Precisely structured nitric-oxide-releasing copolymer brush defeats broad-spectrum catheter-associated biofilm infections in vivo

• Main Authors: Hou, Zheng, Wu, Yang, Xu, Chen, Reghu, Sheethal, Shang, Zifang, Chen, Jingjie, Pranantyo, Dicky, Marimuth, Kalisvar, De, Partha Pratim, Ng, Oon Tek, Pethe, Kevin, Kang, En-Tang, Li, Peng, Chan-Park, Mary B.
• Other Authors: School of Chemical and Biomedical Engineering
• Format: Article
• Language: English
• Published: 2021
• Subjects: Engineering::Chemical engineering::Polymers and polymer manufacture; Coating Materials; Infectious Diseases
• Online Access: https://hdl.handle.net/10356/154112
• Institution: Nanyang Technological University

Gram-negative bacteria cannot be easily eradicated by antibiotics and are a major source of recalcitrant infections of indwelling medical devices. Among various device-associated infections, intravascular catheter infection is a leading cause of mortality. Prior approaches to surface modification, such as antibiotics impregnation, hydrophilization, unstructured NO-releasing, etc., have failed to achieve adequate infection-resistant coatings. We report a precision-structured diblock copolymer brush (H(N)-b-S) composed of a surface antifouling block of poly(sulfobetaine methacrylate) (S) and a subsurface bactericidal block (H(N)) of nitric-oxide-emitting functionalized poly(hydroxyethyl methacrylate) (H) covalently grafted from the inner and outer surfaces of a polyurethane catheter. The block copolymer architecture of the coating is important for achieving good broad-spectrum anti-biofilm activity with good biocompatibility and low fouling. The coating procedure is scalable to clinically useful catheter lengths. Only the block copolymer brush coating ((H(N)-b-S)) shows unprecedented, above 99.99%, in vitro biofilm inhibition of Gram-positive and Gram-negative bacteria, 100-fold better than previous coatings. It has negligible toxicity toward mammalian cells and excellent blood compatibility. In a murine subcutaneous infection model, it achieves >99.99% biofilm reduction of Gram-positive and Gram-negative bacteria compared with <90% for silver catheter, while in a porcine central venous catheter infection model, it achieves >99.99% reduction of MRSA with 5-day implantation. This precision coating is readily applicable for long-term biofilm-resistant and blood-compatible copolymer coatings covalently grafted from a wide range of medical devices.