Project Summary/Abstract
The major limiting factors to clinical applications of blood-contacting materials, ranging from small catheters to
large extracorporeal circulation (ECC) devices, include platelet activation leading to thrombosis and infection.
Thrombus formation can further lead to obstruction of blood vessels, device malfunction, or even life-threatening
situations such as embolism. Systemic anticoagulation is required to prevent clotting in the devices; however,
one of the resulting major complications of this is bleeding. During the COVID-19 pandemic, extracorporeal
membrane oxygenation (ECMO) has received critical attention as a therapy for patients where mechanical
ventilation alone is ineffective. Significant challenges remain due to the increased risks of thrombosis in the
circuitry that can be further exacerbated by hypercoagulable blood exhibited by COVID-19 patients. Therefore,
there is an urgent necessity and opportunity to combine strategies for preventing thrombosis and infection into
multifunctional device coatings for enhanced patency and safety.
Our work and others have demonstrated that nitric oxide (NO) release from polymers prevent platelets activation
and infection. This technology mimics the vascular endothelial cells lining the blood vessels, as well as other
cells in our bodies, producing NO locally to prevent clotting and bacterial biofilm and subsequent infections.
Recently we discovered that all of the positive effects can be achieved from polymers physically blended with
the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to
synthesize. Nitric oxide release can prevent platelet activation/adhesion and exhibit broad-spectrum
antimicrobial properties, but low NO levels may not completely eradicate the bacterial colonization. Our recent
work has shown that by combining active NO release via synthesis of S-nitrosothiol modified ampicillin species
when incorporated in medical grade polymers reduces bacterial infection significantly better than NO-releasing
polymers alone. The goal of this proposal is to develop, optimize, and evaluate polymer comprised of S-
nitrosothiol (RSNO) modified ampicillin (RSNO-icillin) with active NO release (to inhibit platelet
adhesion/activation and bactericidal activity) covalently bound to ampicillin (a broad-spectrum antibiotic
to ensure eradication of bacteria), resulting in a significantly improved, non-thrombogenic,
antimicrobial, and hemocompatible polymer surface. The new polymers will be applicable to any blood-
contacting device; however, this proposal will focus on studying the combined antibiotic and NO-releasing
strategy in vitro for antimicrobial properties and in a rabbit extracorporeal circulation model for prevention of
thrombosis and infection. Successful completion of this project will allow progression to early clinical trials and
development of a new generation of extracorporeal circuits that can reduce complications while improving the
success of patient care.
