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. 2021 May 5;13(17):19613-19624.
doi: 10.1021/acsami.1c01330. Epub 2021 Apr 27.

Development of Novel Amphotericin B-Immobilized Nitric Oxide-Releasing Platform for the Prevention of Broad-Spectrum Infections and Thrombosis

Ryan Devine  1 , Megan Douglass  1 , Morgan Ashcraft  1   2 , Nicole Tayag  1 , Hitesh Handa  1
Affiliations

Development of Novel Amphotericin B-Immobilized Nitric Oxide-Releasing Platform for the Prevention of Broad-Spectrum Infections and Thrombosis

Ryan Devine et al. ACS Appl Mater Interfaces. .

Abstract

Indwelling medical devices currently used to diagnose, monitor, and treat patients invariably suffer from two common clinical complications: broad-spectrum infections and device-induced thrombosis. Currently, infections are managed through antibiotic or antifungal treatment, but the emergence of antibiotic resistance, the formation of recalcitrant biofilms, and difficulty identifying culprit pathogens have made treatment increasingly challenging. Additionally, systemic anticoagulation has been used to manage device-induced thrombosis, but subsequent life-threatening bleeding events associated with all available therapies necessitates alternative solutions. In this study, a broad-spectrum antimicrobial, antithrombotic surface combining the incorporation of the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) with the immobilization of the antifungal Amphotericin B (AmB) on polydimethylsiloxane (PDMS) was developed in a two-step process. This novel strategy combines the key advantages of NO, a bactericidal agent and platelet inhibitor, with AmB, a potent antifungal agent. We demonstrated that SNAP-AmB surfaces significantly reduced the viability of adhered Staphylococcus aureus (99.0 ± 0.2%), Escherichia coli (89.7 ± 1.0%), and Candida albicans (93.5 ± 4.2%) compared to controls after 24 h of in vitro exposure. Moreover, SNAP-AmB surfaces reduced the number of platelets adhered by 74.6 ± 3.9% compared to controls after 2 h of in vitro porcine plasma exposure. Finally, a cytotoxicity assay validated that the materials did not present any cytotoxic side effects toward human fibroblast cells. This novel approach is the first to combine antifungal surface functionalization with NO-releasing technology, providing a promising step toward reducing the rate of broad-spectrum infection and thrombosis associated with indwelling medical devices.

Keywords: antimicrobial surfaces; hemocompatible; medical device; multifunctional surfaces; nitric oxide-releasing surfaces.

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Conflict of interest statement

Author Contributions

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: “Dr. Hitesh Handa is the founder of inNOveta Biomedical LLC. inNOveta Biomedical LLC is exploring possibilities of using nitric oxide releasing materials for medical applications.”

Figures

Figure 1.
Figure 1.
Schematic of SNAP-AmB synthesis. (a) PDMS is swelled with SNAP using THF at a concentration of 25 mg mL−1. (b) SNAP is exposed to oxygen plasma to force −OH groups onto polymeric surface. (c) APTMS is immobilized onto the surface through chemical vapor deposition. (d) AmB is covalently bound using EDS/NHS coupling.
Figure 2.
Figure 2.
SEM and EDS mapping of PDMS (A–D), AmB-PDMS (E–I), SNAP-PDMS (J–O), and SNAP-AmB-PDMS (P–U). Silicon (yellow), oxygen (blue), carbon (purple), nitrogen (green), and sulfur (pink) were detected. No significant detection of nitrogen and/or sulfur were found for PDMS and AmB-PDMS samples. White bar, 10 μm.
Figure 3.
Figure 3.
Average real-time NO release of SNAP and SNAP-AmB PDMS at 37 °C submerged in PBS (n = 6). Data is reported in mean ± SD. Statistical significance (*) was calculated between SNAP and SNAP-AmB surfaces for each time point (p < 0.05).
Figure 4.
Figure 4.
Adhered bacterial and fungal viability after 24 h exposure of materials to S. aureus (A), E. coli (B), and C. albicans(C) quantified in CFU/cm2. Statistical significance (p < 0.05) is indicated by *, %, and # compared to PDMS, AmB, and SNAP samples, respectively. Measurements are reported in mean ± SD.
Figure 5.
Figure 5.
In vitro platelet adhesion normalized to surface area. Statistical significance (p < 0.05) is indicated by * and % compared to PDMS and AmB, respectively. Measurements are reported in mean ± SD.
Figure 6.
Figure 6.
In vitro cytotoxicity measurements against human fibroblasts. Measurements are reported in mean ± SD.
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