Antimicrobial Coatings and Modifications on Medical Devices

Healthcare-associated infections (HAIs) are a leading cause of mortality and morbidity globally. Intensive care unit (ICU)-acquired infections represent the majority of HAIs and are most often associated with the use of invasive medical devices. These infections highly correlate with bacterial colonization and biofilm formation on the devices and can be complicated by other device-associated complications. In this chapter, advances in antimicrobial modifications on implantable medical devices, especially on typical critical care implants, are reviewed. The first part of the chapter introduces biofilm formation and its clinical linkage to HAIs. The second part reviews three infections classified by devices, i.e., catheter-related bloodstream infection (CRBSI), ventilator-associated pneumonia (VAP), and catheter-associated urinary tract infection (CAUTI), summarizing their causes, etiologic agents, and infection–complication relationship. The third part of the chapter investigates three typical critical care implants, i.e., vascular catheters, endotracheal tubes, and urinary catheters, focusing on substrate polymers and functional coatings to reduce device-associated complications especially those have been clinically evaluated. The last part overviews technologies have yet been clinically approved on medical implants but shown promising results to reduce bacterial colonization or biofilm formation.

This chapter introduces the public health challenge of medical device healthcare associated infections (MD-HAIs) and the regulatory science challenges involved with antimicrobial and anti-biofilm medical device technologies, including coatings and other modifications. In the United States, regulatory science is the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products. Good regulatory science can facilitate consumer access to innovative medical products that are safe and effective. Section I looks at our increasing understanding of how colonization and biofilm may play a role in the pathogenesis of medical device associated infections as well as in the emergence of drug resistant microbes. Device colonization and biofilm have unique clinical features such as persistence that make them challenging to address. This challenge requires a coordinated response from medical device manufacturers, clinicians and public health/regulatory authorities. In Section II, we take a broad view beyond antimicrobial coatings to consider the range of possible medical therapies (e.g., device coatings, antimicrobials, vaccines) to prevent MD-HAIs, their use, limitations and safety. In Section III, we discuss regulatory definitions of the different types of technology and discuss mechanisms of action and the importance of understanding combination products. Then in Section IV, we focus specifically on the regulatory science of antimicrobial technologies for medical devices. We show how the paradigm shift from a planktonic model of microbial life to a biofilm model introduces significant challenges to the scientific assessment process.

Antimicrobial materials require careful characterization and testing to evaluate their performance. Multiple methods exist for evaluating whether a material or coating prevents bacterial adhesion and/or biofilm formation. Given that the scenario and conditions in which the material or coating will be used must be taken into account to accurately assess anti-fouling efficacy, the selection of appropriate characterization techniques is critical. This chapter introduces the basic concepts associated with analyzing cell adhesion and describes several analytical methods that are used for testing. The testing procedure, benefits, and limitations of various techniques are also discussed.

Bacteria dwelling within medical device-associated biofilms are remarkably difficult to treat with antibiotics or antimicrobials. To better engineer and develop strategies to control these medical device-based biofilms, considerable interest has been focused on developing new types of diagnostic methods to study the architecture of, and metabolism within, such biofilms. Traditional studies of biofilm formation on medical devices have been carried out using selective plating techniques with destructive samples. However, selective plating is based on cultivation methods that may underestimate the overall extent of the population and only provides cell population measures over the spatially averaged population instead of providing an insight on the local scale of the population. Molecular-based approaches, especially coupled with other tools such as microscopy, flow cytometry, etc., have revolutionized the ability to rapidly detect, identify, and evaluate microorganisms in medical device-associated biofilms. Compared with conventional culture methods, molecular techniques not only can provide species information for bacteria present in biofilms but also help to understand the function and activities of the medical device-associated biofilms.

Examples of such molecular analysis methods include 16S rRNA gene sequencing, denaturing gradient gel electrophoresis (DGGE), terminal restriction fragment length polymorphism (T-RFLP), denaturing high-performance liquid chromatography (DHPLC), and pyrosequencing. In addition, the application of DNA probes (checkerboard DNA-DNA hybridization) or 16S rRNA probes hybridization (FISH) coupled with microscopy allows the detection and enumeration of bacterial species with the additional function of multi-parametric analysis. Other innovative methods, including flow cytometry (FCM), fluorescence-activated cell sorting (FACS), and imaging flow cytometry (IFCM), have also paved the way for new possibilities in biofilm research through gaining a wide range of data on specific proteins related to biofilm function and biochemical measurement. Further, the combination of molecular-based techniques with immunological approaches creates new possibilities in medical device-associated biofilm research through understanding the function and activities of taxa present in the biofilms, rather than just recognizing microbes. However, these approaches are not perfect as they still possess some weaknesses, including high cost, time-consuming nature, lower specificity, potential for artificial results, and high requirements for user expertise in instrument operation and sample processing, etc. Despite many big challenges ahead, molecular-based techniques for the analysis of medical device-associated biofilms are likely to become more important in determining taxa present in biofilms as well as help to understand the function and pathogenicity of microbial populations within biofilms. The combined usage of molecular-based experimental approaches with other methods, such as immunological analysis and microscopy, will further broaden its applications in clinically relevant diagnosis and treatment of biofilm infections associated with medical devices.

Implantable medical devices possess great utility for patients who require medical intervention and/or replacement of biological functions. Though providing a critical purpose, medical devices are prone to complications such as infection that often result in significant morbidity and mortality. Medical device-associated infections present a large challenge to the healthcare industry in terms of treatment and cost. Several approaches to mitigate infection have been explored and most focus on preventing initial colonization of the device with infectious microorganisms. One method that has been employed successfully in the medical device industry is the incorporation of antimicrobial agents in devices to inhibit or kill invading microbes. This chapter discusses current products in use in the healthcare field as well as some promising active agents that are in the beginning or advanced stages of market approval and release.

Biofilms cause a significant amount of all human microbial infections. Nosocomial infections are the fourth leading cause of death in the United States with ~60% of these infections being biofilms associated with some type of implanted medical device. Biofilms have profound implications for the patient, because microbes growing within biofilms are significantly less susceptible to antibiotics and host defenses than are their planktonic counterparts. Worldwide production of biomedical devices and tissue engineering-related materials is a $180 billion per year industry and expanding rapidly but could be severely compromised by unresolved infection issues. Antimicrobial resistance in bacteria is also a major worldwide healthcare pandemic. The worldwide explosion in multidrug-resistant bacteria (MDRB) is further exacerbated by the precipitous decline in the 1980s of new antibiotic development. The biomaterial/medical device community over the past 30 years has attempted to produce anti-infective devices or implants by either (1) mechanical design alternatives (liquid/air breaks, skin cuffs, antibiotic fills, all for indwelling catheters); (2) non-fouling anti-adhesive surface treatments; (3) tethered anti-infective agents, bound directly to the surface of the material (silver coatings, tethered quaternary ammonium salts, synthetic antibiotics); or (4) the controlled release of soluble toxic agents (chlorhexidine, antibiotics) into the adjacent surroundings. Most, if not all, of these approaches are only effective for very short periods of time (if at all), and none provide long-term protection (≥ 5–15 years) of device-based infections (e.g., late-stage endocarditis of heart valves can occur 15–20 years post-implantation).

Reviewed here are alternative approaches to the current use of systemic or localized delivery of toxic agents to prevent biomedical implant-based infections. These anti-antibiotic-based therapies include (1) disruption of bacterial iron metabolism, (2) enhancing phagocytosis, and (3) preventing amyloid fibril production within the biofilm extracellular matrix.

Microporous materials, a class of material that includes inorganic zeolites, hybrid inorganic-organic metal-organic frameworks, and organic polymers, are of great interest in the development of antibacterial materials. In this chapter, the current and potential uses of these materials as antimicrobial agents are discussed. These include delivery agents for silver and antibiotic molecules, as well as storage and delivery vehicles for gases such as nitric oxide. The potential of these materials as multifunctional antibacterial materials will also be discussed.

The medical device industry faces a ubiquitous threat of biofouling, generally leading to reduced efficacy or outright failure of implanted devices combined with increased healthcare cost. The use of polymers to make medical device surfaces nonadhesive to bacteria and other foulants in general is increasingly becoming a more attractive strategy in combatting this threat than active killing of bacteria. This chapter first introduces typical surface modification techniques that have been effectively used in medical devices, including physical adsorption, chemical attachment, chemical vapor deposition (CVD), and plasma-enhanced CVD. Then, specific anti-fouling surface chemistries and their respective anti-fouling mechanisms are overviewed, focusing on hydrophilic polymers, hydrophobic polymers, featured surfaces, and superhydrophobic surfaces. The current and potential medical applications of these anti-fouling modifications, in particular the distinctively versatile zwitterionic polybetaines, are therein also reviewed.

Biofilms are complex communities of microbial cells covered in an exopolysaccharide matrix and adhered to a surface. Colonization of medical devices is a significant problem in healthcare-associated infections, especially those related to implanted medical devices such as intravascular catheters and urinary catheters. Recent advances in light technology highlight the potential for light inhibition of biofilm formation in medical devices. This chapter reviews the microbial responses to light, mechanisms of photoinactivation, and some recent research on the use of light to eliminate biofilms. Although light holds a tremendous opportunity to treat antibiotic-resistant infections, challenges in relation to patient safety need to be evaluated. We also discuss some of the research aimed at translating the knowledge into clinical treatment of biofilm-associated infections.

Light can be used in conjunction with a number of light-sensitive compounds to confer anti-infective properties to medical device surfaces. These properties can be tailored according to requirements due to the ease with which light can be controlled in terms of wavelength and dose. Three main groups of compounds are currently used or being studied for applications in the field of medical devices: photosensitizers, photocatalysts, and photocleavables. Whilst many compounds within each group have previously found use in various aspects of medical or antimicrobial treatment, their exploitation in the field of anti-infective medical device surfaces is more recent. This chapter describes each group including the differing mechanism of action of each, highlighting relevant research, and focusing particularly on their use within medical device materials and recent clinical use.