The Preparation and Study of Lipophilic S-Nitrosothiols for Use in Improving the Biocompatibility of Medical Grade Polymers.

[摘要] Advances in biomaterials, polymer science, and biotechnology have resulted in the development and implementation of a wide array of implantable biomedical devices and drug/device combination products such as catheters, drug-eluting stents, and artificial organs. Unfortunately, inserting a foreign material into the body can cause undesirable effects, the nature of which depends upon the device’s biocompatibility with blood or tissue.Common complications resulting from the use of implantable biomedical devices include cellular proliferation, thrombosis, and the increased risk of infection.The work described in this thesis aims to develop novel lipophilic S-nitrosothiols (RSNOs) that, when incorporated into polymers, provide nitric oxide (NO) release capable of greatly improving the material’s biocompatibility.Initial studies focused on developing methodologies to synthesize fourteen lipophilic RSNOs with LogP values ranging from 1.7 to 10.8.Of these, S-nitroso-tert-dodecylmercaptan (SNTDM) and S-nitrosotriphenylmethanethiol (SNTPMT) exhibited the most promising stability for potential practical use in polymeric materials.Silicone rubber (SR), Elasteon-E2As (E2As), and CarboSil (CS) films containing 10 wt% SNTDM released NO at physiological levels for approximately one month.SR and CS films containing 10 wt% SNTPMT released NO at physiological levels for 41 d, while SNTPMT in E2As lasted 33 d. SNTDM and SNTPMT leached minimally from SR (2.4 ± 0.4%, 2.0 ± 0.2%), CS (3.1 ± 0.5%, 1.8 ± 0.3%), and E2As (2.3 ± 0.4%, 1.5 ± 0.3%).An LDH assay was used to measure the relative amounts of platelets adhered to polymers doped with the different RSNOs.SNTDM and SNTPMT demonstrated excellent antiplatelet activity by reducing levels on SR (3.0 ± 0.3%, 8.6 ± 0.1%), CS (12.3 ± 2.0%, 22.1 ± 5.9%) and E2As (14.0 ± 3.4%, 23.8 ± 6.2%) relative to the controls.A solvent swelling method was developed to impregnate SNTDM in SR catheters which released NO at or above physiological levels for ~26 d.The catheters were incubated in a CDC bioreactor containing S. aureus for 21 d and killed or inhibited growth of 99.9% of the bacteria.Polymer films containing SNTDM demonstrated substantial photoinduced NO release, more than an order of magnitude greater than any RSNO previously tested in the literature.

[发布机构] University of Michigan

[效力级别] Nitric oxide

[关键词] S-Nitrosothiol;Nitric oxide;Biocompatibility;Biomaterials;NO Donor;RSNO;Chemistry;Science (General);Science;Chemistry