Silk Nanoparticles: A Natural Polymeric Platform for Nitric Oxide Delivery in Biomedical Applications (original) (raw)
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Due to the role of nitric oxide (NO) in regulating a variety of biological functions in humans, numerous studies on different NO releasing/generating materials have been published over the past two decades. Although NO has been demonstrated to be a strong antimicrobial and potent antithrombotic agent, NO-releasing (NOrel) polymers have not reached the clinical setting. While increasing the concentration of the NO donor in the polymer is a common method to prolong the NO release, this should not be at the cost of mechanical strength or biocompatibility of the original material. In this work, it was shown that the incorporation of S-nitroso-penicillamine (SNAP), an NO donor molecule, into Elast-eon E2As (a copolymer of mixed soft segments of polydimethylsiloxane and poly(hexamethylene oxide)), does not adversely impact the physical and biological attributes of the base polymer. Incorporating 10 wt% of SNAP into E2As reduces the ultimate tensile strength by only 20%. The inclusion of SNAP did not significantly affect the surface chemistry or roughness of E2As polymer. Ultraviolet radiation, ethylene oxide, and hydrogen peroxide vapor sterilization techniques retained approximately 90% of the active SNAP content and did not affect the NO-release profile over an 18-day period. Furthermore, these NOrel materials were shown to be biocompatible with the host tissues as observed through hemocompatibility and cytotoxicity analysis. In addition, the stability of SNAP in E2As was studied under a variety of storage conditions, as they pertain to translational potential of these materials. SNAP-incorporated E2As stored at room temperature for over six months retained 87% of its initial SNAP content. Stored and fresh films exhibited similar NO release kinetics over an 18-day period. Combined, the results from this study suggest that SNAP-doped E2As polymer is suitable for commercial biomedical applications due to the reported physical and biological characteristics that are important for commercial and clinical success.
Bioengineering, 2018
Polyvinyl chloride (PVC) is one of the most widely used polymers in medicine but has very poor biocompatibility when in contact with tissue or blood. To increase biocompatibility, controlled release of nitric oxide (NO) can be utilized to mitigate and reduce the inflammatory response. A synthetic route is described where PVC is aminated to a specified degree and then further modified by covalently linking S-nitroso-N-acetyl-D-penicillamine (SNAP) groups to the free primary amine sites to create a nitric oxide releasing polymer (SNAP-PVC). Controllable release of NO from SNAP-PVC is described using photoinitiation from light emitting diodes (LEDs). Ion-mediated NO release is also demonstrated as another pathway to provide a passive mechanism for NO delivery. The large range of NO fluxes obtained from the SNAP-PVC films indicate many potential uses in mediating unwanted inflammatory response in blood-and tissue-contacting devices and as a tool for delivering precise amounts of NO in vitro.
Science and Technology of Advanced Materials, 2011
Nitric oxide (NO) plays a critical role in the regulation of a wide variety of physiological processes. It is a potent inhibitor of platelet adhesion and aggregation, inhibits bacterial adhesion and proliferation, is implicated in mediating the inflammatory response toward implanted devices, plays a role in tumor growth and proliferation, and is a neurotransmitter. Herein, we describe the synthesis and NO-release properties of a modified polydimethylsiloxane that contains S-nitroso-N-acetyl-D-penicillamine covalently attached to the cross-linking agent (SNAP-DMS). Light from a C503B-BAN-CY0C0461 light-emitting diode (470 nm) was used as an external trigger to allow precise control over level and duration of NO release ranging from a surface flux of zero to approximately 3.5 × 10 −10 mol cm −2 min −1. SNAP-PDMS films stored in the dark released NO after 297 days, indicating the long-term stability of SNAP-PDMS.
Journal of Controlled Release, 2016
Nitric oxide (NO) is a fascinating and important endogenous free-radical gas with potent antimicrobial, vasodilating, smooth muscle relaxant, and growth factor stimulating effects. However, its wider biomedical applicability is hindered by its cumbersome administration, since NO is unstable especially in biological environments. In this work, to ultimately develop sitespecific controlled release vehicles for NO, the NO donor S-nitroso-N-acetyl-D-penicillamine (SNAP) was encapsulated within poly(lactic-co-glycolic acid) 50:50 (PLGA) microspheres by using a solid-in-oil-in-water emulsion solvent evaporation method. The highest payload was 0.56(±0.01) μmol SNAP/mg microspheres. The release kinetics of the donor were controlled by the bioerosion of the PLGA microspheres. By using an uncapped PLGA (Mw = 24,000-38,000) SNAP was slowly released for over 10 days, whereas by using the ester capped PLGA (Mw = 38,000-54,000) the release lasted for over 4 weeks. The presence of copper ions and/or ascorbate in solution was necessary to efficiently decompose the released NO donor and obtain sustained NO release. It was also demonstrated that light can be used to induce rapid NO release from the microspheres over several hours. SNAP exhibited excellent storage stability when encapsulated in the PLGA microspheres. These new microsphere formulations may be useful for site-specific administration and treatment of pathologies associated with dysfunction in endogenous NO production, e.g. treatment of diabetic wounds, or in diseases involving other biological functions of NO including vasodilation, antimicrobial, anticancer, and neurotransmission.
ACS Applied Materials & Interfaces, 2019
Modern crisis in implantable or indwelling blood-contacting medical devices are mainly due to the dual problems of infection and thrombogenicity. There is a paucity of biomaterials that can address both the problems simultaneously through a singular platform. Taking cues from the body's own defense mechanism against infection and blood clotting (thrombosis) via the endogenous gasotransmitter nitric oxide (NO), both of these issues are addressed through the development of a layered S-nitroso-N-acetylpenicillamine (SNAP) doped polymer with a blended selenium (Se)-polymer interface. The unique capability of the SNAP-Se-1 polymer composites to explicitly release NO from the SNAP reservoir as well as generate NO via the incorporated Se is reported for the first time. The NO release from the SNAP doped polymer increased substantially in the presence of the Se interface. The Se interface is also able to generate NO in the presence of S-nitrosoglutathione (GSNO) and glutathione (GSH), demonstrating the capability of generating NO from endogenous S-nitrosothiols (RSNO). Scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) traces distribution of elemental Se nanoparticles on the interface and the surface properties were evaluated by surface wettability and roughness. The SNAP-Se-1 efficiently inhibits the growth of bacteria and reduces platelet adhesion while showing minimal cytotoxicity, thus potentially eliminating the risks of systemic antibiotic and blood coagulation therapy. The SNAP-Se-1 exhibits antibacterial activity of ~2.39 and ~2.25 log reductions in the growth of clinically challenging adhered Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. SNAP-Se-1 also significantly reduces platelet adhesion by 85.5% compared to corresponding controls. WST-8 based cell viability test performed on NIH 3T3 mouse fibroblast cells provide supporting evidence for the potential biocompatibility of the material in vitro. These §
Biomaterials science, 2018
Semi-crystalline thermoplastics are an important class of biomaterials with applications in creating extracorporeal and implantable medical devices. In situ release of nitric oxide (NO) from medical devices can enhance their performance via NO's potent anti-thrombotic, bactericidal, anti-inflammatory, and angiogenic activity. However, NO-releasing semi-crystalline thermoplastic systems are limited and the relationship between polymer crystallinity and NO release profile is unknown. In this paper, the functionalization of poly(ether-block-amide) (PEBA), Nylon 12, and polyurethane tubes, as examples of semi-crystalline polymers, with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) within, is demonstrated via a polymer swelling method. The degree of crystallinity of the polymer plays a crucial role in both SNAP impregnation and NO release. Nylon 12, which has a relatively high degree of crystallinity, exhibits an unprecedented NO release duration of over 5 months at a low NO le...
S-nitrosothiol-terminated Pluronic F127: Influence of microstructure on nitric oxide release
Journal of Colloid and Interface Science, 2020
Hypothesis: Nitric oxide (NO)-releasing Pluronic F127 hydrogels (F127) containing dissolved S-nitrosothiols or pendant N-diazeniumdiolate (NONOate) groups have been described. The NO charging of these hydrogels is usually limited by their low stability or disruption of the micellar packing. S-nitrosothiol-terminated F127 may emerge as a new strategy for allowing NO delivery at different rates in biomedical applications. Experiments: Terminal hydroxyl groups of F127 were esterified and reduced to produce F127mercaptopropionate (HS-F127-SH), which was subsequently S-nitrosated to generate S-nitrosothiolterminated F127 (ONS-F127-SNO). Micro-differential scanning calorimetry, 1 H NMR spin-spin relaxation (T 2), temperature-dependent small-angle X-ray scattering, and cryo-transmission electron microscopy, were used to determine the micellar packing structure, while real-time chemiluminescence NO detection and UV-Vis spectrophotometry were used to evaluate the kinetics of NO release. Findings: HS-F127-SH micellization and gelation processes were analogous to native F127, however, with a decreased short-range ordering of the micelles. ONS-F127-SNO hydrogels released NO thorough a preferentially intramicellar SNO dimerization reaction. Increasing ONS-F127-SNO concentration reduces the rate of SNO dimerization and increases the overall rate of NO release to the gas phase, opening up new possibilities for tailoring NO delivery from F127-based hydrogels.
Biomaterials, 2013
Nitric oxide (NO) is known to be a potent inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5e4 Â 10 À10 mol cm À2 min À1 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, five biomedical grade polymers doped with S-nitroso-Nacetylpenicillamine (SNAP) were investigated for their potential to control the release of NO from the SNAP within the polymers, and further control the release of SNAP itself. SNAP in the Elast-eon E2As polymer creates an inexpensive, homogeneous coating that can locally deliver NO (via thermal and photochemical reactions) as well slowly release SNAP. Furthermore, SNAP is surprisingly stable in the E2As polymer, retaining 82% of the initial SNAP after 2 months storage at 37 C. The E2As polymer containing SNAP was coated on the walls of extracorporeal circulation (ECC) circuits and exposed to 4 h blood flow in a rabbit model of extracorporeal circulation to examine the effects on platelet count, platelet function, clot area, and fibrinogen adsorption. After 4 h, platelet count was preserved at 100 AE 7% of baseline for the SNAP/ E2As coated loops, compared to 60 AE 6% for E2As control circuits (n ¼ 4). The SNAP/E2As coating also reduced the thrombus area when compared to the control (2.3 AE 0.6 and 3.4 AE 1.1 pixels/cm 2 , respectively). The results suggest that the new SNAP/E2As coating has potential to improve the thromboresistance of intravascular catheters, grafts, and other blood-contacting medical devices, and exhibits excellent storage stability compared to previously reported NO release polymeric materials.
Free Radical Biology and Medicine, 2004
The synthetic methods used recently in this laboratory to prepare a variety of novel nitric oxide (NO)releasing hydrophobic polymers are reviewed. Nitric oxide is a well known inhibitor of platelet adhesion and activation. Thus, such NO release polymers have potential applications as thromboresistant coatings for a large number of bloodcontacting biomedical devices (e.g., in vivo sensors, arteriovenous grafts, stents, catheters, extracorporeal circuits). The approaches taken to prepare NO releasing poly(vinyl chloride) (PVC), silicone rubber (SR), polymethacrylate (PM), and polyurethane (PU) materials are grouped into three categories: (1) dispersion/doping of discrete diazeniumdiolated molecules within the polymeric films; (2) chemical derivatization of polymeric filler microparticles (e.g., silicon dioxide, titanium dioxide) to possess NO release chemistry and then their dispersion within the hydrophobic polymers; and (3) covalent attachment of NO release moieties to polymer backbones. Specific chemical examples of each of these approaches are summarized and the advantages and disadvantages of each are discussed. Other related work in the field of NO release polymers is also cited. It is further shown that several of the NO-releasing polymeric materials already prepared exhibit the expected improved thromboresistivity when tested in vivo using appropriate animal models.