Biomaterials Associated Infection

Implant-associated infections are caused by microorganisms which adhere to the device and form biofilms. Medical devices are highly susceptible to bacterial and fungal infections. The minimal abscess-producing inoculum is >10,000-fold lower in the presence than in the absence of a foreign body. This is mainly due to a local granulocyte defect. Not only abiotic, but also biological (devitalized) implants are prone to infection. Among the clinically most important devices are prosthetic joints. These implants are at life-long risk for infection. During the first 2 years after implantation, the majority of the infections are exogenous; later, they are mainly caused by the hematogenous route. The treatment goal is complete eradication of infection, freedom of pain, and correct function of the joint. Reaching this goal requires rapid diagnosis and a rational treatment strategy including adequate surgery (debridement, one-stage or two-stage exchange) combined with prolonged antibiotic therapy. Surface adhering biofilms are highly resistant to host defense and antimicrobial agents. According to animal experiments and clinical studies, rifampin is more efficacious against surface adhering staphylococci than other agents. In view of the limited efficacy of treatment, novel preventive options are required such as implant coating or quorum sensing inhibitors.

Coagulase-negative staphylococci, mainly Staphylococcus epidermidis, are currently the most frequent cause of hospital acquired infections in the USA. Mostly, but not exclusively, S. epidermidis infections are linked to the use of implanted medical devices like central venous catheters, prosthetic joints and heart valves, pacemakers, cardiac assist devices, cerebrospinal fluid shunts, and intraocular lenses. As new molecular techniques reveal that S. epidermidis are by no means the most prominent bacteria of the skin and mucous membrane flora, the implication is that S. epidermidis has specific virulence factors, which transforms this commensal bacterial species into one of the most successful pathogens in modern medicine. A vast array of specific attachment factors for native and host protein-modified device surfaces and the ability to accumulate in adherent multilayered biofilms appear to be vital for the success of S. epidermidis as a pathogen. Biofilm formation contributes to the ability of the organism to withstand the host’s innate and acquired immune defense mechanisms and to resist antimicrobial therapy, so that device removal is a regular feature for the treatment of S. epidermidis biomaterial-associated infection. Recent developments in the understanding of S. epidermidis virulence are reviewed in this chapter.

While it is generally accepted that Staphylococcus spp., including coagulase-negative staphylococci (CoNS), are associated with biomaterial-associated infection, it has become increasingly clear that Propionibacterium acnes is also a significant cause of such infections, especially in relation to prosthetic joint failure. P. acnes outnumbers CoNS in sebaceous gland-rich areas of the skin and has considerable pathogenic potential. Molecular phylogeny studies have revealed that P. acnes comprises major evolutionary lineages with distinct differences in the production of putative virulence determinants. Strains may, therefore, be benign skin commensals or have pathogenic and pro-inflammatory potential. The role of P. acnes in biofilm infections is often overlooked as, although P. acnes is microaerophilic-to-aerotolerant, for optimal isolation from clinical material, samples must be processed as for obligately anaerobic bacteria; biomaterials must be maintained in an anaerobic atmosphere immediately upon removal from the patient and adherent biofilm dislodged by mild ultrasound treatment. The application of non-culture methods does, however, overcome this problem and provides the potential to improve detection rates.

Biomaterial-associated infections constitute a major clinical problem that is difficult to treat and often necessitates implant replacement. Pathogens can be introduced on an implant surface during surgery or postoperative and compete with host cells attempting to integrate the implant. The fate of a biomaterial implant has been depicted as a race between bacterial adhesion and biofilm growth on an implant surface versus tissue integration. Until today, in vitro studies on infection risks of biomaterials or functional coatings for orthopedic and dental implants were performed either for their ability to resist bacterial adhesion or for their ability to support mammalian cell adhesion and proliferation. Even though the concept of the race for the surface in biomaterial-associated infections has been intensively studied before in vivo, until recently no in vitro methodology existed for this purpose. Just very recently various groups have proposed coculture experiments to evaluate the simultaneous response of bacteria and mammalian cells on a surface. As an initial step towards bridging the gap between in vitro and in vivo evaluations of biomaterials, we here describe bi- and tri-culture experiments that allow better evaluation of multifunctional coatings in vitro and therewith bridge the gap between in vitro and in vivo studies.

This chapter presents our efforts to develop a better mechanistic understanding of how biomaterial interactions with blood components lead to alteration of the basic pathophysiologic mechanisms, in particular, inflammation and the foreign body response, which increase the probability of bacterial interactions, colonization, biofilm formation, and infection. In particular, we present perspectives on mechanisms of S. epidermidis biofilm formation, the role of surface chemistry on biofilm formation, the role of bacterial slime production in device infections, the apoptosis of adherent polymorphonuclear leukocytes in the acute inflammatory response, neutrophil mobility and phagocytosis of bacteria on biomaterials, generation of reactive oxygen and nitrogen species by biomaterial-adherent neutrophils, and quorum sensing in S. epidermidis biofilm formation. Our work has focused on infection mechanisms of cardiovascular prostheses and devices where blood hemodynamics and shear stress play important roles in inflammatory cell interactions with biomaterial surfaces. However, we believe that much of our results also are applicable to static implant situations found in orthopedic, cosmetic (plastic), and other surgical areas.

Biomaterials are used in several clinical applications. Yet they often induce a strong immune response that can lead to implant malfunction and replacement. Thus, it is of crucial importance to deeply understand the biological response to biomaterials. Here, we focus on the molecular mechanisms underlying biomaterial–dendritic cell (DC) interactions. Biomaterials regulate DC adhesion via podosomes in a β2 integrin-dependent manner. Moreover, they primarily affect DC phenotype and function by impinging on multiple Toll-like receptor signaling pathways. By putting biomaterial–DC interactions (and their consequences) in the context of the foreign body response (FBR), we propose that DCs, whose function has been altered by biomaterials, could be engaged in multiple juxtacrine and paracrine interactions with other immune cells including macrophages and neutrophils. Through this complex intercellular network, DCs could affect the immune response at the implantation site initiating (or sustaining) the series of events leading to the FBR. The detailed knowledge of biomaterial–DC interactions could be exploited to design more inert biopolymers, thus minimizing the FBR or biomaterials that elicit controlled and specific immune reactions.

Biomedical devices made of biomaterials predispose to infection as they provide surfaces for biofilm formation by microorganisms. Moreover, their presence in host tissue also compromises the local host immune response, allowing bacteria to persist in the vicinity of medical devices to cause infection. Biofilm formation, particularly by staphylococci, has been described in depth in Chaps.​ 2 and Chaps.​ 6. This chapter therefore focuses on the colonization of peri-biomaterial tissue and host cells by bacteria, particularly staphylococci, on the characteristics of staphylococci residing intracellularly, the efficacy of antibiotics against intracellular staphylococci, and the pathogenic process leading to peri-implant tissue ­colonization and how immune modulation can contribute to prevent this.

Difficulties in eradicating medical device-related infections are primarily related to the presence of bacterial biofilms. The foreign body can often facilitate such infections, which may be usually caused by non-aggressive microorganisms with the ability to form biofilms even at low inoculum size.

The biofilm is responsible for several phenotypic changes in the bacteria including increased minimal bactericidal concentrations (tolerance to antibiotics). Other factors that have also been related to difficulties in the treatment of medical device-related infections are functional abnormalities in the activity of phagocytic cells in contact with the foreign body and the presence of intracellular bacteria.

While the anatomical location of the medical device can determine certain aspects of the treatment of these infections, this therapy must include an appropriate and lengthy antibiotic treatment combined with adequate surgical intervention. Antimicrobial therapy needs to be carefully designed, and the antibiotics to use against device-related infections can be chosen according both to their activity against bacterial biofilms and nongrowing microorganisms, and to their intracellular efficacy.

The specific characteristics of medical device-related infections, as well as the difficulties involved in their treatment, mean that multidisciplinary medical teams are required to ensure the optimal approach to and management of this pathology.

Transcutaneous medical devices are indispensible in medicine. Infection is the most frequently reported complication of indwelling devices and is associated with substantial costs, morbidity, and even mortality. Since antibiotics have limited efficacy in the treatment of such infections, removal of the device is required to eradicate the infection in a considerable number of cases. Therefore, measures to prevent contamination of devices during and after insertion are of crucial importance to minimize the incidence of device-related infection. Since the patient’s own skin microflora is considered a major source of infection of transcutaneous devices, reduction of skin colonization at the insertion site of devices has high priority as a means to reduce the incidence of infection. Strategies to reduce the risk for contamination of transcutaneous devices with skin bacteria include (1) hygiene measures during surgery, (2) promoting integration of implanted devices with host tissues, (3) surface modification of the device to prevent adherence of bacteria, and (4) topical antimicrobial prophylaxis. Use of antibiotics for topical antimicrobial prophylaxis is strongly discouraged in view of the risk for resistance development. Antiseptics can be effective to reduce the incidence of infection of transcutaneous devices, but application of these compounds is mainly restricted to superficial skin disinfection. In addition, there are increasing concerns regarding antiseptic ­resistance development related to the widespread use of these agents. Therefore, alternative antimicrobial strategies are urgently needed. The potential of antimicrobial peptides and of honey as novel antimicrobial agents to prevent infection of transcutaneous devices is discussed.

Contemporary Restorative and Regenerative Dentistry mandates the use of implantable devices, as part of the overall treatment plan. The ultimate aim is to restore missing teeth or regenerate defective tissues. This can be achieved by the implementation of devices such osseointegrated dental implants or tissue regeneration materials, respectively. The oral cavity is rich in microbiota, which have the capacity to form polymicrobial biofilm communities on natural or artificial surfaces. It is therefore inevitable that implanted dental devices are also prone to microbial colonisation, and associated oral infections, such as peri-implantitis. Treatment of these infections involves the elimination of the causative factor (biofilms) and restoration of the structure and function of the affected tissues. The present chapter is discussing the aetiology, pathogenesis, diagnosis and therapeutic challenges of these newly emerged infections of the oral cavity.

Musculoskeletal infection remains a great challenge in orthopedic and trauma surgery. Despite best medical and surgical practice and significant advances in research and development, bone and implant associated infections are still difficult to diagnose, impossible to prevent in all cases and require invasive and debilitating treatment. The development and safe clinical implementation of novel preventative, therapeutic or diagnostic strategies requires the use of animal models of infection, which provide crucial evidence regarding performance, cytocompatibility, biocompatibility, and safety prior to clinical implementation.

Many animal models of musculoskeletal infection have been described in the literature; however, there remains a dearth of fully standardized or universally accepted reference models hindering advancement in the field. The following chapter provides an overview of the animal models available for the study of musculoskeletal infection, the latest advances that are expected to improve them, and some of the most important scientific output achieved using these models.

Medical devices are increasingly used worldwide for an expanding ­repertoire of patient clinical needs. Biomaterials and medical device designs have become progressively more complex to accommodate diverse demands for performance and safety in vivo. While a majority of these implants satisfy their clinical expectations with safety and efficacy in their specific applications, a minority of implants induce serious adverse events with substantial health and economic consequences. One recognized challenge is the growing clinical problem with implant-associated infections. Increasing number and types of implants used in patients have resulted in increasing numbers of biomaterial-associated infections. Researchers and medical device manufacturers have responded to this challenge with intensified attention to innovating device designs, surgical implantation protocols, and biomaterials to minimize infection opportunities. Medical devices with claims to limit microbial adhesion and colonization using combinations of pharmacological, topological, and materials chemistry approaches have been brought into clinical use with the intent of reducing device-related infections. Many types of catheters, stents, orthopedic devices, contact lenses, surgical meshes, shunts, sutures, cardiovascular replacements, and many other device categories offer antimicrobial enhancements. Approaches include different biomaterials chemistries that intrinsically resist microbial colonization or that deter active growth on contact, surface modifications that produce topologies observed to limit pathogen attachment, medicinal, antiseptic or bioactive coatings, direct antimicrobial attachment to surfaces, or drug impregnation within the biomaterial, and extended release strategies that control antimicrobial agent release from the device over time after implantation.

Despite considerable research and development efforts, the problem of infections related to biomedical devices and implants persists. Silver has attracted considerable interest for its ability to mitigate bacterial colonization of biomaterials surfaces in vitro and has been used in some commercial products such as wound bandages. Silver ion releasing biomaterials are thus considered to be promising candidates for rendering surfaces of biomedical devices and implants resistant to bacterial attachment. Here we review a number of strategies used for the design of antibacterial coatings containing silver. We also discuss the continuing controversy regarding the potential for silver ions to exert adverse effects on human cells and tissue. Finally we briefly compare the silver release approach with the alternative strategy of antibacterial coatings comprising organic antibiotics covalently coupled onto biomaterials surfaces.

The main cause of failure of biomedical implants is bacterial infections. Despite all efforts, it will never be possible to completely free operating theaters from bacteria, as human bodies contain already 10¹⁴ bacteria. Once on a surface, bacteria start proliferating, while protecting themselves with a slime layer against the immune system and administered antibiotics. A promising route to prevent or at least reduce bacterial infections caused by implants is by making surfaces of the devices antibacterial. One way to eradicate bacteria on implants is by contact killing.

Quaternary ammonium compounds (quats) are very potent biocides. The generally accepted mechanism is that quats destabilize the cytoplasmic membrane, which leads to leakage and eventually to cell death. Unfortunately, a similar mechanism provokes cytotoxicity. Fortunately, it is feasible to optimize the balance between biocidal activity and cytotoxicity by adapting the chemical structures.

Bacterial infection associated with medical devices is a serious ­complication. One promising strategy to combat this problem is the functionalization of the device surface with a dense layer of polymer chains which can resist bacterial adhesion and colonization. These polymer chains may present large exclusion volumes to inhibit protein and bacterial adhesion and/or possess ­bactericidal functional groups. The coating of surfaces with these polymers may be carried out via a number of techniques such as self-assembly, grafting and ­surface-initiated polymerization. This article focuses mainly on polymer coatings which achieved the antibacterial effect without the leaching of the bactericidal components into the environment.

Musculoskeletal infection is one of the most common complications associated with surgical fixation of bones fractured during trauma. Severe fractures with extensive tissue damage are particularly prone to infection due to the high risk of wound contamination and compromised vascularity in the affected tissues. An infection associated with a fracture fixation device can delay healing, greatly increase patient morbidity, require multiple surgeries for effective treatment outcomes, and may tremendously increase treatment costs. In the following chapter, two approaches to reduce the incidence of infection associated with fracture fixation devices will be described. The first is a passive approach involving aspects of implant design and application, whereby the implant used and the techniques used to place them can influence resistance to infection, at least in animal studies. The second approach involves antibiotic-coated intramedullary nails with a focus on two different gentamicin coatings.

The Foley indwelling bladder catheter is the most commonly deployed prosthetic medical device. While this catheter provides a convenient way to drain urine from the bladder, it also provides easy access to the bladder for bacteria contaminating the skin insertion site. In addition the catheter undermines the basic antibacterial defenses within the lower urinary tract. As a result, catheter-associated urinary tract infections are the most common infections acquired by patients in healthcare facilities. Bacterial biofilms form readily on these catheters and play important roles in the pathogenesis of the conditions that complicate the care and seriously threaten the health of catheterized patients. This chapter reviews the many attempts that have been made to prevent infection and biofilm formation by incorporating antimicrobial agents such as silver, nitrofurazone, minocycline, rifampicin, other antibiotics and biocides into catheters. The failure of antimicrobial catheters to prevent the development of the particularly troublesome crystalline biofilms is discussed and the need explained for fundamental changes in the design of catheters.

Vascular catheters constitute an essential component of modern health care. The escalating use of vascular catheters has highlighted the need to optimize prevention of infectious complications. Bloodstream infection is the most common serious complication of indwelling vascular catheters. Although strict implementation of traditional infection control measures continues to be the primary measure for preventing infection, the level of adherence by medical staff to such measures varies over time, between different units, and across various medical centers. This limitation underscores the need to assess the potential clinical impact of surface modification of vascular catheters. Since catheter colonization can be a prelude to infection, antimicrobial modification of the surfaces of catheters has the potential of not only inhibiting bacterial colonization of the catheter surfaces but also reducing the incidence of catheter-related bloodstream infection. A number of antimicrobial-modified vascular catheters are currently available for patient care, but they differ with regard to the type of antimicrobials, application on the external versus internal catheter surfaces, spectrum and durability of antimicrobial activity, and the ability to clinically protect against catheter-related bloodstream infection. Scientific evidence should guide the present and future applications of antimicrobial-modified catheters.

Implant mucositis and peri-implantitis have an infectious etiology. If left untreated the inflammatory responses and the infection will result in loss of alveolar bone around dental implants. Clinically, this is combined with edema and redness of the soft tissues surrounding the implant. The ultimate consequences of implant mucositis and peri-implantitis may be loss of the implant.

Dental implant manufacturers have focused on implant design, ease of placement, esthetics, and new prosthetic components. Enhancement of osseo-integration has been attempted by changing titanium surface structures, titanium purity, and various coatings.

The biofilm structures at titanium dental implants comprise of bacteria that co-aggregate with each other and are difficult to eliminate mainly due to the rough threaded surfaces of oral implants making them difficult to debride. The microbiota initiates a host inflammatory response that in many aspects are similar to what can be seen in periodontitis. The prevalence of peri-implantitis ranges between 15 and 25%. Patients who have lost teeth due to periodontitis may be more prone to peri-implantitis. The susceptibility may be directly associated with a genetically complex predisposing risk.

Recent data suggest that professional mechanical debridement of pockets around implants and the patients’ own ability to keep implants free from bacteria is unpredictable. Professional debridement may be efficacious over shorter time periods and would most likely require intensive supportive therapy. In the event of limited response to nonsurgical mechanical supportive therapy, the adjunct use of local application of a slow-release antimicrobial agent could be considered. Surgical treatment to eliminate soft tissue pocket and attempts to establish hygienic conditions may not be acceptable to the patient in the esthetic areas. In these situations regenerative therapy may be considered.

Antibiotics are commonly used in medicine to treat infections. Restrictive use of antibiotics is a necessity to prevent the occurrence of wide-spread antibiotic resistance. Peri-implantitis is a local infection confined to the area around the affected implant. Therefore, local administration of an antibiotic drug in a high concentration is logical. Several local antibiotic products have been developed and studied extensively. Such local antibiotic drugs have been on the market for some years but due to a variety of factors some of these local antibiotics have been withdrawn from the market or may only be available in some countries. There is a need to develop new methods allowing effective delivery of local antibacterial and anti-inflammatory agents for the treatment of implant infections.

Methods: Two silver-coated endotracheal tubes have been studied in comparison with similar, uncoated tubes—each beginning with preclinical models and progressing to clinical studies. One is commercially available (Agento^® IC, C. R. Bard, Covington, Georgia, United States) and is coated with silver ions micro-dispersed in a proprietary hydrophilic polymer. The other remains investigational and is prepared by submerging a standard endotracheal tube into silver sulfadiazine (with or without chlorhexidine) and polyurethane.

Results: Both silver-coated tubes were active in preclinical models designed to mimic surrogate endpoints for VAP, such as in vitro bacterial adherence, biofilm formation, and bacterial burden in animal models. Both tubes were active in phase 2 studies of patients requiring mechanical ventilation. The commercially available tube was active in a randomized, phase 3 study and reduced the incidence of microbiologically confirmed VAP at any time after intubation (silver vs. uncoated, 37/766 [4.8 %] vs. 56/743 [7.5 %]; P = 0.03; relative risk reduction, 35.9 %) and within 10 days of intubation (27/766 [3.5 %] vs. 50/743 [6.7 %]; P = 0.005, relative risk reduction, 47.6 %).