HIP PROSTHESIS BIOMATERIALS: A CHALLENGE IN PREVENTION OF BIOFILM FORMATION BIOMATERIAIS DE PRÓTESES DE QUADRIL: UM DESAFIO NA PREVENÇÃO DA FORMAÇÃO DE BIOFILME

The objective of this study was to identify the scientific evidences regarding biofilm formation prevention on hip prosthesis biomaterials. It’s an integrative review that aims to answer the following question: what are the scientific evidences regarding biofilm formation prevention on hip prosthesis biomaterials? The search was performed on PubMed portal and on databases: Web of Science, Embase, Cochrane, CINAHL and LILACS. Primary studies about the topic published online up until November 2017 in English, Spanish and Portuguese are included. Among 16 primary studies, 81.25% were in vitro experimental studies, in which polyethylene showed a higher biofilm formation than metallic biomaterials and polymethylmethacrylate. Among clinical studies, Staphylococcus epidermidis and Staphylococcus aureus were isolated in most of joint prosthesis components. New acylase-containing polyurethane coatings, silver-zirconium carbonitride films, bioactive gentamicin, biodegradable gentamicin-hydroxyapatite, vancomycin, titanium-silicon-carbonoxygen-nitrogen films and cross-linked polyethylene combined with vitamin E and a poly(2-methacryloyloxyethyl phosphorylcholine) layer were developed to prevent biofilm formation. Moreover, cobalt-chromium (Co-Cr) ions inhibited bacterial growth, and cobalt-chromium particles reduced biofilm development. The biomaterials that presented properties against biofilm formation were: bioactive gentamicin, biodegradable gentamicin-hydroxyapatite, vancomycin, acylasecontaining polyurethane, cross-linked polyethylene combined with vitamin E-blended and a poly(2-methacryloyloxyethyl phosphorylcholine) layer, silver-zirconium carbonitride films and titanium-silicon-carbon-oxygen-nitrogen films. Moreover, the Co-Cr particles released from metallic joint prosthesis showed higher antibiofilm activity than Co-Cr ions.


INTRODUCTION
Hip arthroplasty enabled mobility, quality of life and pain relief for patients with musculoskeletal disorders (LAMAGNI, 2014). However, the increase of these revision surgeries, even with the improvement of techniques and progress in prosthesis design and composition, is a factor that has generated problems and challenges in this field (BOZIC et al., 2015).
Only in the United States, the number of total hip arthroplasties (THA) doubled in four years, with nearly 260,000 surgeries done in 2004and 423,000 in 2008(VON RECUM, 1998PUCKETT et al., 2010;WU et al., 2011).
This procedure is liable to complications, since the infection related to implant is considered a major cause of prosthesis restricted movements and reduced durability (BOZIC et al., 2009).
Biofilm formation occurs with microbial adhesion to implant surface and production of a polymeric extracellular matrix (ECM) composed by proteins, polysaccharides and genetic material. The ECM make biofilm sessile microorganisms resistant to antibiotics and inaccessible to the immune system in comparison to planktonic microbiota. The control of microbial adhesion can prevent biofilm formation with a contamination risk reduction (LEONHARDT; OLSSON;DAHLEN, 1995;VON RECUM, 1998;DONLAN, 2001;WASELAU, 2002;ARCIOLA, 2006;FRÖJD, 2010;PUCKETT et al., 2010;WU et al., 2011).
Biofilm formation on medical devices and joint infection must be prevented because they are serious complications that can lead to patient immobilization, prolonged hospitalizations, functional and emotional morbidity as well as high costs to the health system (KLOUCHE; SARIALI; MAMOUDY, 2010).
At present, the treatment of infections associated with hip arthroplasty causes unnecessary risks to patient and additional costs to health service because it consists of removal and replacement of prosthesis by a new device and antibiotictherapy. This way, biofilm formation prevention on orthopaedic devices is of utmost importance to reduce the chances of microbial adhesion. However, there is no formal and standardize recommendation by international headlines regarding what antimicrobial agents can be used, which make it difficult to apply these agents in clinical practice (SOUSA et al, 2017).
In this sense, the objective of this research was to identify scientific evidences regarding biofilm formation prevention on hip prosthesis biomaterials in order to contribute to the preventive and infection control measures as well as reduce the removal of the orthopaedic device.

MATERIAL AND METHODS
It's an integrative literature review. The adoption of the scientific method is based on the ability to summarize publications about a particular subject, obtaining a better understanding of the phenomenon to be investigated. For the search, the following guiding question was formulated: what are the scientific evidences regarding biofilm formation prevention on hip prosthesis biomaterials?
The search of primary studies was performed on PubMed portal and on databases: Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Embase and Cochrane. The search strategy was based on the usage of controlled descriptors "Biofilms", "Hip Prosthesis" and "Arthroplasty, Replacement, Hip", and boolean operators AND and OR.
The controlled descriptors (MeSH terms, CINAHL titles, DeCS and Emtree terms) and the keywords used according to the databases are assembled in chart 1.
Chart 1. Combination of controlled descriptors and keywords according to the portal and databases used on the search of primary studies.

Controlled descriptors and keywords
PubMed Web of Science Cochrane LILACS "BIOFILME" AND "PROTESE DE QUADRIL" OR "ARTROPLASTIA DE QUADRIL" Embase "Biofilm" OR "Biofilms" AND "Hip Prosthesis" OR "Hip Prostheses" OR "Prostheses, Hip" OR "Prosthesis, Hip" OR "Femoral Head Prosthesis" OR "Femoral Head Prostheses" OR "Prostheses, Femoral Head" OR "Prosthesis, Femoral Head" AND "Hip Arthroplasty" OR "Arthroplasty, Replacement, Hip" OR "Arthroplasties, Replacement, Hip" OR "Arthroplasty, Hip Replacement" OR "Hip Prosthesis Implantation" OR "Hip Prosthesis Implantations" OR "Implantation, Hip Prosthesis" OR "Implantations, Hip Prosthesis" OR "Prosthesis Implantation, Hip" OR "Prosthesis Implantations, Hip" OR "Hip Replacement Arthroplasty" OR "Replacement Arthroplasties, Hip" OR "Replacement Arthroplasty, Hip" OR "Arthroplasties, Hip Replacement" OR "Hip Replacement Arthroplasties" OR "Hip Replacement, Total" OR "Replacement, Total Hip" OR "Hip Replacements, Total" OR "Replacements, Total Hip" OR "Total Hip Replacements" OR "Total Hip Replacement" The initial search recovered 237 scientific articles, in which 75 were duplicated studies, resulting in 162 primary studies ( Table 1). The flow chart presents the search strategies used on the portal and databases for article selection (Figure 1).  Primary studies about the topic published online up until November 2017 in English, Spanish and Portuguese are included in this research. On the other hand, the scientific articles that characterized biofilm morphology and its nature, infection treatment/diagnosis, performed with pearls/bone cement, review articles and case study were excluded.

RESULTS
Thus, 16 studies were selected, of which 81.25% were laboratory / experimental in vitro, that is, studies that simulate biological conditions in the laboratory and don't involve human beings nor animals. According to publication year, there was a concentration of articles published in 2015 (3/18.75%). Chart 2 presents a summary of the main information of each study.

Chart 2.
Synopsis of publications about the biofilm implications on biomaterials used on hip prostheses. Clinical studies that analyzed bacterial adhesion on different joint prosthesis biomaterials evidenced that polyethylene (PE) presented greater number of colony forming units than metallic materials and polymethylmethacrylate (PMMA). Staphylococcus epidermidis and Staphylococcus aureus were isolated on most of joint prosthesis components, being S. epidermidis, Staphylococcus capitis and S. aureus the bacteria with the greatest numbers of colony forming units (TOMÁŠ; NACHTNEBL; OTIEPKA, 2007;NURYASTUTI et al., 2011;GÓMEZ-BARRENA et al., 2012;LASS et al., 2014).

Metals and biofilm formation
Regarding titanium roughness, a study compared biofilm formation on three titanium alloy surfaces with different roughness, since each alloy presented a different surface finish according to certain hip prosthesis region. Results demonstrated that there was a difference in biofilm formation on biomaterials with distinct roughness (RAMAGE et al., 2003). Another studied metal was tantalum, but it did not presented antibiofilm activity in comparison to titanium (HARRISON et al., 2017).

Antibiotic coatings
Researchers developed a technology to covalently tether vancomycin to titanium without damaging biological properties of the metal surface and with antimicrobial activity (PARVIZI et al., 2004). Other studies with gentamicin and gentamicin-hydroxyapatite coatings showed that the developed biomaterials presented wide spectrum of antibacterial activity (NEUT et al., 2012(NEUT et al., , 2015.

Ion influence on biofilm formation
Researchers evaluated how cobaltchromium (Co-Cr) ions could influence on bacterial growth and biofilm formation. 200,000 / 93,000 µg/L Co-Cr concentrations reduced by 15% biofilm formation in S. aureus samples and by 26% in coagulase-negative Staphylococcus samples. Moreover, images obtained by confocal laser scanning microscopy demonstrated that the ions resulted in a reduction in biofilm thickness of more than 50% (HOSMAN et al., 2009). Similar study concluded that Co-Cr particles presented bacteriostatic activity against S. aureus under dynamic growth conditions (HOSMAN et al., 2011).
The biofilm is a complex problem, and its importance is acknowledge by health researchers and professionals. Hence, researchers have intensified efforts to prevent infection associated with prostheses and other medical devices (ARCIOLA et al., 2012).
Among the factors that influence biofilm adhesion, biomaterial composition stands out. In this review, polyethylene was the material with higher biofilm adhesion compared to PMMA and to hip prosthesis metals, once polyethylene components presented the highest microbial load (TOMÁŠ; NACHTNEBL; OTIEPKA, 2007;NURYASTUTI et al., 2011;GÓMEZ-BARRENA et al., 2012;HOLINKA et al., 2012;LASS et al., 2014). Co-Cr particles and ions released due to friction generated by artificial joint movement were also identified as factors that interfere in biofilm formation, reducing its development (HOSMAN et al., 2009(HOSMAN et al., , 2011. However, in another study Co-Cr particles allowed bacterial growth in planktonic form (ANWAR et al., 2007).
In scientific literature, development trend of coatings aiming for biofilm formation prevention was evidenced. Among adopted strategies, the antibiotic incorporation in orthopaedic cement used for fixation stands out. However, with the increasing progress in biomaterial models that promote better osseointegration, a technology capable of binding antibiotics to non-cemented prostheses was necessary and was developed. Antibiotic coatings that bind themselves to a metal were developed to provide antimicrobial effect without losing biomaterial properties (PARVIZI et al., 2004;NEUT et al., 2012NEUT et al., , 2015. Moreover, studies evidenced initiatives of production of new biomaterials with antibiofilm activity, but without antibiotic incorporation. This integrative literature review gathered five of this new coatings. Cross-linked polyethylene combined with vitamin E-blended and a poly(2methacryloyloxyethyl phosphorylcholine) layer coatings, silver-zirconium carbonitride (Ag-ZrCN) films, acylase-containing polyurethane coatings and titanium-silicon-carbon-oxygen-nitrogen (Ti-Si-C-O-N) films had antibacterial activity. However, nanocrystalline diamond coatings did not presented the same effect (HENRIQUES et al., 2009;LEWIS et al., 2010;FERRERI et al., 2015;KYOMOTO et al., 2015;GROVER et al., 2016).
The results of this study showed direct applicability in clinical practice because there are gaps in scientific literature about recommendations of antibiofilm agents to be used on orthopaedic prostheses. Besides, it is possible to infer that the choice of a biomaterial with better antibiofilm activity may reduce the risk of infection and loss of implant due to biofilm formation.
Thus, this research presented limitations by restricting articles published in Portuguese, Spanish and English as well as the fact that not all studies reported the calculation or sample randomization. However, the objective of identifying the scientific evidences about biofilm formation prevention on hip prosthesis biomaterials was achieved in this integrative literature review, allowing the progress of knowledge in this field.

CONCLUSION
In the scientific literature, the biomaterials that presented properties against biofilm formation were: bioactive gentamicin, biodegradable gentamicin-hydroxyapatite, vancomycin, acylasecontaining polyurethane, cross-linked polyethylene combined with vitamin E-blended and a poly(2methacryloyloxyethyl phosphorylcholine) layer, silver-zirconium carbonitride films and titaniumsilicon-carbon-oxygen-nitrogen films. Moreover, the Co-Cr particles released from metallic joint prosthesis showed higher antibiofilm activity than Co-Cr ions.

ACKNOWLEDGEMENTS
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -Brasil (CAPES) -Finance Code 001.