Background
Implant-related infections (IRIs) are the result of bacteria adhesion to an implant surface and subsequent biofilm formation at the implantation site [
1]. The incidence of IRIs in orthopedic trauma patients was from 5 to 10% depending on the severity of the injury, condition of soft tissue, and the type of fracture [
2]. It remains challenging and expensive to treat IRIs, despite advances in antibiotics and new operative techniques. The traditional management of IRIs includes irrigation and debridement, obliteration of dead space, intravenous antibiotics, and removal of the hardware [
3]. Each year, 750,000–1,000,000 IRIs occur in the USA, and the government needs to spend more than $1.6 billion to cover the expense of the excess hospital charges [
4]. Especially, with the widely use of orthopedic implants, the number of infected implants was continued to increase [
5]. Even if the infected implants can be successfully removed by secondary surgery, the functionality of the limb and the fracture healing may be limited, which may eventually lead to fatal surgical operations such as amputation, joint arthroplasty, or arthrodesis.
So how to prevent the occurrence of fatal IRIs is more important than the treatment. IRIs are typically caused by microorganisms which grow in biofilms and adhere to the implant surface in a highly hydrated extracellular matrix. Avoiding biofilms forming can effectively prevent or treat IRIs [
6‐
9]. As the elective surgery could not be performed under an absolutely sterile environment, bacteria may prefer to adhere to the surface of the bioinert titanium implants and form biofilms, especially when the host’s immunological defense functions are compromised and/or the systemic antibiotic prophylaxis is not very effective [
10,
11]. Bacteria which can resist immune responses in biofilms were much less susceptible to antibiotics [
12]. Therefore, it is difficult to truly eliminate the biofilm infections and, typically, there are chronic recurring symptoms, even after antibiotic therapy. So the prevention of the growth of nosocomial pathogens is more important than the elimination of the biofilm in IRIs.
Because of the restrictions of traditional systemic drug treatment of bone infection, such as poor effect or hepatorenal toxicity, drugs for IRIs should be performed locally and specifically for implants sites at optimal concentrations over appropriate stages [
13].
Numerous strategies have been attempted to prevent and treat IRIs by either implant surface fabrication or incorporation of antibiotics into the implant devices. Recent developments in material science showed that implants with biodegradable polymer coatings can be used as controllable means to deliver antibiotics in a sustained fashion. Polymer coatings are capable of completely releasing all antibiotics in a sustained fashion thus minimizing any local or systemic toxicity associated with high fluctuating antibiotic concentrations. For example, Buchholz et al. [
14] reported that implant with a synthetic polymers coating as a local drug delivery system significantly reduced the infections and representing a promising approach in the treatment of IRIs. One of the main advantages of implant surface coating-mediated local drug delivery is keeping other parts of the body out of affected so as to avoid serious systemic side effects [
15]. A sustained and high antibiotic concentration over minimal inhibitory concentration (MIC) of pathogenic bacteria at the implant site is expected to inhibit bacterial adhesion, colonization, and biofilm formation [
16].
The antibacterial implant coating can be divided into calcium or silicon bone cements, polymer hydrogels, and antibacterial ion coatings based on the materials selected by different manufacturing processes like spraying, smearing, and electroplating [
17,
18]. In this review, we will focus on (1) implants coated with antimicrobial substances and (2) the usage of coating in prevention of IRIs.
Mechanism of the IRIs—biofilm
Biofilms are aggregates of microorganisms as a self-produced matrix of extracellular polymeric substances (EPS) where bacteria are frequently embedded. EPS adherent to the medically surface (skin, implants, wearing) are accounting for most of microbial infections in the internal fixation devices [
16]. Bioinert surfaces attract the biofilm formation [
18‐
20]. The ligand of bacterial fimbriae can be bound to electrovalent bond or hydrophobic bond on the surface of the material. The factors of a surface that determine initial bacterial attachment are its hydrophobicity and roughness [
19‐
21].
In most previous studies on bacterial adhesion on titanium and ceramic surfaces, the quantity of bacterial adhesion showed a direct positive correlation with surface roughness [
22‐
24]. From an atomic force microscopy (AFM) viewpoint, most surfaces are rough and all kinds of surfaces provide adequate conditions for bacterial adhesion [
25]. According to the thermodynamic model of microbial adhesion, hydrophobic materials are preferentially colonized by hydrophobic bacteria [
26‐
28]. Consequently, the adhesion properties of different bacteria are affected by the hydrophobicity of the bacterial cell surface [
29,
30]. Both
S. aureus and Methicillin-resistant
Staphylococcus aureus (MRSA) which are common bacteria in IRIs are known to prefer hydrophobic surfaces [
31,
32]. Titanium implants are often bioinert, smooth (Ra = 280 nm) but enough for bacterial adhesion [
33] and hydrophobicity to prevent blood clotting. Thus, biofilm formation occurs commonly [
22‐
33].
Biofilms are complicated systems with high microorganisms’ densities, ranging from 10
8 to 10
11 bacteria g
− 1 wet weight [
12]. Most of the biofilm biomass comprises hydrated EPS instead of bacteria. The intermolecular interactions among EPS components originating from self-organization of EPS matrix determine the mechanical characteristics and the biological activity of the matrix in the biofilm [
12]. The biofilm architecture formation is a continuous process that creates a micro spatial organization where bacteria clusters present in the biofilm in micro colonies. As the ramparts of bacteria, biofilms have the feature of antibiotics tolerance.
Antibiotics tolerance of biofilms is due to the properties of the biofilm matrix and of the slow growth which occurs in biofilms. The components of EPS matrix can deactivate antimicrobial substances diffused through the biofilm as diffusion–reaction inhibition [
34,
35]. Antimicrobial resistance may be promoted by diffusion–reaction inhibition form biofilms through decreasing the effective concentration of antimicrobials that bacteria are exposed to. On the other side, dormancy and slow growth rates have been considered to be ways of bacteria survival in biofilms being exposed to antimicrobials for a long time [
36]. The formation and antibiotics resistance of biofilm is time-dependent. The initial bacterial attachment (within an hour) is crucial for the biofilm formation [
37‐
39]. Cell wall-anchored (CWA) proteins of bacteria promote attachment to surfaces in the following 24 h bacteria adhesion stage. The scanning electron microscope (SEM) revealed implants surface was comprised of bacteria clusters always associated with fibrils, which was presumed as fibrin, and surrounded by diameter host cells [
35,
37]. When the bacteria are anchored to the implants, biofilm formation begins to develop. There was a new structure which was called “lacunae” till day 7 [
15,
35]. The lacunae is the shallow depressions consistent with the size of bacteria, which meant the matrix spaces left by dispersed bacteria. The accumulation of bacteria during biofilm formation is attributed only to the polysaccharide intercellular adhesin (PIA) [
38‐
40]. Next, the biofilm proliferation and maturation remodeling by phenol-soluble modulins (PSMs) begin [
41]. After 14–28 days, empty lacunae and a few bacteria were the main morphological characteristics of EPS matrix. This phenotype of EPS matrix remained the same till 6 months post-implantation and showed an unexpectedly outstanding stability of EPS mature biofilm in chronic implant-related infection [
35]. In summary, typical biofilm formation is first shaping at day 7 and its growth diffusion peaks covering 30–40% of the implant is at 2 weeks.
Unlike the distinct biofilm formation phenotypes in vitro, the in vivo biofilm formation comprised of strains is hard to be indistinguishable [
42]. The biofilm formation in vivo takes longer time than in vitro, which may be due to the “race to surface” between bacteria and host cells. Bacterial attachment and biofilm formation stage lasted 12–24 h, and the biofilm proliferation and maturation lasted 36–72 h for completion [
43,
44]. The early infection may be defined up to 3–4 weeks during which debridement and antibiotic therapy with the retained stable implants were performed in the traditional management perspective [
45,
46]. The residual biofilms on retained implants may cause the recurrence of IRIs in many clinical cases. Bioinert polymer coatings like polymethylmethacrylate (PMMA) [
47] with antibacterial agents have been used to prevent early fibrin and bacteria adhesion through its barrier and antibacterial effect for IRIs [
48,
49].
Over time, the complete biofilms are gradually formed, so is the antibiotic resistance. On the basis of time- and dose- dependent effect of antibiotic susceptibility [
50‐
53], ideal cumulative prevention and cure antibiotics release kinetics of the coatings should have the releasing peak over the minimal bactericidal concentration (MBC) during 7–14 days that prevent biofilm formation followed by sustained release between the MIC and MBC over several weeks. By inhibiting the biofilm formation, cells are in a dominant position in the competition against bacteria for growth, so the ideal releasing should have the concentration above MIC over at least 28 days.
At least 1% bacteria in stationary phase in biofilms are tolerant to antibiotics [
54]. As time goes on, more bacteria in the biofilm moved into the stationary phase. Hence, for some kinds of antibiotics like vancomycin, antibiotics tolerance of biofilms showed temporal correlation, which denoted that higher tolerance was shown in older biofilms for these antibiotics as well as metal nanoparticles like Ag [
34]. Moreover, biofilms would always die from the outside-in instead of the inside-out [
53]. According to the characteristics of biofilm, the treatment is more difficult than prevention. Depending on the type of fracture and contamination of the trauma, second operation for IRIs may be avoided by the use of coating with the ideal antibiotics release curve for prevention.
Conclusion
Prevention is better and more important than treatment for IRIs. The characteristics of time- and dose-dependence of biofilm formation require a more constant and sustained antibiotics release from implant coatings. Surface coating as one of implant surface fabrication approaches has been extensively investigated for the purpose of preventing and treating IRIs by either local antibiotics eluting or forming an antibacterial surface to resist the biofilm formation. A desired antibacterial implant coating is expected to enhance the adhesion and growth of host cells, while inhibiting bacterial adhesion and biofilm formation, so that host cells can be the winner in the “race to surface.” The formation of biofilm and antibiotic resistance are time- and dose-dependent, so that the antibacterial effect of coating should be sustained and constant at effective concentration at least for 4 weeks with a short-term releasing peak at 4–7 days. According to the characteristic of biofilms, layer by layer coating was more appropriate than monolayer coating for IRIs prevention.
S. aureus is one of the leading pathogens involved in IRIs [
138]. As shown in Tande et al.’s [
139] study that summarized the microbiological results of 2400 patients with IRIs, around 60% of IRIs was caused by
S. aureus. Patients with
S. aureus IRIs frequently have multiple medical comorbidities [
140], such as diabetes (30 to 40%) [
141] and rheumatoid arthritis (10 to 20%) [
142]. Gentamicin and vancomycin are commonly used antibiotics for local drug eluting. For many years, antibiotic (gentamicin and vancomycin)-impregnated PMMA bone cement has been widely used to prevent IRIs [
47]. Though PMMA cement is mechanically strong, the therapeutic efficacy of this treatment was questioned in recent studies. Major problems with antibiotic-loaded cements are their burst release and limited release of embedded antibiotics because of the diffusion through surface roughness, superficial pores, and surface erosion [
46,
59]. It is estimated that over 90% of loaded antibiotics are retained within the PMMA cement [
58]. Regarding the IRIs prevention, the polymers hydrogel coating significantly extended the antibiotics release. The hydrogels release the drug steadily through the crosslinking structure [
78‐
81]. Drug release is closely related to gel degradation through chemical bonds or ionic bonds [
82‐
85]. The silver or silver ion coating seems to be the best way of prevention because of its broad antibacterial spectrum, a stable time- and dose-releasing effect, stable structure. But it has certain side effects on the human body, even if it is partially sustained releasing.
There are great opportunities and challenges to construct an ideal local drug delivery system. It is necessary to further establish a polymer system that has appropriate mechanical strength, matrix formation, desired drug-releasing profiles, and is biodegradable in clinical application. Through data generated from many in vivo and in vitro studies were promising, there was lack of clinical trials for further validation. Therefore, future research should be concentrated on the clinical evaluation of polymer systems such as their clinical efficiency and analysis of post-operative surface of coatings. As for functional groups, drugs and agents can be improved in embedding method to achieve an ideal releasing curve, active ingredient, and conventional drug in new use or effective factors loaded.
In short, for modified implants, translational medicine is important. Whether the antibacterial polymer coatings are effective for prevention of IRIs or not needs clinical validation.