In this study, in situ–forming quercetin-conjugated heparin hydrogels to be used to coat metal surfaces for blood compatibility were developed and characterized. Four units of quercetin and poly(ethylene glycol)–tyramine were conjugated per heparin for blood compatibility and hydrogel formation, respectively. The product, quercetin-conjugated heparin–poly(ethylene glycol)–tyramine, was cross-linked in situ via an enzymatic reaction using horseradish peroxidase and hydrogen peroxide to form a hydrogel. The physicochemical properties, such as the gelation time and swelling/degradation time as well as the release kinetics of quercetin, were controlled by changing the catalytic concentrations. The quercetin-conjugated heparin hydrogel, when adhered to a metal surface, enhanced blood compatibility and reduced platelet adhesion by 77%. The release of quercetin inhibited the proliferation of smooth muscle cells. The quercetin-conjugated heparin–poly(ethylene glycol)–tyramine hydrogel is a promising biomaterial with a stable-coated metal surface, with enhanced blood compatibility and antiproliferation effects.
WeltFGRogersC. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol2002; 22: 1769–1776.
2.
IndolfiLCausaFNettiPA. Coating process and early stage adhesion evaluation of poly(2-hydroxy-ethyl-methacrylate) hydrogel coating of 316L steel surface for stent applications. J Mater Sci Mater Med2009; 20: 1541–1551.
3.
ChenYKZhengXBLiBO. In vitro bioactivity, cytotoxicity and blood compatibility of anti-bacterial vacuum plasma sprayed titanium coatings. Mater Sci Forum2010; 658: 511–514.
4.
HuangYVenkatramanSSBoeyFY. In vitro and in vivo performance of a dual drug-eluting stent (DDES). Biomaterials2010; 31: 4382–4391.
5.
KazmierskaKACiachT. Bioactive coatings for minimally invasive medical devices: surface modification in the service of medicine. Recent Pat Biomed Eng2009; 2: 1–14.
6.
SilvestriDCristalliniCGagliardiM. Acrylic copolymers as candidates for drug-eluting coating of vascular stents. J Biomater Appl2009; 24: 353–383.
7.
AksoyEAHasirciVHasirciN. Plasma protein adsorption and platelet adhesion on heparin-immobilized polyurethane films. J Bioact Compat Polym2008; 23: 505–519.
8.
GodaTKonnoTTakaiM. Photoinduced phospholipid polymer grafting on parylene film: advanced lubrication and antibiofouling properties. Colloid Surf B Biointerfaces2007; 54: 67–73.
9.
BayramCMizrakAKAkturkS. In vitro biocompatibility of plasma-aided surface-modified 316L stainless steel for intracoronary stents. Biomed Mater2010; 5: 055007.
10.
ChoiJKonnoTTakaiM. Controlled drug release from multilayered phospholipid polymer hydrogel on titanium alloy surface. Biomaterials2009; 30: 5201–5208.
LipkeEAWestJL. Localized delivery of nitric oxide from hydrogels inhibits neointima formation in a rat carotid balloon injury model. Acta Biomater2005; 1: 597–606.
13.
GrechJMRManoJFReisRL. Chitosan beads as templates for layer-by-layer assembly and their application in the sustained release of bioactive agents. J Bioact Compat Polym2008; 23: 367–380.
14.
ClarkTWJacobsDCharlesHW. Comparison of heparin-coated and conventional split-tip hemodialysis catheters. Cardiovasc Intertvent Radiol2009; 32: 703–706.
15.
MehranRAymongEDAshbyDT. Safety of an aspirin-alone regimen after intracoronary stenting with a heparin-coated stent: final results of the HOPE (HEPACOAT and an antithrombotic regimen of aspirin alone) study. Circulation2003; 103: 1078–1083.
16.
LeeYKParkJHMoonHT. The short-term effects on restenosis and thrombosis of echinomycin-eluting stents topcoated with a hydrophobic heparin-containing polymer. Biomaterials2007; 28: 1523–1530.
17.
ErlundI. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr Res2004; 24: 851–874.
18.
HayekTFuhrmanBVayaJ. Reduced progression of atherosclerosis in apolipoprotein E-deficient mice following consumption of red wine, or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation. Arterioscler Thromb Vasc Biol1997; 17: 2744–2752.
19.
FormicaJVRegelsonW. Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol1995; 33: 1061–1080.
20.
GuerreroJALozanoMLCartilloJ. Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor. J Thromb Haemost2005; 3: 369–376.
21.
FanPSGuZLLiangZQ. Effect of quercetin on adhesion of platelets to microvascular endothelial cells in vitro. Acta Pharmacol Sin2001; 22: 857–860.
22.
AlcocerFWhitleyDSalazar-GonzalezJF. Quercetin inhibits human vascular smooth muscle cell proliferation and migration. Surgery2002; 131: 198–204.
23.
MoonSKChoGCJungSY. Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metalloproteinase-9. Biochem Biophys Res Commun2003; 301: 1069–1078.
24.
DugasTRKhandelwalAKleinedlerJJ. Manufacture of benzylated acid violet. US Patent 331965, 2010.
25.
GuglerRLeschikMDenglerHJ. Disposition of quercetin in man after single oral and intravenous doses. Eur J Clin Pharmacol1975; 9: 229–234.
26.
TranNQJoungYKLihE. Supramolecular hydrogels exhibiting fast in situ gel forming and adjustable degradation properties. Biomacromolecules2010; 11: 617–625.
27.
VreelandVWaiteJHEpsteinL. Thermal gelation and tissue adhesion of biomimetic hydrogels. J Phycol1998; 34: 1–8.
28.
BurkeSARitter-JonesMLeeBP. Thermal gelation and tissue adhesion of biomimetic hydrogels. Biomed Mater2007; 2: 203–210.
29.
PeshkovaSLiK. Investigation of chitosan-phenolics systems as wood adhesives. J Biotechnol2003; 102: 199–207.
30.
BootsAWKubbenNHaenenGRMM. Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation. Biochem Biophy Res Commun2003; 308: 560–565.
31.
LihEJoungYKBaeJW. An in situ gel-forming heparin-conjugated PLGA-PEG-PLGA copolymer. J Bioact Compat Polym2008; 23: 444–457.
32.
ParkKLeeGYKimYS. Heparin-deoxycholic acid chemical conjugate as an anticancer drug carrier and its antitumor activity. J Control Release2006; 114: 300–306.
ParkKKimKKwonIC. Preparation and characterization of self-assembled nanoparticles of heparin-deoxycholic acid conjugates. Langmuir2004; 20: 11726–11731.
35.
Van der VeenMStuartMCNordeW. Spreading of proteins and its effect on adsorption and desorption kinetics. Colloid Surf B Biointerfaces2007; 54: 136–142.
