Anti-Biofilm Properties of Polyurethane Biomaterials Tethered With Small Molecules via Polyethylene Glycol Linker

Biofilm-associated microbial infection is one of the main complications for long-term use of biomaterials in implantable medical devices. Bacterial intracellular nucleotide second messenger signaling is widely recognized to be involved in biofilm formation and assists bacteria in monitoring and responding appropriately to changing environments. Interference with the nucleotide signaling mechanisms by small molecules to interrupt biofilm formation provides a novel way to control microbial infection on biomaterial surfaces. This study reports an approach to tether small molecule derivatives of 4-arylazo-3,5-diamino-1 H-pyrazole (termed as SP02 and SP03) on polyurethane biomaterial surfaces using a polyethylene glycol (PEG) linker. Compared to our previous approach to tether small molecules on surfaces using a short hexamethylene diisocyanate (HMDI) linker, the new modification resulted in surfaces enriched with a higher density of small molecules, SP02 and SP03. Studies of S. epidermidis and P. aeruginosa biofilm formation on surfaces demonstrated that PEG-linked surfaces were more resistant to biofilm formation than the HMDI-linked surfaces. The analysis of intracellular nucleotides in biofilm cells showed that the PEG-linked surfaces significantly reduced c-di-AMP levels in S. epidermidis cells and c-di-GMP levels in P. aeruginosa cells. In vivo experiments with a 7-day subcutaneous rat model suggest that the new small molecule tethered surfaces by the extended PEG linkers show increased resistance to microbial infection and are biocompatible to tissues. Overall, the results suggest that the PEG long linker can be used to tether small molecules on polyurethane biomaterial surfaces and retain the activity of small molecules, providing a new approach to combat microbial infections.