Synthetic polymerspolymers, including poly(vinyl chloride) (PVC), polyurethane (PU), and silicone rubber (SR), are widely used in the medical field with an annual consumption of over one billion pounds. However, when in direct contact with blood, these polymers are still prone to initiate the formation of clots, as platelets and other components of the blood coagulation system are activated (figure 1)
Among the many analytical technologies that could improve the quality of care for critically ill hospital patients, none is potentially more significant, yet technologically challenging, than the development of intravascular chemical sensors that can function reliably for extended periods (days) after implantation. To date, efforts to develop intravascular chemical sensors capable of accurate, real-time monitoring of gas and electrolyte levels within the blood have failed due to problems associated with the initiation of clotting on the sensors’ surfaces as well as arterial constriction that diminishes blood flow at the implant site. A common observation for some sensors during in vivo studies is the performance pattern illustrated in (figure 2).
A potential solution to the problem of thrombogenic polymers may now be realized by creating polymeric materials that are capable of releasing low levels of nitric oxide (NO) at the blood/polymer interface. Indeed, NO is a potent anti-platelet agent that is naturally generated by human endothelial cells (figure 3) to decrease the propensity of blood to clot.
Polymers with equal or higher NO fluxes that that of endothelial cells may prove effective in preventing platelet adhesion onto their surfaces (figure 4), thereby lowering the risk of thrombus formation and other complications associated with interactions between blood and foreign materials.
The redox chemistry of Cu(II)/Cu(I) is known for catalyzing RSNO decomposition to NO in the presence of reducing agent (free thiols (RSHs) or ascorbate), several Cu(II) complexes have been immobilized to create NOGPs, including a Cu(II)-cyclen derivative covalently attached onto polymethacrylate (figure 6), and a lipophilic agent, Cu(II)- dibenzo-[e,k]-2,3,8,9-tetraphenyl-1,4,7,10-tetraazacyclododeca- 1,3,7,9-tetraene (Cu(II)-DTTCT), doped within various polymeric materials.
The NOGPs made in this lab show good and repeatable NO generating profiles (detected by chemiluminesce methods (figure 6)) in the presence of RSNOs and reducing agents. (see figure 7)
Cu(0) Nano- and Micro-Particles
Towards the continuous production of NO in vivo, an NO-generation strategy employing Cu(0)-based catalyst to generate NO in situ via the decomposition of endogenous RSNOs at the blood/polymer interface has also been pursued. Intravascular electrochemical oxygen sensors coated with such particles embedded in a polymer film materials (figure 8) showed improved hemocompatibility upon testing intravascularly within an animal model (see figures 9 and 10).
It has recently been discovered that organodiselenides (e.g., selenocystamine (SeCA) and 3,3’-diselenodipropionic acid (SeDPA)), including certain selenium containing enzymes (e.g., glutathione peroxidase (GPx)), and organoditellurides (e.g., 5,5’-ditelluro-2,2’-dithiophenecarboxlyic acid (DTDTCA)) (figure 11) can carry out similar catalytic NO generation chemistry, but via a completely different mechanism (figure 12). In our lab, both selenium (figure 13) and telulium-based NOGPs have been made and NO can be generated in the presence of RSNO species (figure 14).
The thromboresistancy of a healthy endothelium is not only attributed to NO, but also other secreted (prostacyclin (PGI2), plasminogen, antithrombin III, etc.) and membrane-bound species (heparan sulphate (HS), thrombomodulin (TM)) (fiigure 15). In this regard, polymeric surfaces that combine both NO release (see figures 16 and 17) and surface-bound active heparin (a HS analogue) and/or TM were recently developed in this laboratory as an initial effort towards the fabrication of polymeric coatings that truly mimic the endothelial cell (EC) in functionality (figure 18).
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