S-Nitroso- N -acetyl-D-penicillamine covalently linked to polydimethylsiloxane (SNAP–PDMS) for use as a controlled photoinitiated nitric oxide release polymer (original) (raw)
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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.
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.
Nitric Oxide, 2019
The light induced nitric oxide (NO) release properties of S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) NO donors doped within polydimethylsiloxane (PDMS) films (PDMS-SNAP and PDMS-GSNO respectively) for potential inhaled NO (iNO) applications is examined. To achieve photolytic release of gas phase NO from the PDMS-SNAP and PDMS-GSNO films, narrow-band LED light sources are employed and the NO concentration in a N2 sweep gas above the film is monitored with an electrochemical NO sensor. The NO release kinetics using LED sources with different nominal wavelengths and optical power densities are reported. The effect of the NO donor loading within the PDMS films is also examined. The NO release levels can be controlled by the LED triggered release from the NO donor-doped silicone rubber films in order to generate therapeutic levels in a sweep gas for suitable durations potentially useful for iNO therapy. Hence this work may lay the groundwork for future development of a highly portable iNO system for treatment of patients with pulmonary hypertension, hypoxemia, and cystic fibrosis.
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.
ACS applied materials & interfaces, 2015
The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of S-nitroso-N-acetyl-D-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 d) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC-MS. Raman spectroscopy and powder X-ray diffraction (PXRD) characterization of SNAP-doped CarboSil films demonstrate that a polymer-crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4-4.0 wt%). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form withi...
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.
Bioengineering
Synthetic nitric oxide (NO)-donating materials have been shown to have many beneficial effects when incorporated into biomedical materials. When released in the correct dosage, NO has been shown to increase the biocompatibility of blood and tissue contacting materials, but materials are often limited in the amount of NO that can be administered over a period of time. To address this, hyperbranched polyamidoamine (HPAMAM) was modified with the S-nitrosothiol, S-nitroso-N-acetyl-D-penicillamine, and nitrosated to form a controlled, high-capacity NO-donating compound (SNAP-HPAMAM). This compound has the potential of modifying polymers to release NO over long periods of time by being blended into a variety of base polymers. Nitric oxide release was triggered by photoinitiation and through passive ion-mediated release seen under physiological conditions. A material that delivers the beneficial dose of NO over a long period of time would be able to greatly increase the biocompatibility of...
Journal of Biomedical Materials Research Part A, 2005
A new type of nitric oxide (NO)-releasing material is described that utilizes S-nitrosothiols anchored to tiny fumed silica (FS) particles as the NO donor system. The synthetic procedures suitable for tethering three different thiol species (cysteine, N-acetylcysteine, and N-acetylpenicillamine) to the surface of FS polymer filler particles are detailed. The thiol-derivatized particles are converted to their corresponding S-nitrosothiols by reaction with t-butylnitrite. The total NO loading on the resulting particles range from 21-138 nmol/mg for the three different thiolderivatized materials [S-nitrosocysteine-(NO-Cys)-FS, S-nitroso-N-acetylcysteine (SNAC)-FS, and S-nitroso-Nacetylpenicillamine (SNAP)-FS], with SNAP-FS yielding the highest NO loading. NO can be generated from these particles when suspended in solution via the addition of copper(II) ions, ascorbate, or irradiation with visible light. The SNAC-FS and SNAP-FS particles can be blended in polyurethane and silicone rubber matrixes to create films that release NO at controlled rates. Polyurethane films containing SNAC-FS submerged in phosphate-buffered saline (pH 7.4) generate NO surface fluxes ϳ0.1-0.7 ϫ 10 Ϫ10 mol cm Ϫ2 min Ϫ1 and SNAP-FS films generate NO fluxes of ϳ0-7.5 ϫ 10 Ϫ10 mol cm Ϫ2 min Ϫ1 upon addition of increasing amounts of copper ions. Silicone rubber films containing SNAC-FS or SNAP-FS do not liberate NO upon exposure to copper ions or ascorbate in phosphate-buffered saline solution. However, such films are shown to release NO at rates proportional to increasing intensities of visible light impinging on the films. Such photoinitiated NO release from these composite materials offers the first NO-releasing hydrophobic polymers with an external on/off trigger to control NO generation.
Journal of materials chemistry. B, Materials for biology and medicine, 2016
Recently, considerable research efforts have focused on increasing the biocompatibility a nd bactericidal activity of biomedical polymeric devices (e.g., catheters, etc.) through incorporation of nitric oxide (NO) releasing molecules. NO is an important endogenous molecule that is well known for enhancing blood flow via its vasodilatory activity, but it also exhibits potent antithrombotic and antimicrobial properties. In this work, we demonstrate that silicone rubber tubing can be impregnated with a tertiary S-nitrosothiol (RSNO), S-nitroso-tert-dodecylmercaptan, via a simple solvent swelling method. We further characterize the NO release and RSNO leaching from the tubing over time via use of chemiluminescence and UV/Vis spectroscopy, respectively. The tubing is shown to maintain an NO flux above the physiological levels released by endothelial cells, 0.5-4.0 × 10(-10) molcm(-2)min(-1), for more than 3 weeks while stored at 37 °C and exhibit minimal leaching. Finally, the RSNO impre...
ACS biomaterials science & engineering, 2016
Herein, we report a novel design and the antimicrobial efficacy of a flexible nitric oxide (NO) releasing patch for potential wound healing applications. The compact sized polydimethylsiloxane (PDMS) planar patch generates NO via electrochemical reduction of nitrite ions mediated by a copper(II)-ligand catalyst using a portable power system and an internal gold coated stainless steel mesh working electrode. Patches are fabricated via soft lithography and 3-D printing. The devices can continuously release NO over 4 days and exhibit potent bactericidal effects on both Escherichia coli and Staphylococcus aureus. The device may provide an effective, safe, and less costly alternative for treating chronic wounds.