Viewpoint Cite This: ACS Macro Lett. 2018, 7, 16−25
pubs.acs.org/macroletters
Antimicrobial and Antifouling Strategies for Polymeric Medical Devices Zachary K. Zander and Matthew L. Becker* Department of Polymer Science, The University of Akron, 170 University Ave, Akron, Ohio 44325-3909, United States
ABSTRACT: Hospital-acquired infections arising from implanted polymeric medical devices continue to pose a significant challenge for medical professionals and patients. Often times, these infections arise from biofilm accumulation on the device, which is difficult to eradicate and usually requires antibiotic treatment and device removal. In response, significant efforts have been made to design functional polymeric devices or coatings that possess antimicrobial or antifouling properties that limit biofilm formation and subsequent infection by inhibiting or eliminating bacteria near the device surface or by limiting the initial attachment of proteins and bacteria. In this Viewpoint, we highlight the magnitude of device-associated infections, the role of biofilm formation in human pathogenesis, and recent advances in antimicrobial and antifouling polymers, as well as current strategies employed in commercial devices for preventing infection.
D
countries that are actively participating in consortiums with HAI control programs in place. For less-developed countries, it is expected that the device-associated infection rates in ICUs are 3−5× higher.7 Device-associated HAIs (DA-HAIs) are not always caused by host response to the device and patient bacteria; research has suggested HAI prevention programs that educate hospital personnel on infection-control practices can reduce DA-HAIs by as much as 50−70%.2,9 The conclusions from these reports, however, also suggest that achieving 100% prevention may not be possible, even with comprehensive guidelines in place. Hence, there is a need for antimicrobial and antifouling devices to assist medical professionals when a lapse in infection-control guidelines occurs and to reduce or eliminate DA-HAIs that result directly from implantation and interaction with the host. In either case, the role of antimicrobial or antifouling devices would be to inhibit the growth and reduce/eliminate the bacterial contamination or to prevent the initial attachment and subsequent colonization of the device. According to the U.S. Food and Drug Administration (FDA), medical devices can range from tongue depressors to programmable pacemakers, and are intended to (i) diagnose,
evice-Associated Infections: The National Healthcare Safety Network of the Centers for Disease Control and Prevention (CDC) revealed that 722000 hospital-acquired infections (HAIs) occurred in U.S. acute care facilities in 2011.1 This corresponds to 1 in 25 inpatient admissions having an incidence of HAI that ultimately led to more than 75000 patient deaths. A significant portion of these HAIs (>25%) were directly associated with implanted medical devices.1 These statistics do not include HAIs that occur in intensive care units (ICU) where the overall number of patients is less, but the risk of mortality from infection is increased greatly as a consequence of the patient’s diminished health status. For example: there are nearly 80000 central venous catheter (CVC) associated bloodstream infections that occur each year in U.S. ICUs, with a 12−25% mortality rate.2 The medical costs associated with these patient complications alone are estimated to be between $296 million to $2.3 billion, annually.2,3 In addition, urinary tract infections (UTIs) are believed to account for 30−40% of HAIs worldwide, and 80% are directly linked to catheterization, that is, catheter-associated UTIs (CAUTIs).4,5 Although the mortality rate for CA-UTIs is 30000000 urinary
Figure 2. Onset of biofilm formation is often facilitated by fouling of the device surface with proteins and other compounds present in the body (i.e., a conditioning film). The process of biofilm formation begins with (1) bacterial attachment, followed by (2) coadhesion and matrix production, (3) microcolony formation, (4) further maturation, and (5) results in a mature biofilm that can disperse planktonic bacteria. There is also potential for infiltration by a secondary species during this process. (This figure was modified with permission from ref 8. Copyright 2002 Annual Reviews; http://www.annualreviews.org). 17
DOI: 10.1021/acsmacrolett.7b00879 ACS Macro Lett. 2018, 7, 16−25
Viewpoint
ACS Macro Letters mature biofilm. In a mature biofilm, the bacteria can detach and become planktonic or portions of the film may slough off causing the infection to spread and presenting a life-threatening situation for the host. A multitude of reports are available that describe in detail the process and signaling involved with each step of biofilm formation on a device surface.6,22−25 Even with this knowledge at hand, the question of how to prevent biofilm formation remains. The simplest approaches have aimed to prevent microbial adhesion (antifouling) or to eliminate adhering microbes (antimicrobial). In both approaches, however, the role of a conditioning film is often overlooked. Upon insertion of a medical device, the surface becomes rapidly coated with proteins and other host molecules forming what is known as a conditioning film.24,26 Even if a polymeric device or coating is initially inhospitable for microbial attachment, the accumulation of a conditioning film will eventually lead to microbial attachment and biofilm formation (Figure 2). This issue was highlighted in a recent commentary from an FDA and NSF cosponsored workshop in which Phillips et al. state: “There is ample evidence to support in vitro biofilm prevention capabilities of antibiofilm agents and technologies. However, the most current in vitro test methodologies usually do not incorporate in vivo device conditions.”27 Thus, it is important for researchers developing said technologies to consider the microenvironment of the location intended for device use, and attempt to simulate or screen for nonspecific adsorption of the corresponding host molecules. For example: the conditioning film in vascular catheters is typically an accumulation of platelets and plasma proteins, such as albumin, fibrinogen, and fibronectin, whereas urinary catheters usually become layered with proteins and electrolytes from the patient’s urine.6,26,28 It has been shown that several of the most common microbes responsible for DAHAIs (S. aureus, S. epidermidis, and C. albicans) can adhere to various proteins via site-specific adhesion receptors and produce coagulase enzymes that further promote bacterial adhesion and thrombogenesis.29−33 Alternatively, significant adsorption of plasma proteins alone may cause platelet adhesion and activation, leading to surface-induced thrombogenesis.34−36 Therefore, while it is necessary for a device or coating to thwart microbial attachment, a more sustainable biofilm prevention method would also prohibit nonspecific adsorption of proteins and other biological compounds. To reduce the frequency of DA-HAIs, many physicians resort to administering antibiotics, either orally or intravenously, prior to or immediately following device implantation.37 An unintended consequence of the excessive use of antibiotics has been the emergence of various antibiotic-resistant pathogens, which are a globally known epidemic.38 Biofilmassociated infections that develop on medical devices and in surrounding tissues are often treated with antimicrobial therapy to no avail, and device removal/revision surgery is required.39,40 In addition, antibiotics used to target biofilm infections have limited activity toward bacteria infecting peri-implant tissues, requiring additional antibiotic treatment (e.g., rifampicin) that functions as a monotherapy toward these pathogens and results in high risk for developing resistance.41 Thus, biofilms contribute to a multifold problem as a consequence of the infections they cause and the method by which they are treated. The looming fear associated with bacterial-resistance and a lack of new antibiotics to fight them has highlighted our need to prevent and care for infections using alternative methods.42
Active Research and Current Technology: Active research and technology in current polymeric devices or coatings that aim to prevent DA-HAIs have been reviewed extensively.4,20,43−46 The strategies employed can be divided into two categories: antimicrobial and antifouling (Figure 3). In short, antimicrobial
Figure 3. Classification of common strategies used to achieve antimicrobial and antifouling polymeric constructs for the prevention of DA-HAIs. This figure was adapted with permission from ref 45. Copyright 2012 MDPI.
materials are inhibitory or lethal to approaching microorganisms, whereas antifouling materials prevent the adhesion of microbes and proteins. The primary mode of action for antimicrobial activity is achieved through (i) biocide release or (ii) the presence of contact-killing moieties near the surface. Antifouling strategies generally employ one of several mechanisms to prevent adhesion, including (i) steric repulsion/hydration, (ii) specific protein interactions, or (iii) low surface energy.4,45 Henceforth, the active research pertaining to these strategies and their application in current medical devices will be discussed. Antimicrobial Strategies: Antimicrobial materials that employ biocide release approaches have demonstrated marginal success, with their primary drawback being the inevitable loss of activity once the anti-infective compound has been released or is no longer available at lethal concentrations. In addition, sublethal doses of antibiotics have been shown to accelerate resistance pathways and biofilm formation.18,47 For a comprehensive review of release strategies, the reader is referred elsewhere.43,48,49 However, several alternative release-based strategies that aim to prevent biofilm formation are gaining significant attention. These methods include the use of bacteria-specific antibodies for opsonization, gallium and iron complexes to interfere with bacteria/biofilm metabolism of iron, and nitric oxide release as a mimic of the natural immune response exerted by macrophages.18,20,48,50 The alternative to release-based strategies involves a “contact-active” approach. Contact-active materials feature monomers, functionalized side chains, or surface grafted moieties that are lethal to incoming bacteria upon contact. The majority of contact-active materials employ quaternary ammonium compounds (QAC), host defense peptides or 18
DOI: 10.1021/acsmacrolett.7b00879 ACS Macro Lett. 2018, 7, 16−25
Viewpoint
ACS Macro Letters
peripherally inserted central catheter (PICC) surfaces with zwitterionic polymeric sulfobetaine (polySB). The polySB modified PICCs demonstrated successful reduction of microbial attachment and thrombosis in vitro and in vivo (canine model).75 Because of their synthetic flexibility and orthogonality toward other functional groups, zwitterionic compounds, and polymers could be the next generation of antifouling materials for medical device applications. Additional antifouling strategies utilize specific protein interactions to prevent bacterial adhesion and nonspecific adsorption of other proteins. A classic example of this method involves the passivation of surfaces with albumin, a nonadhesion protein that hinders cell attachment and blocks nonspecific protein adsorption.76 For example, albumin coated tympanostomy tubes have been shown to reduce adhesion of foreign materials within the ear canal.77,78 However, in bloodcontacting devices albumin is eventually replaced by adhesive proteins with higher substrate affinity and leads to device fouling.79,80 Surfaces that are modified by adsorption or covalent attachment of heparin also elicit specific protein interactions that effectively reduce device fouling.81,82 Although heparin is primarily employed to prevent thrombus formation by binding antithrombin and changing its structure to accelerate antithrombin-mediated inhibition of clotting factors, it has demonstrated efficacy at preventing bacterial colonization.83−85 The mechanism by which heparin reduces bacterial adhesion to device surfaces is not certain. Since heparin contains the highest negative charge density of any known biological macromolecule, it is generally assumed that bacteria are repelled through electrostatic interactions. However, electrostatic repulsion of bacteria has only been observed under controlled environments, and some negatively charged surfaces have demonstrated higher protein adsorption in conjunction with reduced bacterial adhesion suggesting that protein interactions may be responsible.86−88 Furthermore, heparin-coated surfaces have demonstrated selective plasma protein adsorption wherein lower amounts of fibrinogen and fibronectin were adsorbed, and studies have shown that heparin inhibits binding of bacterial adhesins to fibronectin in vitro.89,90 Relatively, the vast landscape of solid substrates being explored for medical device applications and their specific interactions with serum proteins is poorly understood. Additional computational modeling and experimentation that examines general surface features (charge density, surface energy, topography, etc.) and their influence on the binding and conformational changes of common plasma proteins could prove useful in this field.91−93 Low surface energy materials exploit the principals of surface free energy and the work of adhesion to achieve low fouling. When the surface free energy is reduced and the interfacial tension between the liquid and substrate is high, the work of adhesion is minimized.94 The majority of low surface energy materials are hydrophobic polymers; fluoropolymers such as poly(tetrafluoroethylene) (PTFE) and silicones such as poly(dimethylsiloxane) (PDMS) have been explored extensively because they possess among the lowest of surface energies (
