Abstract
Blood-contacting medical devices play an important role within healthcare and are required to be biocompatible, hemocompatible and resistant to microbial colonization. Here we describe a high throughput screen for copolymers with these specific properties. A series of weakly amphiphilic monomers are combinatorially polymerized with acrylate glycol monomers of varying chain lengths to create a library of 645 multi-functional candidate materials containing multiple chemical moieties that impart anti-biofilm, hemo- and immuno-compatible properties. These materials are screened in over 15,000 individual biological assays, targeting two bacterial species, one Gram negative (Pseudomonas aeruginosa) and one Gram positive (Staphylococcus aureus) commonly associated with central venous catheter infections, using 5 different measures of hemocompatibility and 6 measures of immunocompatibililty. Selected copolymers reduce platelet activation, platelet loss and leukocyte activation compared with the standard comparator PTFE as well as reducing bacterial biofilm formation in vitro by more than 82% compared with silicone. Poly(isobornyl acrylate-co-triethylene glycol methacrylate) (75:25) is identified as the optimal material across all these measures reducing P. aeruginosa biofilm formation by up to 86% in vivo in a murine foreign body infection model compared with uncoated silicone.
Highlights
Blood-contacting medical devices, such as vascular catheters and venous access ports, are routinely used in healthcare settings [1,2]
Once inserted into the vasculature, biomaterial surfaces become rapidly coated with a blood conditioning film triggering a complex series of closely interlinked events which lead to protein adsorption, platelet and leukocyte adhesion/activation, complement activation, coagulation and thrombosis [7,8]
Zwitterionic polymers have been proposed as bacter ial/protein resistant and hemocompatible materials, suitable monomers were included on the array for comparison (Figure SI1, E-G) [24,25]
Summary
Blood-contacting medical devices, such as vascular catheters and venous access ports, are routinely used in healthcare settings [1,2] Such devices should be biocompatible, hemocompatible, and resistant to surface-initiated blood coagulation processes and adverse immune re actions [3]. Devices such as central venous catheters (CVCs) are associated with unacceptably high levels of treatment complications including occlusion, thrombosis and infection. Biofilms on unconditioned CVC surfaces, their coating with blood pro teins such as fibrinogen provides additional options for adherence via specific bacterial cell surface receptors that facilitate attachment and subsequent biofilm formation [13,14] Pathogens such as Staphylococcus aureus can generate an extracellular matrix from the coagulase-dependent conversion of fibrinogen to fibrin [15]. Selected hits were scaled up for further in vitro and in vivo analysis for selection of an optimal hemo-compatible, anti-biofilm material
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