On-demand antimicrobial release from a temperature-sensitive polymer — Comparison with ad libitum release from central venous catheters Jelmer Sjollema a, ⁎, Rene J.B. Dijkstra a , Caroline Abeln b , Henny C. van der Mei a , Dirk van Asseldonk b , Henk J. Busscher a a University of Groningen and University Medical Center Groningen Department of Biomedical Engineering, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands b Dolphys Medical B.V., De Lismortel 31, 5612 AR Eindhoven, The Netherlands abstract article info Article history: Received 27 March 2014 Accepted 10 June 2014 Available online 17 June 2014 Keywords: Central venous catheters Chlorhexidine Silver Biofilms Infection Antimicrobial releasing biomaterial coatings have found application for instance in the fixation of orthopedic joint prostheses and central venous catheters. Most frequently, the release kinetics is such that antimicrobially-effective concentrations are only reached within the first days to weeks after implantation, leaving no local antimicrobial release available when a biomaterial-associated infection occurs later. Here we compare the ad libitum release of chlorhexidine and silver-sulfadiazine from a central venous catheter with their release from a new, on-demand re- lease coating consisting of a temperature-sensitive copolymer of styrene and n-butyl (meth)acrylate. The copoly- mer can be loaded with an antimicrobial, which is released when the temperature is raised above its glass transition temperature. Ad libitum release of chlorhexidine and silver-sulfadiazine from a commercially- purchased catheter and associated antimicrobial efficacy against Staphylococcus aureus was limited to 16 days. Consecutive temperature-triggers of our on-demand coating yielded little or no antimicrobial efficacy of silver- acetate release, but antimicrobially-effective chlorhexidine concentrations were observed over a time period of 60–80 days. This attests to the clear advantage of on-demand coatings above ad libitum releasing coatings, that may have released their antimicrobial content before it is actually needed. Importantly, glass transition tempera- ture of chlorhexidine loaded copolymers was lower (48 °C) than of silver loaded ones (61 °C), facilitating their clinical use. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Antimicrobial releasing biomaterial coatings have found application for instance in the fixation of orthopedic joint prostheses [1] and central venous catheters (CVCs). CVCs are widely applied to offer vascular ac- cess for e.g. blood dialysis or administration of chemotherapeutics, pa- rental nutrition or antibiotics. The use of CVCs however, is associated with a high incidence of infectious complications ranging from 0.5 to 26%, dependent on the type of catheterization. CVC-associated infec- tions are expensive to treat [2] and moreover, extremely hazardous to patients, as they can easily evolve from a subcutaneous infection of the skin near the entry point into a CVC-associated bloodstream infec- tion. It is estimated that CVC-associated bloodstream infections occur around 80,000 times per year in the United States alone [3]. CVC- associated infections can cause great clinical dilemmas as removal of the catheter is not an easy decision. The number of veins that can be used as entry point is limited (jugular, subclavian vein and femoral veins), while generally a once infected insertion site cannot be used for a second time. Thus removal of a CVC due CVC-associated infection for the administration of chemotherapeutics for instance, may disrupt the chemotherapy, while keeping the catheter in place may yield the risk of death due to sepsis of an already weakened patient. Catheter-related infections are thought to arise mainly through two different routes of infection [4,5]. The first route is through the insertion site: bacteria, primarily from the skin, can migrate along the external catheter surface to cause subcutaneous infection and subsequent blood- stream infection. The second route is through the contamination of the catheter hub, leading to intra-luminal bacterial colonization and migra- tion to the bloodstream. In order to reduce the incidence of CVC- associated infection, topical application of chlorhexidine gluconate as a skin disinfectant for catheter site care has proven to be effective [6]. As another strategy to prevent CVC-associated bloodstream infections, catheters have been equipped with antimicrobial coatings. Specifically catheters releasing chlorhexidine or a combination of chlorhexidine and silver have been demonstrated to reduce the number of CVC- associated bloodstream infections [7]. Most of the antimicrobials how- ever, are released immediately upon contact with human tissue or fluids in a so-called “burst release” followed by a low-level tail-release that is only antimicrobially effective for a limited period of time [8]. As a conse- quence, whenever a CVC-associated infection develops in the later Journal of Controlled Release 188 (2014) 61–66 ⁎ Corresponding author. Tel.: +31 50 3633149; fax: +31 50 3633159. E-mail address: j.sjollema@umcg.nl (J. Sjollema). http://dx.doi.org/10.1016/j.jconrel.2014.06.013 0168-3659/© 2014 Elsevier B.V. All rights reserved. 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