Design of anti-biofilm coating on medical catheters

• Main Author: Wu, Yang
• Other Authors: Chan Bee Eng, Mary
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Engineering::Chemical engineering::Polymers and polymer manufacture
• Online Access: https://hdl.handle.net/10356/141619
• Institution: Nanyang Technological University

Catheters are indispensable tools of modern medicine but the catheter-related infection is a significant clinical problem, even when stringent sterile protocols are observed. When bacteria colonize on catheter surfaces, they tend to form biofilms making them hard to treat with conventional antibiotics. It is known that biofilm bacteria are 1000-fold more resistant to antibiotics than planktonic bacteria. Hence, there is a great need for inherently anti-biofilm catheters that prevent bacterial colonization. In this thesis, we have designed two series of anti-biofilm coatings for catheter tubing using surface-initiated techniques and characterized the anti-biofilm activities in vivo. In Chapter 1, catheter-related infections (CRIs) and strategies of polymer-based anti-biofilm coating design are introduced. In Chapter 2, two series of polymer-based coatings have been reviewed based on its anti-biofilm and anti-fouling applications. In Chapter 3, methodologies of surface characterization and biological testing used are listed in details. Chapter 4 reports the preparation of non-leachable anti-biofilm cationic polymer coatings directly polymerized from actual tubular silicone catheter surfaces via the technique of supplemental activator and reducing agent surface initiated atom transfer radical polymerization (SARA SI-ATRP). Three crosslinked cationic coatings containing (3-acrylamidopropyl) trimethyl-ammonium chloride (AMPTMA), or quaternized polyethylenimine methacrylate (Q-PEI-MA) together with a crosslinker (polyethylene glycol dimethacrylate, PEGDMA) were tested. The in vivo anti-biofilm effect of these non-leachable covalently linked coatings (using a mouse catheter model) can be tuned to achieve 1.95 log (98.88%) reduction and 1.26 log (94.51%) reduction of clinically relevant pathogenic bacteria (specifically with Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin -resistant Enterococcus faecalis (VRE)). The good in vivo bactericidal killing results using the murine catheter-associated urinary tract infection (CAUTI) model show that SARA SI-ATRP grafting-from technique is a viable technique for making non-leachable anti-biofilm coating even on “small” (0.30/0.64 mm inner/outer diameter) catheter. In Chapter 5, we have investigated 3 cationic and 3 anionic monomers to explore 9 mixed-charge copolymer coating formulations on polyurethane (PU) catheter. We have discovered a new anti-biofilm pair comprising AMPTMA (3-Acrylamidopropyl) trimethylammonium chloride) and SPM (3-Sulfopropyl methacrylate potassium salt) that that can achieve high (with > 2 log10) reduction of catheter biofilm from a broad spectrum of clinically important Gram-positive and Gram-negative bacteria. We found that the pair comprising an anionic monomer which has slowest polymerization rate in solution phase, coupled with a cationic monomer which has fastest polymerization rate in solution phase, would result in the most hydrophilic and most effective anti-biofilm surface coating on catheters. The in vitro anti-biofilm efficacy of poly(AMPTMA-ran-SPM) against methicillin-resistant S.aureus (MRSA) can be sustained for 30 days. The coated catheter shows around 2-3 log10 reduction of 5 bacteria with 2 in vivo murine models: urinary tract and subcutaneous wound infection models. In summary, the relative kinetics of the anionic versus cationic monomer polymerization will affect the anti-biofilm performance of the resulting mixed-charge copolymer coating. The conclusion and future works have been summarized in Chapter 6 in the end.