonstrate that ascorbate or thiolate anions can generate Cu(I) from Cu(II) with subsequent catalytic conversion of any nitrite ions present to NO by the unstable Cu(I) species. Incorporation of this same chemistry within a hydrophobic polymeric material requires immobilizing Cu(II) ions into a polymeric phase via use of a lipophilic Cu(II) chelating ligand (dibenzo [e,k]2,3,8,9-tetraphenyl-1,4,7,10-tetraaza-cyclododeca-1,3,7,9-tetraene (DTTCT)). It is shown that this complex can be reduced to its Cu(I) form by appropriate reducing equivalents present in the bathing solution. The resulting Cu(I) complex can then reduce nitrite to NO with the NO generation occurring at the polymer/solution interface at physiological pH. Data from chemiluminescence experiments indicate that the flux of NO at the polymer surface is comparable to that of endothelial cells (greater than or equal to 1 x 10(-10) mol/cm(2) min) when 0.5 mm nitrite/l mm ascorbate are present in the bathing solution. Potentially more useful NO generation can be achieved by doping the polymer film with the Cu(II) complex along with a lipophilic quaternary ammonium nitrite salt. In this case reducing equivalents within the aqueous phase enable the nitrite derived from the polymer to be converted into NO by the Cu(II/I) ligand complex. Films of this type are shown to generate NO for at least 6 h in PBS buffer with fluxes on the order of 1.5 x 10(-10) mol/cm(2) min. Physiologically relevant levels of NO release are also shown to exist at the polymer interface when films are soaked in fresh plasma as well as undiluted whole blood, indicating that endogenous reducing equivalents present in blood can efficiently reduce the Cu(II)-ligand within the polymer film. The prospects of using these new NO releasing films to devise more biocompatible polymeric coatings for biomedical applications are discussed. (C) 2003 Elsevier Ltd. All rights reserved.
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