Novel Nitric Oxide (NO)-Releasing Polymers and their Biomedical Applications.

Two common factors that can cause complications with indwelling biomedical devices are thrombus and infection. Nitric oxide (NO) is known to be a potent inhibitor of platelet activation and an antimicrobial agent. In this dissertation work, two novel approaches to achieving long-term NO release from polymers were studied and evaluated for their potential biomedical applications. First, S-nitroso-N-acetypenicillamine (SNAP)-doped Elast-eon E2As creates an inexpensive polymer that can locally deliver physiologically relevant levels of NO. SNAP was found to be stable in E2As during shelf-life stability and ethylene oxide sterilization studies. The SNAP/E2As polymer was coated on the inner walls of extracorporeal circulation (ECC) circuits and was found to preserve the platelet count at ~100% of baseline and reduce thrombus area after 4 h blood flow in a rabbit model. The SNAP/E2As polymer was also used to fabricate NO-releasing catheters that were implanted in sheep veins for 7 d. The SNAP/E2As catheters significantly reduced the amount of thrombus and bacterial adhesion. In the second approach, the NO release from diazeniumdiolated dibutylhexanediamine (DBHD/N2O2)-doped polymers was significantly improved using poly(lactic-co-glycolic acid) (PLGA) additives. Acid-capped PLGA additives were found to cause high initial bursts of NO, while ester-capped PLGA additives extended the NO release for up to 14 d. Poly(vinyl chloride)- and Elast-eon E2As were used as the base polymers for combined DBHD/N2O2 and PLGA coatings on the inner walls of ECC circuits. After 4 h of blood flow, the E2As-based NOrel circuits preserved platelets at a higher level than PVC-based NOrel circuits (97% and 80% of baseline, respectively). This demonstrates that the inherent hemocompatibility properties of the base polymer can also influence the efficiency of the NO release coatings. A DBHD/N2O2-doped SG-80A polymer material was also studied and used to fabricate patches that were applied to scald burn wounds 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. The results for both of types of NO-releasing polymers studied here demonstrated greatly enhanced hemocompatibility properties that can be applied to a wide variety of blood-contacting medical devices.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/109037/1/brisbel_1.pd

Hemocompatibility Comparison of Biomedical Grade Polymers Using Rabbit Thrombogenicity Model for Preparing Nonthrombogenic Nitric Oxide Releasing Surfaces

Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion/ activation. Nitric oxide releasing (NOrel) materials can be prepared by doping an NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2), within a polymer coating. The inherent hemocompatibility properties of the base polymer can also influence the efficiency of such NO release coatings. In this study, four biomedical grade polymers were evaluated in a 4 h rabbit model of thrombogenicity for their effects on extracorporeal circuit thrombus formation and circulating platelet count. At the end of 4 h, Elast-Eon E2As was found to preserve 58% of baseline platelets versus 48, 40, and 47% for PVC/DOS, Tecophilic SP-60D-60, and Tecoflex SG80A, respectively. Elast-Eon also had significantly lower clot area of 5.2 cm2 compared to 6.7, 6.1, and 6.9 cm2 for PVC/DOS, SP-60D-60, and SG80A, respectively. Based on the results obtained for the base polymer comparison study, DBHD/N2O2-doped E2As was evaluated in short-term (4 h) rabbit studies to observe the NO effects on prevention of clotting and preservation of platelet function. Platelet preservation for this optimal NO release formulation was 97% of baseline after 4 h, and clot area was 0.9 cm2 compared to 5.2 cm2 for controls, demonstrating that combining E2As with NO release provides a truly advanced hemocompatible polymer coating for extracorporeal circuits and potentially other blood contacting applications

In Vitro and in Vivo Study of Sustained Nitric Oxide Release Coating Using Diazeniumdiolate-doped Poly(vinyl chloride) Matrix with Poly(lactide-co-glycolide) Additive

Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion and activation that can be released from a NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) within a polymer coating. In this study, various Food and Drug Administration approved poly(lactic-co-glycolic acid) (PLGA) species were evaluated as additives to promote a prolonged NO release from DBHD/N2O2 within a plasticized poly(vinyl chloride) (PVC) matrix. When using an ester-capped PLGA additive with a slow hydrolysis time, the resulting coatings continuously release between 7 and 18 × 10−10 mol cm−2 min−1 NO for 14 days at 37 °C in PBS buffer. The corresponding pH changes within the polymer films were visualized using pH sensitive indicators and are shown to correlate with the extended NO release pattern. The optimal combined diazeniumdiolate/PLGA-doped NO release (NOrel) PVC coating was evaluated in vitro and its effect on the hemodynamics was also studied within a 4 h in vivo extracorporeal circulation (ECC) rabbit model of thrombogenicity. Four out of 7 control circuits clotted within 3 h, whereas all the NOrel coated circuits were patent after 4 h. Platelet counts on the NOrel ECC were preserved (79 ± 11% compared to 54 ± 6% controls). The NOrel coatings showed a significant decrease in the thrombus area as compared to the controls. Results suggest that by using ester-capped PLGAs as additives to a conventional plasticized PVC material containing lipophilic diazeniumdiolates, the NO release can be prolonged for up to 2 weeks by controlling the pH within the organic phase of the coating

The Ktunaxa Interactive Language Adventure: Interactive fiction and story-based games for community language engagement

This presentation addresses the benefits (and challenges) of developing a story-based language learning adventure as a community project, an approach that might be attractive for language communities who aim to engage youths and self-driven learners with their language in a casual way, as players and as game designers

Attenuation Of Thrombin-Mediated Fibrin Formation: Via Changes In Fibrinogen Conformation Induced By Reaction With S -Nitroso- N -Acetylpenicillamine, But Not S -Nitrosoglutathione

Previous work using a 4 h rabbit thrombogenicity model has shown that a nitric oxide (NO)-generating polymer extracorporeal circuit (ECC) with infusion of S-nitroso-N-acetyl-penicillamine (SNAP) preserved platelets even though platelets were activated, as shown by an increase in the glycoprotein p-selectin. The platelet preservation mechanism was shown to be due to a changing fibrinogen structure leading to attenuation of platelet aggregation. To understand the effects that SNAP, another RSNO, S-nitroso-glutathione (GSNO), as well as the non-RSNO, sodium nitroprusside (SNP), may have on human fibrinogen polymerization, this in vitro study evaluated the effects of released NO on thrombin-mediated fibrin formation and fibrinogen structure. Thrombin-induced fibrin formation at 300 μM SNAP (50 + 11% of baseline) was significantly reduced compared to SNAP\u27s parent, N-acetyl-penicillamine (NAP), (95 ± 13%) after 1 h of RSNO exposure. GSNO, its parent, glutathione (GSH), and 1000 ppm NO gas did not attenuate the thrombin-mediated fibrin formation. SNAP, NAP and SNP exposure for 1 h, however, did not decrease thrombin activity by directly inhibiting thrombin itself. Changes in fibrinogen conformation as measured by intrinsic tryptophan fluorescence significantly decreased in the 300 μM SNAP (38:057 ± 1196 mean fluorescence intensity (MFI)) and SNP (368:617 ± 541 MFI) groups versus the NAP control (47:937 ± 1196 MFI). However, infused 1000 ppm NO gas had no direct effect on the ITF after 1 h of incubation at 37 °C. High performance liquid chromatography (HPLC) showed that fibrinogen degradation by 0.03 U ml-1 thrombin was concentration-dependently reduced after 1 h with SNAP but not with NAP or SNP. Western blotting analysis was done on the RSNOs, SNAP and NAP, and the non-RSNO, SNP, incubated fibrinogen solutions and the results showed that the percent level of the Aγ dimer with respect to total Aγ dimer + γ monomer was significantly reduced in the case of the SNAP group when compared to the SNP group. These results suggest that NO donors such as SNAP and SNP induce fibrinogen conformational changes by potentially nitrosating fibrinogen tyrosine residues. These NO-mediated fibrinogen changes induced via NO donors may provide another mechanism of NO for improving thromboresistance in ECCs

The immobilization of a direct thrombin inhibitor to a polyurethane as a nonthrombogenic surface coating for extracorporeal circulation

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