Achieving Long-Term Biocompatible Silicone via Covalently Immobilized S-Nitroso- N-acetylpenicillamine (SNAP) That Exhibits 4 Months of Sustained Nitric Oxide Release - PubMed (original) (raw)

Achieving Long-Term Biocompatible Silicone via Covalently Immobilized S-Nitroso- N-acetylpenicillamine (SNAP) That Exhibits 4 Months of Sustained Nitric Oxide Release

Sean P Hopkins et al. ACS Appl Mater Interfaces. 2018.

Abstract

Ever since the role of endogenous nitric oxide (NO) in controlling a wide variety of biological functions was discovered approximately three decades back, multiple NO-releasing polymeric materials have been developed. However, most of these materials are typically short lived due to the inefficient incorporation of the NO donor molecules within the polymer matrix. In the present study, S-nitroso- N-acetyl penicillamine (SNAP) is covalently attached to poly(dimethylsiloxane) (PDMS) to create a highly stable nitric oxide (NO) releasing material for biomedical applications. By tethering SNAP to the cross-linker of PDMS, the NO donor is unable to leach into the surrounding environment. This is the first time that a sustainable NO release and bacterial inhibition for over 125 days has been achieved by any NO-releasing polymer with supporting evidence of potential long-term hemocompatibility and biocompatibility. The material proves to have very high antibacterial efficacy against Staphylococcus aureus by demonstrating a 99.99% reduction in the first 3 days in a continuous flow CDC bioreactor, whereas a similar inhibitory potential of 99.50% was maintained by the end of 1 month. Hemocompatibility of SNAP-PDMS was tested using a rabbit extracorporeal circuit (ECC) model over a 4 h period. Thrombus formation was greatly reduced within the SNAP-PDMS-coated ECCs compared to the control circuits, observing a 78% reduction in overall thrombus mass accumulation. These results demonstrate the potential of utilizing this material for blood and tissue contacting biomedical devices in long-term clinical applications where infection and unwanted clotting are major issues.

Keywords: S-nitroso-N-acetyl penicillamine; antimicrobial; bioreactor; extracorporeal circulation; hemocompatibility; nitric oxide.

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Figures

Figure 1.

Figure 1.

Synthesis route for covalently binding the SNAP molecule to hydroxy terminated PDMS polymer.

Figure 2.

Figure 2.

Nitric oxide releasing kinetics of SNAP-PDMS films where (A) continuous NO release flux measurements were taken on specified days while storing the films in PBS with EDTA at 37 °C (n=4). The green line represents the minimum physiological level of NO flux (0.5 × 10−10 mol cm−2 min−1). (B) Cumulative NO release over the 125-day testing period was measured and normalized per cm2 of SNAP-PDMS. (C) Representative NO release profile on day 0 from SNAP-PDMS films when placed in PBS with EDTA at 37 °C. Error bars represent standard deviation.

Figure 3.

Figure 3.

Cumulative leaching of SNAP into PBS from SNAP blended PDMS and covalent bound SNAP-PDMS films with and without a topcoat over the course of 48 hours (n=3). P<0.05 were used for comparison. Error bars represent standard deviation.

Figure 4.

Figure 4.

Long term antimicrobial ability of S. aureus adhesion to SNAP-PDMS. (A) Bacterial adhesion in 28-day bioreactor study on control PDMS and SNAP-PDMS films (n=3 per timepoint), showing approximately a 4, 3, and 2 log reduction in bacterial adhesion by days 3, 14, and 28 respectively. P<0.05 was used for comparison between groups. Error bars represent standard deviation.

Figure 5.

Figure 5.

Films previously tested for 125 days under physiological conditions were also examined (n=3), still demonstrating a 58.6% reduction in viable bacteria. Error bars represent standard deviation.

Figure 6.

Figure 6.

Hemocompatibility measurements of SNAP-PDMS coated tubing for ECC testing. (A) Time-dependent effects of NO release from the ECC on platelet count over the course of the 4 h study (n=3). (B) Quantification of clot mass obtained from the thrombogenicity chamber. (C) Visual representation of the clotting that occurred in PDMS coated controls (left) and SNAP-PDMS coated circuits (right). P<0.05 was used for comparison. Error bars represent standard deviation.

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