title: Origin of Long-Term Storage Stability and Nitric Oxide Release Behavior of CarboSil Polymer Doped with S-Nitroso-N-acetyl-D-penicillamine.
abstract: 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 days) 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 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 within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of Staphylococcus aureus biofilm (a leading cause of nosocomial bloodstream infections) (in vitro) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility.
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Wo
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Zi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Brisbois
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colletta
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Terry C
authors.initials: TC
authors.lastname: Major
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Chuanwu
authors.initials: C
authors.lastname: Xi
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bartlett
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Matzger
authors.affiliation: Department of Chemistry, ‡Departmental of Surgery, University of Michigan Medical Center, and §Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Meyerhoff
mesh_terms: D000818:Animals; D018441:Biofilms / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000627:therapeutic use; D006860:Hydrogen Bonding; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D011076:Polycarboxylate Cement / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011817:Rabbits; D026423:S-Nitroso-N-Acetylpenicillamine / Q000737:chemistry*; D012825:Silicon / Q000737:chemistry; D013059:Spectrum Analysis, Raman; D013211:Staphylococcus aureus / Q000502:physiology; D013499:Surface Properties; D013927:Thrombosis / Q000517:prevention & control; D014520:Urethane / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D005343:Fibrinolytic Agents; D011076:Polycarboxylate Cement; D011108:Polymers; C005506:polycarbonate; D009569:Nitric Oxide; D014520:Urethane; D026423:S-Nitroso-N-Acetylpenicillamine; D012825:Silicon
keywords: S-nitroso-N-acetyl-d-penicillamine (SNAP); antimicrobial catheters; biocompatibility; controlled release; nitric oxide; polymer−crystal composite; thromboresistance