Hindawi Publishing Co po a ion
Jou nal o Nanoma e ials
Volume 2009, A icle ID 498505, 6pages
doi:10.1155/2009/498505
Resea ch A icle
Syn hesis and An imic obial Ac i i y o
a Sil e -Hyd oxyapa i e Nanocomposi e
Ma cos D´
ıaz,1Flo a Ba ba,2Mi iam Mi anda,3F ancisco Gui i´
an,4Ram´
on To ecillas,3
and Jos´
eS.Moya
1
1Depa men o Bioma e ials and Bioinspi ed Ma e ials, Ins i u o de Ciencia de Ma e iales de Mad id (ICMM-CSIC),
Can oblanco, 28049, Mad id, Spain
2Depa men o Ce amic, Ins i u o de Ce ´
amica y Vid io (ICV-CSIC), Can oblanco, 28049, Mad id, Spain
3Depa men o Nanos uc u ed Ma e ials, Cen o de In es igaci´
on en Nanoma e iales y Nano ecnolog´
ıa (CINN-CSIC),
F ancisco Pin ado Fe 26, 33011, O iedo, Spain
4Ins i u o de Ce ´
amica de Galicia, Uni e sidad de San iago de Compos ela, 15706, San iago de Compos ela, Spain
Co espondence should be add essed o Ram´
on To ecillas, [email p o ec ed]
Recei ed 21 Augus 2008; Re ised 14 Janua y 2009; Accep ed 13 Ma ch 2009
Recommended by Ma yam Tab izian
A sil e -hyd oxyapa i e nanocomposi e has been ob ained by a colloidal chemical ou e and subsequen educ ion p ocess in
H2/A a mosphe e a 350◦C. This ma e ial has been cha ac e ized by TEM, XRD, and UV-Visible spec oscopy, showing he
sil e nanopa icles (∼65 nm) suppo ed on o he HA pa icles (∼130 nm) su ace wi hou a high deg ee o agglome a ion. The
bac e icidal effec agains common G am-posi i e and G am-nega i e bac e ia has been also in es iga ed. The esul s indica ed
a high an imic obial ac i i y o S aphylococcus au eus, Pneumococcus and Esche ichia coli, so his ma e ial can be a p omising
an imic obial bioma e ial o implan and econs uc i e su ge y applica ions.
Copy igh © 2009 Ma cos D´
ıaz e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License,
which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
1. In oduc ion
Theoccu enceo bone ac u esdue o heg owingnumbe
o affic acciden s, as well as he musculoskele al condi ions
equi ing econs uc i e su ge y de i ed om he inc ease in
he human li e expec ancy, has led o an inc easing numbe
o people in he wo ld ha ing a leas one o hopedic o
den al implan . In addi ion o he conside able impac on
he heal h and quali y o li e ha hese ypes o su ge y ha e
on he popula ion, hey impose an impo an bu den o he
economy o coun ies. Only in he Uni ed S a es, he numbe
o o hopedic p ocedu es pe o med each yea —including
knee a h oplas y, o al and pa ial hip eplacemen , and
spinal usion—inc eased by nea ly 25 pe cen be ween 1997
and 2005, climbing om 822000 o 1.3 million, acco ding o
he la es News and Numbe s summa y om he Agency o
Heal hca e Resea ch and Quali y [1]. The same epo inds
also ha he cos s ela ed o hospi al s ays o o hopedic
p ocedu es o alled $31.5 billion. I has also been es ima ed
ha 2 million new den al implan s a e pe o med e e y yea
[2]. The e o e he need o eliable and economically easible
bioma e ials o healing ac u es o ea ing musculoskele al
diseases has inc eased in he las yea s.
Hyd oxyapa i e (HA, Ca10(PO4)6(OH)2) is he main
mine al componen o bone, and i s syn he ic o m is one o
he mos widely used bioma e ials o econs uc ion o he
skele on due o he lack o local o sys emic oxici y oge he
wi h i s os eoconduc i e p ope ies [3–5]. I is used as an
implan ma e ial bo h in i s bulk mainly po ous o m, o
illing in o econs uc ing bone de ec s, and as a hin coa ing
on me als, i anium and CoC Mo alloys, o hip, knee, and
den al p os heses. Al hough success a es o hese kinds o
implan s a e dependen on bone-implan os eoin eg a ion,
he success and long- e m su i al o he implan s a e also
dependen on he p e en ion o bac e ial in ec ion a e
implan placemen .
Despi e he use o pe iope a i e an imic obial p ophy-
laxis and lamina low ope a ing ooms, he in ec ion a es
associa ed wi h p os he ic join s ange be ween 1% and
9%, depending on he ype o implan [6]. Al hough he
2Jou nal o Nanoma e ials
in ec ion-associa ed implan ailu es occu less equen ly
han asep ic ones, hey a e he second eason o e ision
su ge y in he case o o al hip eplacemen s [7]and ep esen
he mos de as a ing complica ion wi h high mo bidi y and
ele a ed medical cos . Mo eo e , in ec ion a es a e su ge y
e ision a e 40% highe han a e p ima y eplacemen
[8]. S udies on o hopaedic pa ien s e ealed ha he
es ima ed a e age o al di ec cos associa ed wi h an in ec ed
case anges be ween $15 000 and $30 000—an inc ease o
app oxima ely 3 imes han he ini ial in e en ion—and
shown ha he pa ien s spen on a e age 14 ex a days in he
hospi al a e eadmission [9]. In he case o den al implan s,
complica ions de i ed om an implan -associa ed in ec ion
do no usually equi e pa ien hospi aliza ion, bu lead o
a de imen in he pa ien quali y o li e and sa is ac ion
because i is one o he easons o ea ly ailu es by lack o
osseoin eg a ion and he majo cause o la e ailu es [10].
The e o e, efficien p e en ion o implan -associa ed
in ec ions o a oid su gical e isions and expensi e and
long hospi al s ays ha inc ease he pa ien mo bidi y is o
pa amoun impo ance. One common and accep ed s a egy
o ea and p e en in ec ions associa ed wi h o hopedic
implan s is o deli e an ibio ics in a con olled manne a he
si e o implan a ion in o de o adminis e high local doses
wi hou exceeding he sys emic oxici y o hese d ugs [11–
13]. An ibio ic elease has been achie ed using a wide a ie y
o biocompa ible ma e ials in he o m o coa ings o beads.
Some o hese ma e ials a e polyme s (polyu e hane, poly-
hyd oxylalkanoa es, polyme hylme hac yla e (PMMA), poly
L-lac ic acid (PLA), poly(lac ic-co-glycolic) acid (PLGA),
e c.), and syn he ic hyd oxyapa i e (HA) [14–16]. Al hough
con olled d ug deli e y has been shown o nonbiodeg ad-
ablepolyme s,suchasPMMA,i seffec i eness, howe e ,
is s ongly dependen on he an ibio ic elease p o ile om
he polyme , which is a unc ion o he chemical simila i y
be ween he d ug and he polyme , as well as o he physical
p ope ies o he polyme i sel [14,15,17]. Mo eo e , he
nonbiodeg adable polyme s do no eso b and equi e a
subsequen ope a ion o emo al.
The biodeg adable an ibio ic-loaded polyme coa ings,
such as PLA o PLGA, a e able o eso b, so i o e comes his
la e disad an age, bu i s high hyd ophobici y is ano he
impo an d awback, since i places p ac ical cons ain s on
o mula ing de ices wi h sufficien an ibio ic loading and
dispe sion o eliable deli e y o an imic obials [14].
A good app oach o he local ea men o implan -
associa ed in ec ions is he use o HA coa ings o an ibio ics
deli e y, exploi ing he os eoconduc i e p ope ies o his
ma e ial. Howe e , he loading and elease a e is s ongly
dependen on he acidic o basic cha ac e o an ibio ics.
Acidic an ibio ics a e inco po a ed wi h g ea e efficiency
han basic an ibio ics because o he calcium-chela ing p op-
e ies o he ca boxyla e g oups. Howe e , h ough calcium-
ca boxyla e chela ing in e ac ions, he acidic an ibio ics a e
e ained o a g ea e ex en ela i e o he basic an ibio ics
[15]. This ac imposes ce ain limi a ions in cases ha
equi e he use o acidic an ibio ics, o example amoxicillin.
The capaci y o ce ain bac e ial s ains o de elop esis-
ance agains an ibio ics has a oused an inc easing in e es
o he con olled deli e y o o he an ibac e ial agen s wi h a
b oade ac i i y and low incidence o esis ance, such me als
like sil e o zinc, being an al e na i e s a egy o a oid he
o ma ion o adhesi e bac e ial ilms [18]. The an ibac e ial
p ope ies o sil e a low concen a ions o e a wide ange o
pa hogens, including he common bac e ial s ains in ol ed
in implan -associa ed in ec ions as well as he lack o oxici y
o he mammalian cells, a e well known [19–24].
Mos sil e -con aining an imic obial bioma e ials consis
o ei he elemen al sil e o Ag+(sil e sal s o sil e com-
plexes) inco po a ed in o o ganic (polyme s) o ino ganic
(bioglasses and HA) ma ices. While he in i o an imi-
c obial ac i i y o sil e -con aining polyme s (polyamides,
polyu e hane, and PMMA) and bioglasses has been ex en-
si ely s udied [25–28], he bac e icide ac ion o Ag-HA
ma e ials has been epo ed in less ex ension. Recen ly, Ag-
loaded HA composi es ob ained by ion-exchange me hods
(sol-gel o cop ecipi a ion) ha e been epo ed [29–32].
These ou es in ol e he sil e subs i u ion o calcium,
esul ing in a Ca-de icien hyd oxyapa i e. The an imic obial
esponse o hese ma e ials is good, bu hey ha e wo main
d awbacks: (i) he deple ion o calcium could ha e nega i e
effec s on he s uc u al s abili y o nano HA [31]aswell
as on i s os eoconduc ion abili y [32]; (ii) a apid elease o
sil e , depending on he pH, can ake place. These ac s ha e
b ough ou an inc easing in e es on sil e nanopa icles as
bac e icidal ese oi due o hei low solubili y in aqueous
media. S udies on nanosil e -loaded polyme ilms e eal
ha he du a ion o sil e elease is s ongly dependen on
he o al amoun o sil e nanopa icles [19]. The biocide
ac i i y o colloidal sil e nanopa icles is in luenced by
hei size— he smalle he pa icles, he g ea e an imi-
c obial effec [22]—howe e , he agg ega ion p oblems o
nanopa icles a e well known. A common solu ion o a oid
his disad an age is o suppo he nanopa icles on he
su ace o diffe en subs a es. Despi e he po en ial clinical
applica ions o nAg-HA composi es due o he combina ion
o os eoconduc i e and bac e icide p ope ies, he e a e ew
examples in he li e a u e o sil e nanopa icles suppo ed
on o hyd oxyapa i e pa icles. These ma e ials ha e been
ob ained by cospu e ing o sil e and hyd oxyapa i e o o m
coa ings on i anium su aces [33], and by in si u educ ion
o sil e ca ions on he su ace o HA pa icles [34]. In he
p esen wo k, a simple and low-cos me hod o suppo
sil e on he su ace o hyd oxyapa i e o ob ain a nano-nano
hyb id composi e, con aining 1 w % o elemen al sil e , wi h
an imic obial ac i i y is p esen ed.
2. Ma e ials and Me hods
2.1. P epa a ion. The p epa a ion me hod comp ises wo
s eps: (i) syn hesis o HA nanopa icles by a sol-gel p o-
cessing ou e, and (ii) p ecipi a ion o Ag2O nuclei om
sil e ni a e aqueous solu ion and u he educ ion wi h
an A /H2gas mix u e a low empe a u e o ob ain sil e
nanopa icles a ached on o nano-HA.
The p ecu so s employed in he HA nanopa icles
we e ie hylphosphi e (98%, Ald ich) and calcium ni a e
Jou nal o Nanoma e ials 3
(b)
(a)
In ensi y
0204060
2θ(deg ees)
Figu e 1: XRD pa e ns co esponding o diffe en s ages o HA
syn hesis: (a) amo phous d y gel; (b) c ys alliza ion a 550◦C.
e ahyd a e (≥99%, Fluka). Aqueous solu ions 3 M we e
p epa ed o eachp ecu so ino de oob aina inalCa/P
mola a io o 1.67. The phospho ous solu ion was added
d opwise o he calcium solu ion unde igo ous s i ing
while main aining he empe a u e a 65◦C and pH =8.
The pH was con olled by addi ion o NH4OH (28% w/w,
Fluka) aqueous solu ion. The esul ing colloidal suspension
was s i ed a 70◦C o wo hou s and hen aged a oom
empe a u e o 24 hou s o ob ain whi e and iscous gel. The
gel was d ied in a acuum chambe a 100◦C un il he sol en
was comple ely emo ed. The d y powde was g ound and
calcined a 550◦C o 2 hou s. A well-c ys allized HA powde
was ob ained.
In o de o p epa e he nAg-HA composi e 5g o he HA
powde ob ained in he p e ious syn hesis we e suspended
in 50.55 mL o dis illed wa e (9 w % o solids loading).
Subsequen ly, he suspension pH was adjus ed o 5 by adding
d opwise a 0.1 N HNO3aqueous solu ion unde s i ing a
60◦C.Then,10mLo a4.7×10−2MAgNO
3aqueous solu-
ion we e added o ob ain an nAg-HA composi e con aining
1 w % o me allic sil e . Unde con inuous s i ing, he pH
was adjus ed o 9 by adding d opwise a 1 M NaOH aqueous
solu ion o p ecipi a e Ag+ca ionsasAg
2O, acco ding o
he po en ial-pH diag am in aqueous solu ion o sil e
[35]. The suspended whi e powde slowly u ned o g ay,
indica ing he p esence o Ag2O p ecipi a ion nuclei. Finally,
he suspension was il e ed and washed wice wi h dis illed
wa e a 60◦C. The esul ing powde was d ied a 60◦Cand
calcined a 350◦C o 2 hou s in a gas mix u e o A /H290/10
in o de o educe he sil e oxide o me allic sil e , yielding
a pale b own powde . All s eps o his syn hesis we e ca ied
ou in absence o ligh o a oid he spon aneous educ ion o
sil e ca ions o elemen al sil e .
2.2. Cha ac e iza ion Techniques. X- ay powde diff ac ion
(XRD) pa e ns we e egis e ed using a B uke D8 Ad ance
diff ac ome e wi h a Cu Kα adia ion sou ce a a scan speed
o 0.5◦/min and a s ep scan o 0.02◦.
The powde pa icle size dis ibu ion was ca ied ou in
a ins umen Coul e ?LS 13320 using lase adia ion (λ=
750 nm).
T ansmission elec on mic oscopy images we e eco ded
on a Jeol 2000 FXII ins umen ope a ing a 200 kV.
0
5
10
15
20
Numbe (%)
0.11
Pa icle diame e (μm)
Figu e 2: Pa icle size dis ibu ion o hyd oxyapa i e powde .
UV- is spec oscopy was pe o med using a Ca y 4000
u - is spec opho ome e .
2.3. An imic obial Ac i i y. To in es iga e he bac e icidal
effec o he nAg-HA composi e, wo ypes o es s we e
pe o med as ollows.
(i) A quali a i e diffusion disk es using 105colony
o ming uni s (CFUs) o he S aphylococcus au eus
(Sa), Pneumococcus (Pn), and Esche ichia coli (Ec).
They we e cul u ed on LB aga pla es. Pelle s o
0.05 g, 8 mm in diame e , p essed a 100 MPa o
HA (as con ol) and o nAg-HA composi e we e
loca ed a he cen e o he Pe i pla e. The pla es
we e incuba ed o 24 hou s a 37◦C. The mic obial
inhibi ion zone was obse ed unde op ical mic o-
scope. The inhibi ion zone size a ound h ee pelle s
co esponding o he nAg-HA sample and he con ol
o he diffe en bac e ial cul u es was a e aged.
(ii) A quan i a i e analysis using 105CFU o a G am-
nega i e bac e ium Ec s ain B which we e cul u ed
on LB aga pla es con aining diffe en concen a ions
o composi e, 1, 5, and 10 mg/cm3, co esponding
o 10, 50, and 100μg/cm3o sil e nanopa icles,
espec i ely. Sil e - ee HA LB aga pla es cul u ed
unde he same condi ions we e used as a con ol.
Thepla eswe eincuba ed o 24hou sa 37
◦C, and
he numbe s o colonies we e coun ed. The coun s on
he h ee pla es co esponding o each sample we e
a e aged.
3. Resul s and Discussion
The c ys alliza ion p ocess o he hyd oxyapa i e powde is
shown in Figu e 1. The g anulome ic analysis (Figu e 2)
e ealed a s e ch size dis ibu ion wi h an a e age size (d50)
o 137 nm, in ag eemen wi h he TEM images o he powde
shown in Figu e 3.
The XRD pa e n o he esul ing HA-nAg powde
is shown in Figu e 4. The e lec ions a 38.1◦and 44.3◦
co espond o me allic sil e . No o he phases bu HA we e
4Jou nal o Nanoma e ials
50nm
Figu e 3: TEM image showing he size and mo phology o he HA
nanopa icles syn hesized.
0
30
60
90
Rela i e in ensi y
10 20 30 40 50 60 70
2θ
Figu e 4: XRD pa e n co esponding o he 1 w % Ag-con aining
HA composi e a e educ ion ea men (Ag (0)).
de ec ed, which indica es ha des abiliza ion o dissolu ion
o hyd oxyapa i e has no aken place du ing he Ag nanopa -
icles syn hesis.
The a e age pa icle size o sil e , calcula ed om he
Sche e o mula, was ound o be 65 nm. TEM images
show in Figu e 5 a size dis ibu ion o globula -shape sil e
pa icles ha ange be ween less han 20 nm and 100 nm.
The majo i y o la ge sil e pa icles occu on o agg ega es
o HA pa icles. This ac could be ela ed wi h a pa ial
des abiliza ion o HA pa icles in aqueous suspension ha
gi es ise o he o ma ion o agg ega es, whe e he g ow h o
Ag2O nuclei could be a o ed. I is well known ha he size o
he pa icles o med om a solu ion is in e sely p opo ional
o he numbe o small p ecipi a ion nuclei, so he g ea e he
numbe o hese, he smalle he pa icles ob ained [36]. The
dec ease o he speci ic su ace o HA agg ega es can affec he
dis ibu ion o he p ecipi a ion nuclei a hese si es, leading
o he g ow h o he pa icles. On he o he hand, bigge Ag
pa icles can also be o med by coalescence o smalle ones
du ing he educ ion p ocess.
50 nm
(a)
20 nm
(b)
Figu e 5: (a) TEM image showing he size dis ibu ion o Ag
nanopa icles; (b) high magni ica ion TEM image showing n-Ag
pa icles less han 20 nm a ached on he HA su ace.
The pale b own colo o he Ag-HA powde is due
o he exci a ion o su ace plasmon ib a ions o sil e
nanopa icles on he HA su ace. The UV-VIS spec um is
shown in Figu e 6.Theb oadbandcen e eda 450nmag ees
wi h a size dis ibu ion due o he pa ial agg ega ion o
sil e nanopa icles [34]. The colloidal sil e solu ions a e
yellow when he nanopa icles a e well dispe sed. Howe e ,
i he pa icles a e close enough, he e is an o e lap o he
su ace plasmon ib a ions be ween neighbo ing pa icles
and esul s in changes in he op ical p ope ies. This can
occu due o he agg ega ions o he sil e nanopa icles,
leading o an effec i e dec ease in he a e age in e pa icle
dis ance. The absence o highe -wa eleng h ea u es (see
Figu e 6) indica es he lack o aniso opy o he sil e
nanopa icles, in good ag eemen wi h he TEM images.
Jou nal o Nanoma e ials 5
Abso bance (a.u.)
350 450 550 650 750
λ(nm)
450 nm
Figu e 6: UV- is spec um o he Ag-HA powde showing he
su ace plasmon band o sil e nanopa icles.
0
20
40
60
80
100
Numbe o E. coli colonies (%)
HA Ag-HA
10 μg/cm3
50 μg/cm3
100 μg/cm3
Figu e 7: Numbe o E. coli colonies as a unc ion o he
concen a ion o sil e nanopa icles exp essed as a pe cen age o
he numbe o colonies g own on sil e - ee con ol pla es.
The diffusion disk es s showed, in all he cases, a
simila exclusion a ea ha appea s only a ound he nAg-HA
composi e pelle s, as i is epo ed in Table 1. These esul s
show ha a sil e concen a ion o 10000 ppm is ended up
in oxici y o common G am-posi i e and G am-nega i e
bac e ia. Figu e 7 shows he numbe o bac e ial colonies
g own on LB pla es con aining 1, 5, and 10mg/cm3o nAg-
HA composi e and pu e HA as con ol, when app oxima ely
105CFU we e cul u ed in he pla es. A e 24 hou s, he
p esence o sil e nanopa icles a a concen a ion o 10 and
50 μg/cm3inhibi ed he bac e ial g ow h by 62% and 88%,
espec i ely, while a concen a ion o 100 μg/cm3caused
100% inhibi ion o bac e ial g ow h.
These esul s show a s ong bac e icidal effec agains
Sa, Pn, and Ec. In he pa icula case o G am-nega i e
bac e ium E. coli, i is sligh ly lowe han colloidal sil e
nanopa icles sys ems [20] wi h an a e age pa icle size
be ween 10 and 20 nm. Howe e , he nanocomposi e powde
posseses an in e es ing ad an age: i can be easily handled
and shaped in o pelle s o sponges wi hou special ca e
Table 1: Diffusion disk es o HA-nAg pelle s, con aining
10000 ppm o Ag, agains S aphylococcus au eus,Pneumococcus,and
Esche ichia coli a e 24 hou s a 37◦C.
S. au eus Pneumococcus E. coli
Inhibi ion zone 17 17.5 18
diame e (±0.5 mm)
o a oid he ypical agglome a ion p oblems ela ed o he
colloidal sys ems o nanopa icles.
4. Conclusions
In summa y, we ha e desc ibed a simple and low-cos
me hod o ob ain a HA-Ag nanocomposi e powde wi h
bac e icidal p ope ies. TEM, XRD, and UV- is echniques
ha e showed he p esence o sil e nanopa icles (∼65 nm)
a ached on he hyd oxyapa i e pa icles su ace wi hou
a high deg ee o agglome a ion. The bac e icidal ac i i y
esul s show ha his nanocomposi e is s ongly ac i e
agains some o he mos common G am-posi i e and G am-
nega i e bac e ial s ains, so i can be conside ed as an
an imic obial bioma e ial ha can be used in implan and
econs uc i e su ge y applica ions.
Acknowledgmen s
This wo k was suppo ed by Bioke Resea ch S.L. and by
he Spanish Minis y o Educa ion and Science unde P ojec
CENIT-INTELIMPLANT ( e .: 20071210). M. D´
ıaz has been
suppo ed by Spanish Minis y o Educa ion and Science and
CSIC unde I3P P og am inanced by Eu opean Social Fund.
The au ho s hank Raul Pina o he echnical suppo in he
TEM s udy.
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