Clm 4002

8/10/2019 Clm 4002

1/6

Inuence of material on the development of device-associatedinfections

E. T. J. Rochford, R. G. Richards and T. F. Moriarty

AO Research Institute Davos, Davos, Switzerland

Abstract

The use of implanted devices in modern orthopaedic surgery has greatly improved the quality of life for an increasing number of

patients, by facilitating the rapid and effective healing of bone after traumatic fractures, and restoring mobility after joint replacement.

However, the presence of an implanted device results in an increased susceptibility to infection for the patient, owing to the creation

of an immunologically compromised zone adjacent to the implant. Within this zone, the ability of the host to clear contaminating bacte-

ria may be compromised, and this can lead to biolm formation on the surface of the biomaterial. Currently, there are only limited dataon the mechanisms behind this increased risk of infection and the role of material choice. The impacts of implant material on bacterial

adhesion, immune response and infection susceptibility have been investigated individually in numerous preclinical in vitro and in vivo

studies. These data provide an indication that material choice does have an impact on infection susceptibility; however, the clinical impli-

cations remain to be clearly determined.

Keyword: Bacterial adhesion, biocompatibility, macrophage, preclinical testing, surface chemistry, surface topographyArticle published online: 30 July 2012Clin Microbiol Infect 2012; 18: 11621167

Corresponding author: T. F. Moriarty, AO Research InstituteDavos, AO Foundation, Clavadelerstrasse 8, Davos Platz CH7270,SwitzerlandE-mail: [email protected] ;http://www.aofoundation.org/ari

General introduction

All patients receiving implanted medical devices are atincreased risk of developing an infection at the surgical site.

This increased susceptibility to infection is observed for allmedical devices, ranging from fracture xation implants andprosthetic joints to catheters, shunts, stents, and prostheticheart valves. The increase in infection risk is linked to a local-ized immunological decit at the interface between the implantand the host. This immune deciency leads to a reduced abilityto clear microorganisms from the vicinity of the biomaterial,and any contaminating bacteria are therefore more likely tocause a device-associated infection. Thus, the medical deviceparadoxically becomes both the cause of and substrate for thedeveloping infection. This minireview describes the role of the

material of which the medical device is composed and how thisimpacts on the development of infection.

The most commonly used materials in modern orthopae-dic surgery include titanium and its alloys, stainless steel,cobaltchromium, and various polymers, including ultra-high

molecular weight polyethylene (UHMWPE), polyetheretherk-etone, silicone, various ceramics, and hydroxyapatite. Thesematerials obviously differ widely in both chemical andmechanical characteristics; however, they all have propertiesthat make them ideal for use in specic biomedical applica-tions, such as an appropriate modulus of elasticity, wearresistance, and a propensity for tissue integration. All of theaforementioned materials are generally considered to be welltolerated once implanted into the human body; however, adetailed understanding of how these materials impact oninfection risk is not yet available.

2012 The AuthorsClinical Microbiology and Infection 2012 European Society of Clinical Microbiology and Infectious Diseases

REVIEW 10.1111/j.1469-0691.2012.04002.x

8/10/2019 Clm 4002

2/6

The Effect of Implant Material inPreclinical in vivo Studies

In 1973, Andriole was among the rst investigators to real-

ize that foreign bodies could potentiate the development of osteomyelitis [1]. In this study, rabbit medullary canals wereinoculated with Staphylococcus aureus in either the presenceor the absence of a stainless steel pin [1]. In the presenceof the foreign body, osteomyelitis developed in 88% of cases, whereas none of those without the pin showed evi-dence of infection. Later studies then showed that theactual type of biomaterial implanted into bone could furtheraffect the chances of developing an infection [2]. Cylinderscomposed of stainless steel, cobaltchromium alloy, highmolecular weight polyethylene, pre-polymerized polymethyl-methacrylate (PMMA) bone cement or PMMA bone cementat the doughy, preset stage (i.e. polymerized in vivo) wereinserted into canine femoral canals, and signicant variabilityin the infection rate between the materials was observed.PMMA (polymerized in vivo) was found to be the most sus-ceptible to infection; at the time, this was surmised to beattributable to the heat created during PMMA polymeriza-tion and the possibility of toxicity, although the precisemechanism was not identied, and follow-up mechanisticstudies have not been performed. Heat-induced necrosis of the local tissues could certainly lead to increased cell death,and it has been shown that a localized zone of tissue necro-

sis can facilitate bacterial survival [3,4]. It has also beenshown that more subtle effects, such as changes in surfacetopography, can also play a role; for example, Cordero et al.[5] investigated the differences between cobaltchromium molybdenum (CoCrMo) and titaniumaluminiumvanadiumalloys with either a smooth polished surface or a micropo-rous coating. For both materials, the porous surfacesrequired signicantly fewer bacteria to cause a bone infec-tion in rabbits, and this could be attributed to the poroussurfaces providing a site for contaminating bacteria to multi-ply while shielding them from host immune defences. In arecent study investigating the numbers of bacteria presenton implants explanted from patients with infected hip andknee arthroplasties [6], it was found that there was no clearmaterial-based trend in the numbers of adherent bacteria.This study had a limited number of cases, and could notdetermine whether a particular material was more or lesslikely to lead to infection. Interestingly, one of the ndingsof this investigation was that, once implants are actuallyinfected, the total amounts of bacteria growing as biolmsupon the implants are similar, regardless of the materials of which they are composed.

Bacterial Adhesion

Bacterial contamination of the implant via adhesion is the rststep towards the development of device-associated infection.

Therefore, initial adhesion to an implant surface is an impor-tant step in the development of an infection. Bacterial adhe-sion may occur preoperatively or postoperatively, the keydifference being that, in the postoperative scenario, a condi-tioning lm composed of numerous host proteins is presenton the implant; this distinction is also seen in the literature. Aconditioning lm is formed rapidly after implantation, as pro-teins, such as brinogen, bronectin, and vitronectin, areadsorbed onto the surface of the device. The exact format of the conditioning lm is dependent on implant surface chemis-try (charge and hydrophobicity), topography, and exposuretime. This then affects all of the postoperative downstreamevents, including cellular and immune responses, tissue inte-gration, and bacterial adhesion [7]. Many bacteria have mecha-nisms, such as the microbial surface components recognizingadhesive matrix molecules of S. aureus, for adhering to theproteins of host protein conditioning lms, and these are con-sidered to be important virulence factors. Therefore, it is of importance to quantify bacterial adhesion and, if relevant, theefcacy of any antimicrobial strategies in the presence of phys-iologically relevant conditioning lms to assess the postopera-tive contamination risk.

In the absence of a host conditioning lm, surface roughness

has been consistently shown to alter and sometimes dominatebacterial adhesion [811]. For example, when standard micro-rough implant metals such as titanium and titaniumalumin-iumniobium alloy, or polymers such as UHMWPE, are com-pared with smoother variants, there is often a signicantdecrease in adhesion to the smoother surfaces when the sur-face features are of a smaller scale than the contaminating bac-teria [9,1214]. Once the bacteria have adhered to the surfaceof the biomaterial, it has been shown that expression of the icalocus, which is involved in staphylococcal adhesion and intra-cellular aggregation and biolm formation, is not affected bythe precise substrate upon which the biolm is formed, as wasobserved for polymers and metals, including stainless steel of varying topographies and titanium [15,16].

Host Response to Biomaterials andInfection

The host response to an implanted material may be summa-rized under the somewhat broad term biocompatibility.There is no precise denition of biocompatibility, and the

CMI Rochford et al . Implant material and infection 1163

2012 The AuthorsClinical Microbiology and Infection 2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 , 11621167

8/10/2019 Clm 4002

3/6

8/10/2019 Clm 4002

4/6

all the commonly used orthopaedic implant materials, tita-nium leads to the greatest direct osseo-integration. This canbe attributed to the three-dimensional roughness of the clini-cally used standard titanium, which facilitates osteoblastattachment and bone integration [33,34]. In contrast,

electropolished stainless steel, which has an extremelysmooth surface, often leads to brousosseous integration.Considering the obvious and signicant effect on cellularresponse that occurs, depending on implant surface chemis-try and topography, there is also a potential impact on infec-tion susceptibility. The micro-rough surface of commerciallyavailable titanium implants has been shown to confer greaterresistance to infection than electropolished stainless steel inthe rabbit tibia xed with dynamic compression plates [35].No clear reason for this effect was identied, other than theimproved biocompatibility of titanium. In a similar model

using low-contact locking plates, which do not cause contactnecrosis to the same extent as the dynamic compressionplates, neither the material nor the topography of theimplant impacted on infection susceptibility [36].

There are surprisingly few clinical data on the infectionrates associated with orthopaedic implants differing inimplant material. A trend towards reduced infection ratesfor titanium percutaneous pins [37] and spinal implants [38]has been identied in some studies; however, they were lim-ited in numbers, and less than conclusive. The clinical andthe preclinical results indicate that the role of materialchoice in infection risk is interlinked with implant design

[39], and the combination of both factors determines thetrue susceptibility to infection of an implant.

Designing Surfaces to Combat Infection

The implanted biomaterial also represents a technologicalopportunity for biomaterials science to offer design improve-ments for limiting these infections. Current antimicrobial-containing materials may be subcategorized on the basis of their means of achieving antimicrobial action: (i) those that

bind antimicrobial agents directly to the implant surface andthat act only on local bacteria that contact the surface, e.g.vancomycin covalently linked to titanium [40]; (ii) those thatrelease the antimicrobial agent from the implanted bulk bio-material, creating a local zone of killing around the implant,e.g. gentamicin-loaded PMMA [41]; and (iii) those thatrelease antibiotic agents from a lm or coating over theimplant, e.g. silver-coated endotracheal tubes [42], gentami-cin-coated intramedullary nails [43], and rifampinminocy-cline-coated central venous catheters [44].

To date, the portfolio of antimicrobial agents releasedfrom implanted biomaterials has most often involved tradi-tional antibiotics. In addition, other antimicrobial agents havebeen incorporated into biomaterials. These include silvernanoparticles [45], quaternary ammonium compounds [46],

peptides [47], furanones [48], nitric oxide [49], and numer-ous other novel molecular entities [5052]. Nanotechnologyalso offers some promise with regard to minimizing the bur-den of implant-associated infections, as reviewed by Monta-naro [53]. Techniques such as micropatterning of antifoulingsurfaces have shown that bacterial-repellent and tissue-friendly surfaces may be achieved [54]. Similarly, nanoparti-cles other than silver have also been investigated for antibac-terial efcacy. In one example, Shi et al. [50] incorporatednanoparticles composed of quaternary ammoniumchitosanderivatives; it was found that not only did these particles dis-

play antibacterial activity that supplemented the gentamicinthat is often added to the cement, but that they offered anti-bacterial protection for a longer duration than antibioticalone. These studies clearly indicate the potential for thedevelopment of antimicrobial surfaces by the use of novelmicrotechnologies and nanotechnologies.

Summary

In general, it seems that implant material can play a role in

all of the most important factors in relation to susceptibilityto infection, including bacterial adhesion, immune activation,and phagocytosis of bacteria. However, there are only spo-radic references in the clinical literature focusing on thetopic and the combined role of these features, and this rep-resents an area requiring greater investigation. To achieve asignicant impact in preventing infection in high-risk cases,active antimicrobial biomaterials have been developed thathave been shown to have signicant clinical impacts in reduc-ing the incidence of infection. However, for effective transla-tion of novel biomaterials from the laboratory to the clinic,the current commonly used preclinical validation methods

must be improved, to more accurately reect the clinical sit-uation, including incorporating the inuence of conditioninglms and the host response.

Transparency Declaration

The author declares having no conict of interest related tothe present article.



8/10/2019 Clm 4002

5/6

References

1. Andriole VT, Nagel DA, Southwick WO. A paradigm for humanchronic osteomyelitis. J Bone Joint Surg Am 1973; 55: 15111515.

2. Petty W, Spanier S, Shuster JJ, Silverthorne C. The inuence of skele-tal implants on incidence of infection. Experiments in a canine model. J Bone Joint Surg Am 1985; 67: 12361244.

3. Arens S, Eijer H, Schlegel U, Printzen G, Perren SM, Hansis M. Inu-ence of the design for xation implants on local infection: experimen-tal study of dynamic compression plates versus point contact xatorsin rabbits. J Orthop Trauma 1999; 13: 470476.

4. Schlegel U, Perren SM. Surgical aspects of infection involving osteo-synthesis implants: implant design and resistance to local infection.Injury 2006; 37 (suppl 2): S67S73.

5. Cordero J, Munuera L, Folgueira MD. Inuence of metal implants oninfection. An experimental study in rabbits. J Bone Joint Surg Br 1994;76: 717720.

6. Gomez-Barrena E, Esteban J, Medel F et al. Bacterial adherence toseparated modular components in joint prosthesis: a clinical study. J

Orthop Res 2012; [Epub ahead of print].7. Patel JD, Ebert M, Ward R, Anderson JM. S. epidermidis biolm for-mation: effects of biomaterial surface chemistry and serum proteins. JBiomed Mater Res A 2007; 80: 742751.

8. Edwards KJ, Schrenk MO, Hamers R, Baneld JF. Microbial oxidationof pyrite: experiments using microorganisms from an extreme acidicenvironment. Am Mineral 1998; 83: 14441453.

9. Harris LG, Meredith DO, Eschbach L, Richards RG. Staphylococcusaureus adhesion to standard micro-rough and electropolished implantmaterials. J Mater Sci Mater Med 2007; 18: 11511156.

10. Hosoya N, Honda K, Iino F, Arai T. Changes in enamel surfaceroughness and adhesion of Streptococcus mutans to enamel after vitalbleaching. J Dent 2003; 31: 543548.

11. Verheyen CCPM, Dhert WJA, de Blieck-Hogervorst JMA, van derReijden TJK, Petit PLC, de Groot K. Adherence to a metal, polymer

and composite by Staphylococcus aureus and Staphylococcus epidermidis.Biomaterials 1993; 14: 383391.

12. Kinnari TJ, Esteban J, Zamora N et al. Effect of surface roughness andsterilization on bacterial adherence to ultra-high molecular weightpolyethylene. Clin Microbiol Infect 2010; 16: 10361041.

13. Whitehead KA, Verran J. The effect of surface topography on theretention of microorganisms. Food Bioprod Process 2006; 84: 253259.

14. Wu Y, Zitelli JP, TenHuisen KS, Yu X, Libera MR. Differentialresponse of staphylococci and osteoblasts to varying titanium surfaceroughness. Biomaterials 2011; 32: 951960.

15. Patel JD, Colton E, Ebert M, Anderson JM. Gene expression duringS. epidermidis biolm formation on biomaterials. J Biomed Mater Res A2012; [Epub ahead of print].

16. Hudetz D, Ursic HS, Harris LG, Luginbuhl R, Friederich NF, Land-mann R. Weak effect of metal type and ica genes on staphylococcal

infection of titanium and stainless steel implants. Clin Microbiol Infect2008; 14: 11351145.

17. Williams DF. On the mechanisms of biocompatibility. Biomaterials2008; 29: 29412953.

18. Zimmerli W, Lew PD, Waldvogel FA. Pathogenesis of foreign bodyinfection. Evidence for a local granulocyte defect. J Clin Invest 1984;73: 11911200.

19. Saldarriaga Fernandez IC, Da Silva Domingues JF, van Kooten TGet al. Macrophage response to staphylococcal biolms on crosslinkedpoly(ethylene) glycol polymer coatings and common biomaterialsin vitro. Eur Cell Mater 2011; 21: 7379.

20. Sherertz RJ, Carruth WA, Marosok RD, Espeland MA, Johnson RA,Solomon DD. Contribution of vascular catheter material to the path-

ogenesis of infection: the enhanced risk of silicone in vivo. J Biomed Mater Res 1995; 29: 635645.

21. Marosok R, Washburn R, Indorf A, Solomon D, Sherertz R. Contri-bution of vascular catheter material to the pathogenesis of infection:depletion of complement by silicone elastomer in vitro. J Biomed Mater Res 1996; 30: 245250.

22. Anderson JM, Marchant RE. Biomaterials: factors favoring infection.In: Waldvogel FA, Bisno AL, eds. Infections associated with indwelling medical devices, 3rd edn. Washington, DC: ASM Press, 2000; 89109.

23. Zimmerli W, Waldvogel FA, Vaudaux P, Nydegger UE. Pathogenesisof foreign body infection: description and characteristics of an animalmodel. J Infect Dis 1982; 146: 487497.

24. Shanbhag A, Yang J, Lilien J, Black J. Decreased neutrophil respiratoryburst on exposure to cobaltchrome alloy and polystyrene in vitro. JBiomed Mater Res 1992; 26: 185195.

25. Brodbeck WG, Patel J, Voskerician G et al. Biomaterial adherentmacrophage apoptosis is increased by hydrophilic and anionic sub-strates in vivo. Proc Natl Acad Sci USA 2002; 99: 1028710292.

26. Hosman AH, van der Mei HC, Bulstra SK, Busscher HJ, Neut D.Metal-on-metal bearings in total hip arthroplasties: inuence of cobaltand chromium ions on bacterial growth and biolm formation. J Bio-

med Mater Res A 2009; 88: 711716.27. Hosman AH, Bulstra SK, Sjollema J, van der Mei HC, Busscher HJ, NeutD. The inuence of CoCr and UHMWPE particles on infection persis-tence: an in vivo study in mice. J Orthop Res 2012; 30: 341347.

28. Jakobsen SS, Larsen A, Stoltenberg M, Bruun JM, Soballe K. Effects of as-cast and wrought cobaltchromemolybdenum and titaniumalu-miniumvanadium alloys on cytokine gene expression and proteinsecretion in J774A.1 macrophages. Eur Cell Mater 2007; 14: 4554.

29. Lacey DC, De KB, Clanchy FI et al. Low dose metal particles can inducemonocyte/macrophage survival. J Orthop Res 2009; 27: 14811486.

30. Boelens JJ, Dankert J, Murk JL et al. Biomaterial-associated persis-tence of Staphylococcus epidermidis in pericatheter macrophages. JInfect Dis 2000; 181: 13371349.

31. Boelens JJ, van der Poll T, Zaat SA, Murk JL, Weening JJ, Dankert J.Interleukin-1 receptor type I gene-decient mice are less susceptible

to Staphylococcus epidermidis biomaterial-associated infection than arewild-type mice. Infect Immun 2000; 68: 69246931.

32. Broekhuizen CA, de Boer L, Schipper K et al. Staphylococcus epidermi-dis is cleared from biomaterial implants but persists in peri-implanttissue in mice despite rifampicin/vancomycin treatment. J Biomed Mater Res A 2008; 85: 498505.

33. Hayes JS, Richards RG. The use of titanium and stainless steel in frac-ture xation. Expert Rev Med Devices 2010; 7: 843853.

34. Hayes JS, Richards RG. Surfaces to control tissue adhesion for osteo-synthesis with metal implants: in vitro and in vivo studies to bringsolutions to the patient. Expert Rev Med Devices 2010; 7: 131142.

35. Arens S, Schlegel U, Printzen G, Ziegler WJ, Perren SM, Hansis M.Inuence of materials for xation implants on local infection. Anexperimental study of steel versus titanium DCP in rabbits. J Bone Joint Surg Br 1996; 78: 647651.

36. Moriarty TF, Debefve L, Boure L, Campoccia D, Schlegel U, RichardsRG. Inuence of material and microtopography on the developmentof local infection in vivo: experimental investigation in rabbits. Int J Ar-tif Organs 2009; 32: 663670.

37. Pieske O, Geleng P, Zaspel J, Piltz S. Titanium alloy pins versus stain-less steel pins in external xation at the wrist: a randomized pro-spective study. J Trauma 2008; 64: 12751280.

38. Soultanis KC, Pyrovolou N, Zahos KA et al. Late postoperative infec-tion following spinal instrumentation: stainless steel versus titaniumimplants. J Surg Orthop Adv 2008; 17: 193199.

39. Moriarty TF, Schlegel U, Perren S, Richards RG. Infection in fracturexation: can we inuence infection rates through implant design? JMater Sci Mater Med 2010; 21: 10311035.

1166 Clinical Microbiology and Infection, Volume 18 Number 12, December 2012 CMI


8/10/2019 Clm 4002

6/6

40. Antoci V Jr, King SB, Jose B et al. Vancomycin covalently bonded totitanium alloy prevents bacterial colonization. J Orthop Res 2007; 25:858866.

41. Henry SL, Ostermann PA, Seligson D. The prophylactic use of anti-biotic impregnated beads in open fractures. J Trauma 1990; 30: 1231 1238.

42. Kollef MH, Afessa B, Anzueto A et al. Silver-coated endotrachealtubes and incidence of ventilator-associated pneumonia: the NAS-CENT randomized trial. JAMA 2008; 300: 805813.

43. Schmidmaier G, Lucke M, Wildemann B, Haas NP, Raschke M. Pro-phylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury 2006; 37 (suppl 2): S105S112.

44. Raad I, Darouiche R, Dupuis J et al. Central venous catheters coatedwith minocycline and rifampin for the prevention of catheter-relatedcolonization and bloodstream infections. A randomized, double-blindtrial. The Texas Medical Center Catheter Study Group. Ann InternMed 1997; 127: 267274.

45. Martinez-Gutierrez F, Olive PL, Banuelos A et al. Synthesis, charac-terization, and evaluation of antimicrobial and cytotoxic effect of sil-ver and titanium nanoparticles. Nanomedicine 2010; 6: 681688.

46. Majumdar P, Lee E, Gubbins N et al. Combinatorial materials research

applied to the development of new surface coatings XIII: an investiga-tion of polysiloxane antimicrobial coatings containing tethered quater-nary ammonium salt groups. J Comb Chem 2009; 11: 11151127.

47. Chen R, Cole N, Willcox MD et al . Synthesis, characterization andin vitro activity of a surface-attached antimicrobial cationic peptide.Biofouling 2009; 25: 517524.

48. Baveja JK, Willcox MD, Hume EB, Kumar N, Odell R, Poole-WarrenLA. Furanones as potential anti-bacterial coatings on biomaterials.Biomaterials 2004; 25: 50035012.

49. Hetrick EM, Schoensch MH. Antibacterial nitric oxide-releasingxerogels: cell viability and parallel plate ow cell adhesion studies.Biomaterials 2007; 28: 19481956.

50. Shi Z, Neoh KG, Kang ET, Wang W. Antibacterial and mechanicalproperties of bone cement impregnated with chitosan nanoparticles.Biomaterials 2006; 27: 24402449.

51. Brooks B, Brooks A, Grainger DW. Antimicrobial technologies inpreclinical and clinical medical devices. In: Moriarty TF, Busscher HJ,Zaat SAJ, eds. Biomaterials associated infection: immunological aspectsand antimicrobial strategies. New York: Springer, 2012 (in press.)

52. Wu P, Grainger DW. Drug/device combinations for local drug thera-pies and infection prophylaxis. Biomaterials 2006; 27: 24502467.

53. Montanaro L, Campoccia D, Arciola CR. Nanostructured materialsfor inhibition of bacterial adhesion in orthopedic implants: a minire-view. Int J Artif Organs 2008; 31: 771776.

54. Wang Y, Subbiahdoss G, Swartjes J, van der Mei HC, Busscher HJ,Libera M. Length-scale mediated differential adhesion of mammaliancells and microbes. Adv Funct Mater 2011; 21: 39163923.



Documents

Clm 4002