Polymeric Nanoarchitectures on Ti-Based Implants for Antibacterial Applications

23 Pages·2014·3.74 MB·English

Review
www.acsami.org
Polymeric Nanoarchitectures on Ti-Based Implants for Antibacterial
Applications
Long Zhang,†,‡ Chengyun Ning,†,§ Tian Zhou,‡ Xiangmei Liu,*,‡ K.W. K. Yeung,⊥ Tianjin Zhang,‡
Zushun Xu,‡ Xianbao Wang,‡ Shuilin Wu,*,‡ and Paul K. Chu*,∥
‡
Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Ministry-of-Education Key Laboratory for the
Green Preparation andApplicationofFunctional Materials, HubeiProvince KeyLaboratory ofIndustrial Biotechnology, Facultyof
Materials Science & Engineering, Hubei University, Wuhan, China
§
School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China
⊥
DivisionofSpineSurgery,DepartmentofOrthopaedics&Traumatology,LiKaShingFacultyofMedicine,TheUniversityofHong
Kong, Hong Kong, China
∥
Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China
ABSTRACT: Becauseoftheexcellentmechanicalpropertiesandgoodbiocompatibility,titanium-basedmetalsarewidelyused
in hard tissue repair, especially load-bearing orthopedic applications. However, bacterial infection and complication during and
aftersurgeryoftencausesfailureofthemetallicimplants.Toendowtitanium-basedimplantswithantibacterialproperties,surface
modification is one of the effective strategies. Possessing the unique organic structure composed of molecular and functional
groups resembling those of natural organisms, functionalized polymeric nanoarchitectures enhance not only the antibacterial
performancebutalsootherbiologicalfunctionsthataredifficulttoaccomplishonmanyconventionalbioinertmetallicimplants.
In this review, recent advance in functionalized polymeric nanoarchitectures and the associated antimicrobial mechanisms are
reviewed.
KEYWORDS: polymeric nanoarchitecture, antibacterial properties, biomedical implants, titanium, surface modification
1. INTRODUCTION example, the Norwegian Arthroplasty Register has reported
infection rates of about 17 and 11% for total hip arthroplasty
The aging population spurs increasing demand for orthopedic
and total knee arthroplasty in 2009, respectively,8 and as a
devices and implants. For instance, about 69.4 million people
overthe ageof50sufferfromosteoporosis inChina andthere result, the need for recurring surgery is rapidly rising. Clinical
analysisshowsthattheinfectionrateafterafollow-upsurgeryis
are more than 687000 hip fracture and 1.8 million vertebral
fracture incidents per year.1 Since the use of pure titanium in higher (5−40%) than that after the first one.9 Although
bone implants in vivo in the 1930s,2 different Ti-based alloys infectionisgenerallylesslikelytohappenthanasepticfailure,it
including first-generation pure titanium products and new- can cause complications with high morbidity and incur
generation Al- and V-free titanium alloys have been developed substantial cost.10 To prevent infection, it is essential to
to repair or substitute for damaged hard tissues. Ti-based endow metallic implants with the self-antibacterial ability. The
materials offer advantages such as good biocompatibility, coatingstrategyhasbeenproventobeeffectivetoenhancethe
corrosion resistance, and wear resistance, suitable Young’s antimicrobial properties of Ti-based implants11,12 and various
modulus,aswellashighstrengthcomparedtoothermetals.3−5
Unfortunately, bacterial infection is a serious complication Received: July12, 2014
during and after surgery jeopardizing long-term fixation of the Accepted: September18, 2014
metallic implants and causing premature failure.6−8 For Published: September18, 2014
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ref 57 59 −63 68
4 5 6, 8, 0 1 6 4 5 6 7, 9 7
5 5 5 5 6 6 1 6 6 6 6 6 1
experimentalmodel S.aureus fibroblast;osteoblast S.aureus S.epidermidis S.aureus;fibroblast;osteoblast S.aureus Streptoccoccus;UMR106cells S.aureus S.aureus;Peripheralbloodmononuclearcells Escherichiacoli;S.aureus;L929cells P.aeruginosa;S.aureus;MG-63 P.aeruginosa;S.aureus;Osteoblasts S.aureus;S.epidermidis;osteoblast
roperties antibacterialefficiency bactericidaleffectlasts17days thereleaseofGSispH-controlledwithanadjustableperiodoftimefrom1to2years;fullbactericidallevels(100%)after96hrelease awell-definedzoneofinhibition almostcompleteinhibitionofS.aureusgrowth inhibitthegrowthofbacteriacellsandimproveosteoblastfunctions significantdecrease(80%ofcontrol)inthebacterialcellnumber largeinhibitionzone;theanti-bacterialeffectofthepoly-mercoatingwasincreasedwiththedecreasedconcen-trationofthepolymer diminishthegrowthofbacteriastrainS.aureus(percentageofcellreductionwas98.17%afterjust1h) largeinhibitionzone;theZOI±is2.850.24mmand±2.130.15fortwobacteria,respectively inhibitbacterialgrowthandbiofilmformation;CFUsofbacteriaweredecreasedbyatleast85%invivo inhibitthebacteriaadhesionandbiofilmformation inhibitbacterialadhesion
P
EnhancedAntibacterial antibacterialmechanism theinhibitionofbacterialcellwallsynthesis theinhibitionofbacterialcellwallsynthesis interruptingproteinsynthesis theinhibitionofbacterialcellwallsynthesis interruptingproteinsynthesis interruptingproteinsynthesis interactionswiththecellmembrane interactionswiththecellmembrane interactionswiththecellmem-brane;interactwithnucleicacids;inhibitrespiratoryen-zymes;acceleratethegenerationofreactiveoxygenspecies. interactionswiththecellmembraneandnucleicacids,etc. interactionswiththecellmembrane interactionswiththecellmembrane electrostaticinteractions
h
Ti-basedMetallicImplantswit theroleofpolymers PLGA:encapsulatedantibioticsandextendedantibioticreleaseupto2.5weeks PPycanreleasedrugsuponelectricalstimulation;biocompatibility NPsallowsahigherdrugdensityandrealizesthereleaseofpH-controlledofGS increasetheloaddensityofvancomycin asacarrierofantibioticandbiomacro-molecule. heparinallowstheefficientbondingofGS/BMP-2;controllingreleaseofBMP-2andGSinasustainedandprolongedmanner antiadhesiveproperties;resistancetoenzymatichydrolysis(dentalimplants);Asadrugdeliverysystems effectivelycontrolthereleaseofCHX ligninasacomponentofHAPcompositecanprovidebetterinterconnectedporousstructureandthuspromptosteogenesis;ligninpossessesantioxidantandantimicrobialproperties goodbiocompatibility;antibacterialproperties asacarrierofTet213;thegraftdensityofTet213iscloselyrelatedtothecompositionsofbrush asanintermediatelinkerforfurtheranchoringofCecB antiadhesionpropertyofPMAA
ureson testcondition invitro invitro invitro invitro invitro invitro invitro invitro invitro invitro invitroandinvivo invitro invitro
t
c
mericArchite fabricationmethods plasma-sprayed electrodeposited NPs:ROMP;bygraftingGS-functionalizedNPsontotita-niumsurfaces photochemicalpolymerization surface-initiatedatomtransferradicalpolymer-ization(ATRP) immersion;covalentbonding solventcastingmethodologies sprayingdeposition electrophoreticdeposition(EPD) layer-by-layertechnique surface-initiatedatomtransferradicalpolymer-ization(SI-ATRP) immersion;covalentbonding surface-initiatedatomtransferradicalpolymer-ization(ATRP)
y
nctionalizedPol ofcoating (vancomycinandcefuroxime)-loadedPLGAcoatings penicillin/streptomycin--loadedPPycoatings GS-functionalizedNPscoatings vancomycin-PEG-acrylatecoatings P(HEMA-SA-GE/Col)-Ti GS/BMP-2/heparinized-DOPA-Ti chlorhexidine-loadedpolybenzylacrylatecoatings chlorhexidine-loadedpolylactidecoatings silver-loadedhydroxyapatite(HAP)/lignincoatings silvernanoparticle-loadedalginate/chitosancoatings antimicrobialpeptideTet213-bondedpoly(DMA-co-APMA)copolymerbrushescoatings cecropinB-loadedpolydopaminecoatings P(MAA-Silk)-Titanium
u
resentativeF types antibiotic-loadedpolymericarchi-tectures nonantibioticbactericideloadedpoly-mericarchitec-tures adhesion-resistantpolymericarchi-tecture
p
e
Table1.R antibacterialmodes bactericidalproperties antiadhesionproperty
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−75 omnican;
ref 70 71 72 37,73 76 77 ellsfrSuccichitos
cA,d
Table1.continued antibacterialfabricationtestexperimentalmodestypesofcoatingmethodsconditiontheroleofpolymersantibacterialmechanismantibacterialefficiencymodel PPy/PEGcoatings;electrodepositedinvitropolypyrroleisaexcellentconductingsurfacehydrophobicity;surfacethepercentageofbacteriaEscherichiacolipolypyrroleandpolymers;PEGcanenhancethemobilitychargeandelectrostaticgrowthinhibitionincreasespolyethyleneglycolofions,improvestability,andenhanceinteractionto88%antibacterialproperties PLL-g-PEG/immersioninvitroPEGcandecreasetheamountofadsorbedsurfacecharges;surfacedecreasetheamountofS.aureus;PEG-RGDcoatingsproteinstopographyadherentbacteriaby69%fibroblast;osteoblast antibacterialulvancovalentbindinginvitroantiadhesivepropertiesofulvansurfacehydrophobicity;surfacedecreasebacterialadhesion,P.aeruginosa;S.polysaccharidespolysaccharides-Tipolysaccharideschargeandelectrostaticwithareductionintheinitialepidermidispolymericinteractionadhesionupto96%.architecture antibacterialantibacterialRGD-Hyaluronicthelayer-by-layerinvitrogoodbiocompatibility;Antibacterialchitosanactsasachelatingagent;exhibitingabout80%reductionS.aureus;propertiespolysaccharidesacid/chitosan(LbL)electro-propertiesinteractswiththemembraneinbacterialadhesionosteoblastspolymericcoatingsstaticdepositionetc.architectureCH-LA-PDA-Tiimmersion;invitroPDA:asanintermediatelinkerforfurtherinteractionswiththecellTheantibacterialrateof93.3%P.eruginosa;S.covalentanchoringofCH-LAmembraneetc.againstP.eruginosaandaureus;bonding95.6%againstS.aureusosteoblast O-CMCS-PDA-Tiimmersion;invitroPDA:asanintermediatelinkerforfurtherinteractionswiththecelltheO-CMCScoatingresultsinS.epidermidis;−covalentanchoringofO-CMCSmembraneetc.7585%reductioninosteoblastbondingadherentbacteriaaAbbreviations:PLGA,poly(lactic-co-glycolicacid);S.aureus,Staphylococcusaureus;S.epidermidis,Staphylococcus.epidermidis;P.aeruginosa,Pseudomonasaeruginosa;MG-63,osteoblast-likehumanosteosarcoma;PPy,polypyrrole;NPs,sphericalnanoparticles;ROMP,ring-openingmetathesiscopolymerization;GS,gentamicinsulfate;HEMA,2-hydroxyethylmethacrylate;SAnhydride;GE,gentamicin;Col,collagen;PEG,polyethyleneglycol;DA,dopamine;PDA,polydopamine;CHX,Chlorhexidine;CH-LA,chitosan-lauricacid;O-CMCS,O-carboxymethylateZOI,zoneofinhibition;CFUs,colony-formingunit.
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kindsofcoatingshavebeendeveloped,forexample, antibiotics functionalized antibacterial polymeric nanostructures on Ti-
loaded coatings,13 inorganic bactericide doped coatings,14 based metallic implants.
bioactive antibacterial polymerization,15 nonantibiotic organic 2.2. Antimicrobial Mechanism. Generally, there are two
bactericideloadedcoatings,16andadhesion-resistantcoatings.17 types of antibacterial modes including the bactericidal and
Among them, antibacterial polymeric coatings possess distinct antiadhesion way. The former is to kill bacteria directly by
advantages such as tunable physical and chemical properties, bactericides on the implants,13 whereas the latter is to prevent
diverse functionalities, simple structure, low cost, and easy adhesionofmicroorganismsthroughantiadhesiveagentsonthe
fabrication.18,19 However, because of the nature of most surface.37,38 Although the precise antibacterial mechanism is
polymers, these polymeric coatings do not possess some stillnotveryclearatpresent,accordingtothereactionbetween
specialsurfacepropertiessuchashydrophilicity,roughness,and antibacterial agents and bacterial cells, it can be generally
surface polarity thereby hampering clinical applications.20,21 In divided into four main antimicrobial mechanisms as follows.
thisrespect,afunctionalizedpolymericnanoarchitectureonthe 2.2.1. Inhibiting the Synthesis of Bacterial Cell Wall. The
materials surface not only preserves the favorable bulk antibacterial activity of penicillin and other antibacterial agents
attributes of the polymer, but also introduces other unique such as vancomycin and cefuroxime can directly inhibit the
functions such as drug delivery, modulation of cell adhesion, synthesis of bacterial cell wall leading to the death of
cell differentiation, as well as inhibition and killing of bacteria. bacteria.39,40
Thispaperaimstoreviewtherecentresearchanddevelopment 2.2.2. Disruption of Protein Synthesis. Protein is often
of antibacterial polymeric nanoarchitectures on Ti-based synthesized directly from genes by translating mRNA.41 If
biomedical implants. inaccurate mRNA translation occurs in this process, the func-
tionsoftheproteincanbechangedandasaresult,theprimary
2. BACTERIAL INFECTION AND ANTIBACTERIAL
enzymesneededforcellsurvivalcannotbesynthesizedthereby
MECHANISM
causing death of the bacteria. Some antibiotics like amino-
2.1. Biofilm-Induced Infection. Implant-associated in- glycosides and chloramphenicol operate in this way. For ex-
fectionoccursfrequentlyduringandaftersurgeryandiscaused ample, gentamicin acts by irreversibly binding the 30S subunit
mainly by staphylococci and streptococcus. Complications can of the bacterial ribosome to disturb protein synthesis.42
lead to implant failure necessitating removal by a second 2.2.3. Interaction with Cell Membrane. Some antibacterial
surgery. Formation of a biofilm is one of the main reason for agentsinteractwiththeplasmamembraneofbacteriatodisrupt
infection. A biofilm that develops quickly after bacteria attach the integrity of membranes and impact the membrane
ontotheimplantsurfaceoftencontainsamacromolecularlayer permeability43 to kill them. Most antimicrobial peptides can
formed under physiological conditions.22 The macromolecular achieve this effect through interaction with the phospholipid
layerconstitutestheso-called“conditioningfilm”renderingthe component of the cell membrane.43−45 However, there is an
surface more hospitable for bacteria to colonize.11,22 Various increasing number of peptides found to proceed under other
kinds ofproteins from surrounding biological fluids like blood, mechanisms such as inhibition of cell wall or protein synthesis
interstitial fluids, salivary proteins, and plasma proteins adsorb or interaction with DNA or RNA.46
on the implants before the first germs appear.22,23 However, 2.2.4. Inhibiting Transcription and Replication of Nucleic
when the conditioning film is formed, bacteria can adhere and Acid. Some antibacterial agents can inhibit the transcription
subsequently colonize to form a biofilm that possesses a and replication of DNA, thus influencing the synthesis of
complex architecture by accumulation.22,24 A biofilm can resist necessary enzymes and cell division. For example, silver ions
the host immune response via host defense mechanism interact with nucleic acids and DNA molecules become
consequently destroying the host immunity ability on the condensed and lose their replication ability after treatment
metallic implant.25,26 Furthermore, it can withstand anti- with silver ions.47 It has also been shown that silver ions can
microbial challenge in two ways.25 The first one is failure of inhibit respiratory enzymes,48 accelerate the generation of
theantimicrobialagentthatpenetratesintothebiofilmsdueto
neutralization reactions between the antibacterial agent and
some components in the biofilms.25,27−29 The second one is
reduced susceptibility of the biofilm to antibacterial agents,
resulting in loss of activity of antibiotics against some slow-
growing bacteria in the biofilm.25,30
Althoughcontaminationduringsurgerycaninduceinfection,
most infection occurring on Ti-based metallic implants is not
related to surgeries.31,32 In the early stage after implantation,
thelocalimmunesystemisaffectedbythesurgicaltrauma,and
consequently bacterial infection often occurs during this
stage.33 Even after tissue integration, the local host immune
abilityispoorandrestrictedbyasmallquantityofbloodvessels
attheinterfacebetweentheimplantandsurroundingtissues.If
biofilm-related infection becomes chronic, implant failure
normally ensues because both surgical debridement and
conventional systemic antibiotic therapy have no effects at
that time.34 Hence, it is critical to prevent the formation of
biofilms by inhibiting initial bacterial adhesion or killing Figure 1. Cumulative concentrations of P/S and Dex after electrical
bacteria directly35,36 and a good understanding of the general stimulation(scanningrate=100mVs−1).Reprintedwithpermission
antimicrobial mechanism is crucial to the fabrication of from ref55. Copyright 2011IOP Publishing.
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Figure2.(A)GraftingofNPsontotitanium.(B)RepresentationofthebioactivematerialsatneutralandacidicpH.(C)Releasekineticprofilesof
titaniumfunctionalizedwithFITC-labeledGSasafunctionofpHforGSgraftedtotitanium,DGS=1.0±0.3μg/cm2.Reprintedwithpermission
fromref 56. Copyright 2012Elsevier.
reactive oxygen species,49 and interfere with the membrane nanoarchitectures by chemical reactions. The polymeric
permeability consequently leading to bacteria death.48,50 nanoarchitecture with a sustainable high concentration of
On the basis of the aforementioned possible antibacterial antibacterial agents can kill microorganism effectively and
mechanisms, while some antibacterial agents work on the cell decreases the amount of drug-resistant bacteria.51 The latter
membraneofthebacteria,othersaretakeninsidethecells.The antibacterialagentscanbereleasedcontrollablyfrompolymeric
former antibacterial agents can be easily fixed on polymeric nanoarchitectures toavoid possiblecytotoxicity andgeneration
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Figure 3. (A) Reaction schematic illustrating the synthesis of VAN bonded to Ti: (a) toluene at room temperature; (b) (i) Fmoc-AEEA,
HATU, MeNCHO, and N-methylmorpholine at room temperature; (ii) piperidine/MeNCHO; (iii) Fmoc-AEEA, HATU, MeNCHO, and
2 2 2
N-methylmorpholine at room temperature; (iv) piperidine/MeNCHO; (c) VAN, HATU, MeNCHO, and N-methylmorpholine at room
2 2
temperature.(B)SchematicoftheTisurfacemodificationprocedure.(d)Anhydroustolueneatroomtemperature.Thisreactionplacesalayerwith
methacrylategroupsonthesurfacetotakepartinfreeradicalpolymerizationandanchorthepolymerchainstothesurface.(e)UVlight,monomer
solution, photoinitiator. The methacrylated surface is covered by a monomer solution containing a polymerizable antibiotic (VPA[3400] in this
case), another polymerizable species (PEG[375]-acrylate), and a photoinitiator followed by exposure to ultraviolet radiation resulting in
polymerization. A fraction of the polymer chains is covalently attached to the surface, albeit in a geometrically structure more complex than that
shown here. In this reaction scheme, a polyacrylate backbone is formed with pendant VPA(3400) and PEG(375) assuming ideal polymerization,
m= 9 andn = 80. Reprinted with permission from refs 59 and87. Copyright 2010Springer and 2005Elsevier.
of drug-resistant bacteria.52,53 In addition, some polymeric Recently, there is more interest in applying this technique to
nanoarchitectureshaveasuitablechemicalcompositiontobody enhancing the antibacterial properties of Ti-based metallic
and good biocompatibility. Owing to the versatility and implants by introducing antibiotic-loaded biocompatible
advantages, functionalized polymeric nanoarchitectures with polymers such as poly(lactic-co-glycolic acid) (PLGA),54 α-ω-
uniqueantibacterialfunctionshavebeendevelopedonTi-based functionalized poly(ethylene oxide) nanoparticles (NPs),56
metallic implants. Table 1 summarizes the fabrication methods PEG-acrylate,58,59 poly(2-hydroxyethyl methacrylate) (P-
andcorrespondingantibacterialactivityoftypicalfunctionalized (HEMA)),60 and heparin-dopamine.61,62
polymericnanoarchitectures,whichcanbecategorizedintotwo Various kinds of antibiotics such as gentamicin sulfate,
groups including the bactericidal and adhesion resistant vancomycin,penicillin,andcefuroximehavebeenincorporated
ones.16,17,37,54−77 Of course, it is possible to combine the two into polymers by encapsulation54 and covalent bonding56,60 to
modes, for instance, antibacterial polysaccharides consisting of
introduce bactericidal functions on Ti-based metallic implants
chitosan (bacteriostatic/bactericidal) and hyaluronic acid because of their broad spectrum being effective against
(antiadhesion), the so-called antibacterial architecture.
infection caused by pseudomonas, proteus organisms, staph-
ylococci, and Staphylococcus aureus.54,56,61,79,80
3. BACTERICIDALPOLYMERICNANOARCHITECTURES The effectiveness of an antibiotic-releasing architecture
3.1. Antibiotic-Loaded Architectures. Conventional depends strongly on the rate and manner in which the drug
systemic antibiotic therapy may cause side effects and drug isreleased,whichisdeterminedmainlybythepropertiesofthe
interactions.78 Furthermore, antibiotic prophylaxis cannot polymericarchitecturesandantibiotictype.PLGAisoftenused
achieve the expected therapeutic effect on periprosthetic as a carrier of these antibiotics on account of its excellent
infection because of the low vascularity at the site of new biocompatibility and biodegradability. The antibiotics encapsu-
metallic implants. In contrast, the application of topical latedinPLGAisreleasedatasustainedrateeitherbydiffusion
antibiotics that can avoid these potential hazards though local of the drug or through degradation of the polymer. For
release of antibacterial agents has attracted growing attention. example,Yehetal.havepreparedavancomycinandcefuroxime
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Figure4.InvitroreleaseofgentamicinorBMP-2fromtheTisubstrate.(A)GentamicinreleasefromGS/Hep-Ti(●)andGS/BMP-2/Hep-Ti(○).
(B) BMP-2 release from BMP-2/Hep-Ti (●) and GS/BMP-2/Hep-Ti (○). (C) Schematic diagram showing immobilization of gentamicin
sulfate and bone morphogenic protein-2 (BMP-2) on the heparinized-Ti substrate. Reprinted with permission from ref 61. Copyright 2012
Elsevier.
loaded PLGA layer on Ti6Al4 V by plasma spraying and the of vancomycin makes it easier to dissolve in the PBS solution
release rate is determined by the antibiotics concentration and and release from the PLGA matrix.
numberofcoating layers ofthe PLGAencapsulation.54Infact, Polypyrrole (PPy), an intrinsic conductive polymer, has been
the optimal PLGA capsulation architecture shows a suitable usedincontrolleddrugdeliveryandsomeuniquecharacteristics.82
initialburstrelease(about8%releasein24h)whichisagood For example, the antibiotics that are encapsulated in PPy on
feature because the relatively high dose initially released to titanium can be released on demand to potentially combat bac-
protect against bacterial infection during the most critical terialinfectionbyapplyingavoltage.55AsshowninFigure1,80%
period after implantation, followed by relatively slow and of thedrugsarereleasedataconstantrateondemandwhenthe
continuousreleaseofcefuroximeoveraperiodof17dayswith voltageis applied forfivecycles at ascanning rateof 0.1 Vs−1.55
aneffectiveinhibitory effect.54,81Subsequent antibiotics release Although the controlled drug delivery system is an excellent
overtheminimuminhibitionconcentration(MIC)canprevent way to improve the lifetime of orthopedic implants, there are
bacterialinfectionattheimplantsiteduringhealing.Theinitial some shortcomings such as the demand for detection of
burstreleasecanbeexplainedbydiffusionoftheantibioticson infection beforehand and lack of suitable early burst release.
the surface or near the surface of the polymer coating, while The ideal drug delivery systems (DDS) should be able to
subsequent release is attributed to the diffusion process release drugs over a periodofseveral months toyears in order
influenced by the degradation rate of the polymer.81 The to prevent “late” infection that can occur 24 months later
hydrophilicityofthepolymerandantibioticsaffectsthe release postsurgery while improved efficacy, reduced toxicity and
profile. For example, the total amount of released vancomycin resistance, improved patient compliance, and convenience are
is about 95% of the loaded amount and larger than that of attained.83,84 Pichavant et al. have developed a drug delivery
cefuroxime (about 65%).54 However, the duration of effective system with automatic capacity on Ti6Al4 V by surface
releaseofvancomycinis5daysshorterthanthatofcefuroxime. silanization, in which pH-sensitive functionalized nanoparti-
This release phenomenon can be explained by the reduced cles (NPs) are formed by ring-opening metathesis copoly-
affinity between the hydrophilic vancomycin and hydrophobic merization in a dispersed medium of norbornene with α−ω-
PLGA after degradation of the initial hydrophilic poly glycolic functionalized macromonomers ended with gentamicin sulfate
acid (PGA).54 Another reason is that the hydrophilic property (GS). This process is schematically illustrated in Figure 2A.56
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Figure 5. Bacterial adhesion on (A) Ti, (B) Ti/PBA, and (C) Ti/PBA-0.35. Percentage of bacterial adhesion to (A) Ti, (B) Ti/PBA, and (C)
Ti/PBA-0.35.(D)Tiisthecontrolsurface(100%).Effectsofthesubstrateon(E)thenumberofsurvivingcellsand(F)ALPactivity.TheUMR106
cellsareculturedondifferentsubstratesfor24h.Thevaluesareshownasthemeans.*p<0.05forTisampleand#p<0.05forTi/PBA.Reprinted
with permission fromref 16. Copyright 2012 Elsevier.
The GS-loaded NPs-APTES (aminopropyltriethoxysilane) (S.aureus)afterthereleaseofGSatpH4,5,and6after48and
polymeric architecture allows local release of GS only under 96 h in vitro.56,57
acidicconditions(asshowninFigure2B,C)becausethebond Unlikearchitecturesthatcanreleaseantibioticscontinuously,
of GS-NPs is pH sensitive and broken gradually as the pH some polymeric architectures immobilize antibiotic macro-
decreases.55,57 In viewofthe decrease ofpH (between 6.9 and molecules on Ti-based metallic implants by means of
6.0) due to inflammation during surgery, about 10% of the intermediate polymeric functional groups. It is schematically
initialGSarereleasedand90%oftheGSremain.56Ingeneral, illustrated in Figure 3.59,87 In these cases, a silane coupling
bacterial infection and inflammation typically occur at pH as agentisoftentetheredtotheTi-basedmetallicimplantsbySi−
low as 5.5−7.0 and local acidosis occurs.56,85,86 There- O−Ti covalent bondto form stable self-assembled monolayers
fore,controlledreleaseofGSatthesiteofsurgicalimplantation (SAMs) through cross-linking,88−90 which acts as a “molecular
has an advantage of adjustable time period and can minimize bridge” between the metal and polymeric macromolecules.
the occurrence of antibiotic-resistant bacteria for a long time. 8-amino-3,6-dioxaoctanoate (aminoethoxyethoxyacetate;
In practice, GS-loaded NPs functionalized titanium im- AEEA) and PEG-acrylate are often used to anchor organic
plants significantly inhibit the growth of Staphylococcus aureus biocides tightly and increase the amount of anchoring organic
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beenreportedtohavethesameeffectsonkillingS.aureuswith
88% ± 16% reduction over 2 h and meanwhile, Vanc-Ti can
retain the antibacterial activity after repetitive challenges.87
Besides conventional radical polymerization, intermediate
polymeric macromolecules that are utilized to anchor anti-
biotics can begrafted onto Ti-based metallic implants by atom
transferradicalpolymerization(ATRP).60,91Inthisprocess,the
properties of the intermediate polymers such as molecular
weight, dispersion effectiveness, composition, and function-
alities can be precisely controlled regardless of the shape and
composition of the substrate.92,93 Therefore, the content and
type of the antibiotics immobilized on the surface can be
modulatedbycontrollingthechainlengthandendgroupofthe
intermediate polymers. For instance, P(HEMA) has been
grafted onto Ti by surface-initiated ATRP.60 Besides favoring
surface silanization on the titanium substrate, the pendant
hydroxyl end groups of P(HEMA) can be converted into
carboxyl groups and introduce amine groups allowing covalent
anchoringofpenicillinontitanium.60,94,95Thesustainablehigh
concentration of antibiotics almost completely inhibits the
growth ofS.aureus onthe antibiotics-P(HEMA)-Ti surfacefor
a long period.60 However, the bactericidal effect of the
antibiotic-tethered architecture depends on the amount of
antibiotics that may be lost during implantation. When the
amountoftheantibioticsfallsbelowMIC,prolongedexposure
increases the bacterial resistance.
In practice, biocides like gentamicin sulfate are often
incorporatedintopolymericarchitecturesonTi-basedimplants
together with bone morphogenic protein-2 (BMP-2), growth
factorsliketransforminggrowthfactor-β(TGF-β),andvascular
endothelial growth factor (VEGF), which not only prevent
bacterial infection but also promote bone integration between
implants and surrounding tissues.96−98 Titanium implants
functionalized by dual drugs (gentamicin sulfate and BMP-2)-
eluting exhibit excellent antibacterial activity and enhanced
differentiation of osteoblasts attributable to the controlled
release ofBMP-2andgentamicin sulfate fromthe heparinized-
Ti surface in a sustained and prolonged manner (shown in
Figure 4A, B).61,62 The functionalized polymeric architecture
is composed of heparin, dopamine, gentamicin sulfate, and
BMP-2. Because of the abundant sulfate and carboxylic groups
as well as high binding affinity, heparin, a highly sulfated
glycosaminoglycan, is often used as the intermediate poly-
meric bridge between the implants and antibiotics as well as
BMP-2.Thepreparationprocessofthiscomplexispresentedin
Figure 4C.61,99
All in all, antibiotics-loaded polymeric architectures have
large potential in enhancing the self-antibacterial properties of
Figure6.Scanningelectronmicroscopyimages:(A)originaltitanium metallic implants. However, the architecture may induce
surface, (B) DAL/CHI multilayer coated surface, and (C) AgNP- antibiotics-resistant bacteria and causes implant failure. Some
DAL/CHImultilayercoatedsurface.Reprintedwithpermissionfrom death-causing microorganisms such as the superbug NDM-1
ref66. Copyright 2013Elsevier.
and the Ebola virus have developed resistance against known
antibiotics.100,101Tosolvetheproblem,theantibiotic-resistance
biocides.58,59,88 The covalent bonds between them are not mechanismmustbebetterunderstood.Agoodwaymaybethe
influenced by the biological conditions such as pH and combineduseofvariousantibioticsandinorganicnanoparticles
composition of the electrolyte. Hence, the surface-tethered suchasZnOandsilvernanoparticlesthatareprimaryinorganic
metallic implants exhibit stable antibacterial activity as well as bactericides against a broad spectrum of antibiotic-resistant
good cytocompatibility and tissue compatibility.80,87,88 For bacteria.
example, Jose and Wickstrom et al. show that vancomycin 3.2. Nonantibiotic-Loaded Architectures. 3.2.1. Chlor-
covalentlyattachedtotheTialloysurface(Vanc-Ti)effectively hexidine. Besides antibiotics, nonantibiotic agents such as
preventcolonizationofStaphylococciepidermidis(S.epidermidis) chlorhexidine (CHX), Ag nanoparticles, and antimicrobial
andformationofbiofilmsevenincontinuousculturingorwhen peptides can be introduced to Ti-based metallic implants by
challenged seven times by S. epidermidis.79 This strategy has the surface polymeric nanoarchitecture.16,64−68 Chlorhexidine
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ACS Applied Materials & Interfaces Review
Figure7.Sketchofdifferentmodelsdescribingthemechanismandstructureofantimicrobialpeptidesinteractingwithlipidbilayers,asdiscussedin
theliterature.(Topleft)α-helicalconformationofmagaininwithitshydrophilicandhydrophobicsidesofthehelix,asquantifiedbyhelicalwheel
analysis,alongwiththerepresentationasanamphiphiliccylinder.(Bottomleft)Wormholeporemodelasproposedformagainin.(Topcenterand
right) Surface (S) state of antimicrobial peptides with the hydrophobic side groups anchored on the hydrophobic core of the bilayer. (Bottom
center)Barrel-staveporemodelasproposedforalamethicin.(Bottomright)Carpetmodel:antimicrobialpeptidescrowdingintheSstateleadingto
micellation. Reprinted with permission fromref 43. Copyright 2006 Elsevier.
(CHX), a symmetrical molecule with two ionizable guanidine both bactericidal effect and antiadhesion function simulta-
moieties, is effective against Gram-positive/negative bacteria neously inthe earlystage. Theformer is ascribed toCHX that
and fungi. In addition, it can be retained by dentinal hard inhibits the gycosydic and proteolytic activity to reduce the
tissues. CHX is thus often to combat bacterial infection by proteinase activity in most oral bacteria and fungi,117,118
immobilizing it on the surface of titanium implants.102−106 whereas the latter is attributed to the nonadhesive properties
IncorporationofCHXintosomebiocompatiblepolymerssuch of PBA suppressing hydrolysis of enzymes.16 However, the
as cyclodextrin andits derivatives (b-cyclodextrin (CD), malto- development of suitable drug carriers for prolonged control-
dextrin (MD), methylated-b-cyclodextrin (MBCD), hydroxy- lable release ofCHX still faces manychallenges because ofthe
propyl-b-cyclodextrin (HPBCD)), PLGA, polylactide (PLA), cytotoxicity of CHX, and good stability of the architecture is
and poly(ethylene-co-vinyl acetate) copolymer can achieve neededconsideringthatCHXismainlyusedindentalimplants.
controllable and continuous release of CHX.16,64,107−109 For 3.2.2. Silver. Silver is a well-known primary inorganic
example, recent studies show that CHX can be released from bactericide against antibiotics-resistant bacteria.119,120 Biomate-
CHX-PLA-modifiedtitaniumandthereleaserateisdetermined rials loades with nano silver particles exhibit higher and long-
by the degradation rate of PLA.64,110 In the process, the term antibacterial efficiency, excellent biocompatibility, as well
titanium substrate is anodized and then coated in a mixed as low cytotoxicity and genotoxicity.121,122 In the case of Ti-
solution composed of PLA and CHX by spraying.64 based metallic implants, coatings incorporated with silver nano
The cytotoxicity of CHX should be considered when this particles are often introduced.65,66 In comparison with
biocide is used to prevent bacterial infection because it can inorganic coatings such as Ag/hydroxyapatite (HA), Ag/
inducedirectcytotoxicityinhumanalveolarosteoblasts,human TiO , Ag/TaN, and Ag/titanate,14,65,66,123−127 the Ag/
2
alveolar bone cells, and stem cells from exfoliated deciduous ceramics/polymeric structure has better properties such as
teeth (SHED).111−116 The best way is to optimize the content higher toughness, better biocompatibility, and controllable
of CHX to achieve a satisfactory balance between cytocompat- release of Ag ions.65,66,128 For example, the Ag/HA/lignin
ibility and antibacterial properties. Cortizo et al. have prepared complex has been prepared by Erakovic et al. and immediate
an effective antibacterial architecture on titanium dental and continuous release of Ag ions from this complex is
implants coated with polybenzyl acrylate (PBA) that is loaded responsible for the reduction of S. aureus.65,128 In comparison
with different contents of CHX (labeled as Ti, Ti/PBA, Ti/ with Ag/HA coatings, the lignin-modified nanoarchitecture is
PBA-0.35, Ti/PBA-0.70, Ti/PBA-1.4).16 When 0.7 and 1.4% homogeneous without fractures.65,129 Similarly, Zhang et al.
CHX are loaded, some harmful signals indicating cytotoxicity have combined silver nanoparticles (AgNPs) with the
are found, for instance, morphological changes, shrinkage, dopamine-modifiedalginate/chitosan(DAL/CHI)polyelectro-
smaller and pyknotic cells, and loss of cytoplasmic processes. lytemultilayer.ThematerialsinhibitthegrowthofS.aureusand
Conversely, assays with 0.35% CHX do not show such effects. Escherichiacoli(E.coli)becauseofthesynergisticeffectsofCHI
In comparison with 0.7% and 1.4% CHX loading in the andembeddedAgNPs.66Furthermore,incorporationofAgNPs
polymericarchitecture,thelowestCHXconcentrationof0.35% into the polymeric multilayer (Figure 6) can avoid cell and
results in better comprehensive performance, i.e., higher tissue toxicity induced by the released AgNPs.66
antibacterial efficiency and greater osteogenic activity (shown In conclusion, nano silver-loaded polymeric architectures
in Figure 5).16 This CHX-loaded PBA architecture exhibits can regulate the release of silver ions and provide multiple
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