Antibacterial Surface Treatment for Orthopaedic Implants

Antibacterial Surface Treatment for Orthopaedic Implants

It is expected that the projected increased usage of implantable devices in medicine will result in a natural rise in the number of infections related to these cases. Some patients are unable to autonomously prevent formation of biofilm on implant surfaces. Suppression of the local peri-implant immune response is an important contributory factor. Substantial avascular scar tissue encountered during revision joint replacement surgery places these cases at an especially high risk of periprosthetic joint infection. A critical pathogenic event in the process of biofilm formation is bacterial adhesion. Prevention of biomaterial-associated infections should be concurrently focused on at least two targets: inhibition of biofilm formation and minimizing local immune response suppression. Current knowledge of antimicrobial surface treatments suitable for prevention of prosthetic joint infection is reviewed. Several surface treatment modalities have been proposed. Minimizing bacterial adhesion, biofilm formation inhibition, and bactericidal approaches are discussed. The ultimate anti-infective surface should be “smart” and responsive to even the lowest bacterial load. While research in this field is promising, there appears to be a great discrepancy between proposed and clinically implemented strategies, and there is urgent need for translational science focusing on this topic.

Biomaterial-associated infection is a disastrous complication of modern orthopaedic surgery that often leads to prolonged patient pain and functional losses. While international efforts to minimize the risk of these infections are underway [1], orthopaedic surgical site infections (SSIs) continue to occur in staggering numbers. Current estimates suggest that up to 2.5% of primary hip and knee arthroplasties and up to 20% of revision arthroplasties are complicated by periprosthetic joint infection (PJI) [2]. According to some authors not only are these numbers underestimates but they are also on the rise [3]. Staphylococcus aureus is the leading cause of both the SSIs and PJIs, and the prevalence of methicillin-resistant S. aureus (MRSA) SSI and PJI is increasing, especially in the United States [4]. Generally, deep infection leads to implant removal and ensuing increased morbidity and even mortality [5]. Moreover, therapy of PJI is associated with enormous costs [6].

Although methods developed for perioperative infection prevention such as antibiotic prophylaxis have been shown to be effective in SSI reduction, most assume a uniform intraoperative environment [7]. As the majority of operating rooms are contaminated within the first few hours of service [8,9], most surgeries are not performed in a bacterial-free environment. Within a certain operating room all patients are exposed to the same environment. The question therefore arises as to why some patients go on to have infections and others do not. This question has recently been re-examined; it is still premature, however, to give strict recommendations for clinical practice [10,11,12,13]. Even though modifiable SSI risk factors have been identified and well-described [7,14,15] it is not often possible to avoid operating on patients who are not “optimized”.

Several recent scientific forums have recommended that researchers should focus on the development of effective antibacterial surfaces that prevent bacterial adhesion, colonisation and proliferation into the surrounding tissues [1]. The aim of this review is to summarize current knowledge in this field with particular emphasis on technologies that could be suitable for prevention of PJI in total joint arthroplasty. Similar technologies could be employed for prevention of SSIs in other orthopaedic cases involving implants such as plates, intramedullary nails, and external fixators.

1.1. How to Win the Race for the Surface? Gristina proposed the concept of a “race for the surface” whereby host and bacterial cells compete in determining the ultimate fate of the implant [16]. Accordingly, when host cells colonize the implant surface first the probability of attachment of bacterial cells is very low and vice versa. This concept has stimulated technological and biomaterial progress while emphasizing the role of implant biocompatibility and tissue-integration. This model, however, can be criticized for its simplicity (simple rules, assumptions etc.), static conditions, and low capacity for prediction of PJI (inability to help with quantification of clinical uncertainty). Specifically, it is not able to interpret a wide zone often found between basic polar items, i.e., complete host cell versus bacterial cell coverage of an implant surface. The most destabilizing factor is the basic yet highly successful survival strategy of bacteria in general: their ability to adhere and survive on virtually all natural and synthetic surfaces [17,18]. Bacterial cell membranes contain various types of adhesins for a wide range of biomaterial surface receptor sites. Environmental and surface characteristics of a biomaterial such as surface roughness, hydrophobicity, and electrostatic charge play only conditional roles [19]. A reservoir of receptors for bacterial adhesive ligands mediating adhesion of free-floating bacteria to the surface of the biomaterial offers a conditional protein film covering an implant immediately after its placement into the host body [20,21,22,23]. Complement and albumin are considered the main components of this conditional protein film [24]. However, the protein spectrum extends much beyond complement and albumin and depends at least in part on a particular type of biomaterial attracting an exact set of host proteins and lipids [25,26,27]. Conceptually, the process of bacterial adhesion can be divided into two basic phases: reversible and irreversible () [28,29]. The former is mechanically and biologically less stable than the latter. The explanation lies in part on the origin of nonspecific interactions between implant surface characteristics and bacterial surface adhesins. The second phase is mediated by molecular and cellular interactions closely associated with expression of biofilm specific gene clusters in reversibly attached bacteria [30]. At least four distinct classes of surface proteins have been identified to participate on firm adhesion of S. aureus micro-colonies to a biomaterial and to each other [31]. An adhesion phase is followed by gene expression for secretion of protective slime. This process makes bacteria extremely resistant to both host immune system and antibiotic diffusion [29,32]. The transition between reversible and irreversible phases of biofilm formation coupled with phenotypical change is the last window of opportunity for clinically reasonable preventative measures. On the host site, the details of tissue integration of a biomaterial are still poorly understood [33,34,35,36]. It is believed that host cells attached to implant fixation surfaces orchestrate the processes leading to periprosthetic bone regeneration and remodelling that protect against bacterial colonization [37]. However, neither osseointegration nor fibrous tissue encapsulation of large non-fixation parts of an implant can eliminate long-term survivorship of bacterial micro-colonies. Moreover, peri-implant fibrous barriers can prevent contact between host immunity sentinel cells and bacterial molecules. This interaction is critical for host immune responses dependent on recognition of bacterial pattern-recognition receptors (PRRs; also microbe associated molecular patterns = MAMPs). This cascade goes on to intracellular signal transduction by first-line cell adaptors that organize the appropriate host response via particular modules of innate and adaptive immunity [38]. Additionally, it has been demonstrated that implantation of a medical device impairs innate local host response and may facilitate the development of PJI [39,40,41]. As a result, there is a strong need for intrinsic implant surface antibacterial functionality that can overcome implant-induced defects in the local immune response. This is of utmost importance especially in patients with underlying compromised immunity [42] and in those undergoing revision surgery [42,43].

An important consideration in designing implants with antibacterial coating relates to the characterization of reasonable and justifiable cost [54]. Theoretically all patients undergoing total joint arthroplasty are at risk for PJI. Revision cases carry an increased risk in part due to the suboptimal local tissue environment [43,55,56,57]. Moreover, several studies emphasize that the risk of PJI across the board in orthopaedic surgery is on the rise [3,58,59]. As a result, one could argue that all patients should benefit from implants coated with a proven anti-infective surface. On the other hand, the risk for PJI is not homogenously distributed among the arthroplasty patients: it is stratified into the specific groups [42,60,61,62,63]. Therefore, it might be convincing to implant “biofilm resistant” prostheses only in patients at increased risk of PJI. A validated tool for screening patients for increased risk of PJI does not currently exist. Despite attempts to identify and stratify patients at risk of PJI [12,42,64,65,66] specific clinical algorithms are not routinely used. In addition, we have no data relevant for determining the potential costs associated with wide range usage of such a screening strategy. Taken together, the preventative strategy involving all patients undergoing primary and revision total joint arthroplasty seems to be more justifiable than a more restrictive approach targeting high risk patients. However, prior to implementation of such devices, it is necessary to demonstrate the significant reduction of PJI in a well-done population-based cost-benefit analysis [37].

1.6. Remarks on the Testing of Antibacterial Coatings A critical step in progress lies in the demonstration that newly developed biomaterials possess antibacterial efficacy [137]. To date there is no widely accepted methodology available that could precisely and reproducibly demonstrate antibacterial behaviour of the proposed anti-infective technologies. Major criticisms lie around static “closed” testing system whereas in vivo the implant has to face a dynamic, continuously changing, mechanically unstable and predominantly fluid environment [138]. As a result, the majority of studies to date have used inappropriate and insufficient protocols. Controllable, standardized testing conditions that closely mimic the human in vivo environment are needed in order to overcome the aforementioned issues [138]. PJIs develop at low shear conditions and under multidirectional low-pressure fluid flow. A variety of testing tools have been proposed that attempt to simulate conditions of continuous or intermittent fluid-displacement in both low and high shear conditions [139]. Protocols for cultivation of particular species (multispecies) biofilms at controllable, constant and reproducible conditions have also been described [140]. Finally, representative in vitro and in vivo models for each particular clinical situation (i.e., total joint arthroplasty, internal, external fixation) should be further developed and appropriately validated. Given the large variability of antibacterial strategies it is likely that testing methods must be better tailored to match the specific proposed strategy at hand [141].

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