Hemocompatibility comparison of biomedical grade polymers using rabbit thrombogenicity model for preparing nonthrombogenic nitric oxide releasing surfaces

Handa, Hitesh; Major, Terry C.; Brisbois, Elizabeth J.; Amoako, Kagya A.; Meyerhoff, Mark E.; Bartlett, Robert H.

doi:10.1039/c3tb21771j

Cited by 60 publications

(83 citation statements)

References 23 publications

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“…The NORel/E2As polymer was shown to have a maximum NO release level of approx. 6 × 10 −10 mol cm −2 min −1 which was comparable to NO flux reported previously from our laboratory [33]. Interestingly, the NO flux was not adversely affected by the top coating of the argatroban-immobilized polymer (6 × 10 −10 before top coat and 6.5 × 10 −10 mol cm −2 min −1 after top coat).…”

Section: Discussionsupporting

confidence: 84%

The effect of a polyurethane coating incorporating both a thrombin inhibitor and nitric oxide on hemocompatibility in extracorporeal circulation

et al. 2014

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Nitric oxide (NO) releasing (NORel) materials have been extensively investigated to create localized increases in NO concentration by the proton driven diazeniumdiolate-containing polymer coatings and demonstrated to improve extracorporeal circulation (ECC) hemocompatibility. In this work, the NORel polymeric coating composed of a diazeniumdiolated dibutylhexanediamine (DBHD-N2O2)-containing hydrophobic Elast-eon™ (E2As) polyurethane was combined with a direct thrombin inhibitor, argatroban (AG), and evaluated in a 4 h rabbit thrombogenicity model without systemic anticoagulation. In addition, the immobilizing of argatroban to E2As polymer was achieved by either a polyethylene glycol-containing (PEGDI) or hexane methylene (HMDI) diisocyanate linker. The combined polymer film was coated on the inner walls of ECC circuits to yield significantly reduced ECC thrombus formation compared to argatroban alone ECC control after 4 h blood exposure (0.6 ± 0.1 AG/HMDI/NORel vs 1.7 ± 0.2 cm2 AG/HMDI control). Platelet count (2.8 ± 0.3 AG/HMDI/NORel vs 1.9 ± 0.1 × 108/ml AG/HMDI control) and plasma fibrinogen levels were preserved after 4 h blood exposure with both the NORel/argatroban combination and the AG/HMDI control group compared to baseline. Platelet function as measured by aggregometry remained near normal in both the AG/HMDI/NORel (63 ± 5%) and AG/HMDI control (58 ± 7%) groups after 3 h compared to baseline (77 ± 1%). Platelet P-selectin mean fluorescence intensity (MFI) as measured by flow cytometry also remained near baseline levels after 4 h on ECC to ex vivo collagen stimulation (16 ± 3 AG/HMDI/NORel vs 11 ± 2 MFI baseline). These results suggest that the combined AG/HMDI/NORel polymer coating preserves platelets in blood exposure to ECCs to a better degree than AG/PEGDI/NORel, NORel alone or AG alone. These combined antithrombin, NO-mediated antiplatelet effects were shown to improve thromboresistance of the AG/HMDI/NORel polymer-coated ECCs and move potential nonthrombogenic polymers closer to mimicking vascular endothelium.

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Section: Discussionsupporting

confidence: 84%

The effect of a polyurethane coating incorporating both a thrombin inhibitor and nitric oxide on hemocompatibility in extracorporeal circulation

et al. 2014

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“…24,[27][28][29] NO-releasing polymers have been shown to preserve platelet count and reduced thrombus formation when tested in a 4 h rabbit model of extracorporeal circulation (ECC) thrombogenicity. [30][31][32][33][34] I-nitrosothiol-modified xerogels were shown to significantly reduce adhesion of platelets and bacteria (Pseudomonas aeruginosa) when tested in vitro. 35,36 Diazeniomdiolate-doped poly(lactic-co-glycolic acid)-based films exhibited antibiofilm properties against both gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacteria when tested using a drip-flow bioreactor over a 7 d period.…”

Section: Introductionmentioning

confidence: 99%

Reduction in thrombosis and bacterial adhesion with 7 day implantation of S-nitroso-N-acetylpenicillamine (SNAP)-doped Elast-eon E2As catheters in sheep

et al. 2015

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Thrombosis and infection are two common problems associated with blood-contacting medical devices such as catheters. Nitric oxide (NO) is known to be a potent antimicrobial agent as well as an inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5~4×10 −10 mol cm −2 min −1 that helps prevent thrombosis. Materials with a NO flux that is equivalent to this level are expected to exhibit similar anti-thrombotic properties. In this study, NO-releasing catheters were fabricated by incorporating S-nitroso-N-acetylpenicillamine (SNAP) in the Elast-eon E2As polymer. The SNAP/E2As catheters release physiological levels of NO for up to 20 d, as measured by chemiluminescence. Furthermore, SNAP is stable in the E2As polymer, retaining 89% of the initial SNAP after ethylene oxide (EO) sterilization. The SNAP/E2As and E2As control catheters were implanted in sheep veins for 7 d to examine the effect on thrombosis and bacterial adhesion. The SNAP/E2As catheters reduced the thrombus area when compared to the control (1.56 ± 0.76 and 5.06 ± 1.44 cm 2 , respectively). A 90% reduction in bacterial adhesion was also observed for the SNAP/E2As catheters as compared to the controls. The results suggest that the SNAP/E2As polymer has the potential to improve the hemocompatibility and bactericidal activity of intravascular catheters, as well as other blood-contacting medical devices (e.g., vascular grafts, extracorporeal circuits).

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“…However, the loss of NO from DBHD/N 2 O 2 creates free lipophilic amine species within the polymer that react with water, thereby increasing the pH within the polymer phase and effectively turning off the NO release. In a recent report, poly(lactic-co-glycolic) acid was used as an additive to promote and prolong the NO release from poly(vinyl chloride) films doped with DBHD/N 2 O 2 [49, 50]. The ester linkages of the PLGA will hydrolyze in the presence of water, producing lactic and glycolic acids that can act as proton sources to promote the NO release from DBHD/N 2 O 2 -doped polymers.…”

Section: Introductionmentioning

confidence: 99%

Optimized polymeric film-based nitric oxide delivery inhibits bacterial growth in a mouse burn wound model

Brisbois

Bayliss

et al. 2014

Acta Biomaterialia

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Nitric oxide (NO) has many biological roles (e.g., antimicrobial agent, promoter of angiogenesis, prevention of platelet activation, etc.) that make NO releasing materials desirable for a variety of biomedical applications. Localized NO release can be achieved from biomedical grade polymers doped with diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) and poly(lactic-co-glycolic acid) (PLGA). In this study, the optimization of this chemistry to create film/patches that can be used to decrease microbial infection at wound sites is examined. Two polyurethanes with different water uptakes (Tecoflex SG-80A (6.2 ± 0.7 wt %) and Tecophillic SP-60D-20 (22.5 ± 1.1 wt%)) were doped with 25 wt% DBHD/N2O2 and 10 wt% of PLGA with various hydrolysis rates. Films prepared with the polymer that has the higher water uptake (SP-60D-20) were found to have higher NO release and for a longer duration than the polyurethane with lower water uptake (SG-80A). The more hydrophilic polymer enhances the hydrolysis rate of the PLGA additive, thereby providing a more acidic environment that increases the rate of NO release from the NO donor. The optimal NO releasing and control SG-80A patches were then applied to scald burn wounds that were infected with Acinetobacter baumannii. The NO released from these patches applied to the wounds is shown to significantly reduce the A. baumannii infection after 24 h (~4 log reduction). The NO release patches are also able to reduce the TGF-β levels, in comparison to controls, which can enhance reepithelialization, decrease scarring, and reduce migration of bacteria. The combined DBHD/N2O2 and PLGA-doped polymer patches, which could be replaced periodically throughout the wound healing process, demonstrate the potential to reduce risk of bacterial infection and promote the overall wound healing process.

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Hemocompatibility comparison of biomedical grade polymers using rabbit thrombogenicity model for preparing nonthrombogenic nitric oxide releasing surfaces

Cited by 60 publications

References 23 publications

The effect of a polyurethane coating incorporating both a thrombin inhibitor and nitric oxide on hemocompatibility in extracorporeal circulation

The effect of a polyurethane coating incorporating both a thrombin inhibitor and nitric oxide on hemocompatibility in extracorporeal circulation

Reduction in thrombosis and bacterial adhesion with 7 day implantation of S-nitroso-N-acetylpenicillamine (SNAP)-doped Elast-eon E2As catheters in sheep

Optimized polymeric film-based nitric oxide delivery inhibits bacterial growth in a mouse burn wound model

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