Biomimetic formation of crystalline bone-like apatite layerson spongy materials templated by bile salts aggregates

Marcos Fernandez-Leyes • Valeria Verdinelli •

Natalia Hassan • Juan M. Ruso • Olga Pieroni •

Pablo C. Schulz • Paula Messina

Received: 28 September 2011 / Accepted: 5 November 2011 / Published online: 16 November 2011

� Springer Science+Business Media, LLC 2011

Abstract Since the trabecular bone exhibit sponge-like

bicontinuity there is a growing interest in the synthesis of

spongy-like sieves for the construction of bio-active

implantable materials. Here, we propose a one step sol–gel

method for the synthesis of bicontinuous pore silica

materials using different bile salts aqueous mixtures as

templates. The influences of the type and amount of bile

salt on the synthesis processes are investigated and corre-

lated with the final material morphology. As a final point,

their structural properties are interrelated with their ability

to induce a bone-like apatite layer in contact with simu-

lated body fluid (SBF). We have confirmed that under

specific template conditions, the synthesized material has

an open bio-active macropore structure that is blanched in a

3D-disordered sponge-like network similar than those

existed in trabecular bone.

Introduction

Sponge-like nanostructures with bicontinous L3 morphol-

ogy consist of randomly connected membranes and appear

as swollen defect-ridded mono or bilayers [1–4]. There is a

growing interest in the synthesis of spongy-like materials

because of their application in bone tissue engineering

[5, 6]. That is because the trabecular bone exhibit sponge-

like bicontinuity at the millimeter scale [7] and the current

advances in biomimesis suggest that it is timely to consider

biomineral inspired approaches as a springboard for the

next generation of biologically and structurally realistic

bone analogs for orthopedic applications [8]. Suitable tis-

sue scaffolds should have features such as a high porosity

along with a macropore size in the range of 10–1000 lm

and 3D interconnected pore structures, in order to have the

permeability and diffusion properties required to promote

the in-growth of bone cells [9, 10]. Hence, porous scaffolds

with highly interconnected structures like those that exist in

the spongy-like phases showing macro and mesoporosity

might exhibit the combined advantages of high-surface

areas from the mesopores and the increased mass transfer

associated with the macropores.

In this article, we propose a simply strategy for the

synthesis of bicontinuous pore silica materials using a one

step sol–gel method employing different bile salts mixed

aggregates as templates. Bile salts are biologically impor-

tant amphiphiles that possess a rigid steroid backbone

having polar hydroxyl groups on the concave a-face and

methyl groups on the convex b-face [11]. This arrangement

creates a unique facial amphiphilicity for this class of

molecules enabling them to aggregate in aqueous media in

a manner different from conventional detergents [12].

Stucky [13, 14], and Ozin [15] determined that silica

materials with highly curved structures are the result of the

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10853-011-6113-4) contains supplementarymaterial, which is available to authorized users.

M. Fernandez-Leyes � V. Verdinelli � O. Pieroni �P. C. Schulz � P. Messina (&)

Department of Chemistry, Universidad Nacional del Sur,

8000 Bahıa Blanca, Argentina

e-mail: pmessina@uns.edu.ar

M. Fernandez-Leyes � V. Verdinelli � O. Pieroni �P. C. Schulz � P. Messina

INQUISUR-CONICET, Bahıa Blanca, Argentina

N. Hassan � J. M. Ruso

Soft Matter and Molecular Biophysics Group,

Department of Applied Physics, University of Santiago de

Compostela, Santiago de Compostela 15782, Spain

123

J Mater Sci (2012) 47:2837–2844

DOI 10.1007/s10853-011-6113-4

appearance of some kind of dislocation or disclination

effects in the liquid crystal formation stage. The particular

structure of bile salt molecules are capable to induce such

disturbing effects and on consequence they are used to

stabilize many bicontinuous structures [16, 17], i.e., col-

loidal stabilization and dispersion of cubic phase in cubo-

some formation [18–20].

The bulk and the interfacial properties of the selected bile

salt mixtures were evaluated in previous works [21–23].

Several phase diagrams were constructed [21, 22] and we

have determined that small differences in the bile salt ste-

roidal backbone can cause great perturbations that altered

the mono and bilayer structures. Here, we investigated the

influence of such effects on the preparation of spongy-like

silica materials and their impacts on the material bonelike

apatite-inducing ability in simulated body fluid (SBF). We

have confirmed that under favorable conditions, the material

has a bio-active open macro-mesopore structure that is

blanched in a 3D-disordered sponge-like network similar

than those existed in trabecular bone.

Experimental methods

Materials

Dehydrocholic acid (HDHC) was obtained from Dr. Theodor

Schuchardt (Munich) and was of analytical grade. Sodium

deoxycholate (NaDC) and didodecyldimethylammonium

bromide (DDAB) were obtained from Aldrich, 90%, and

used as purchased. Tetraethyl orthosilicate (TEOS, Aldrich

98%) and NaOH (Panreac 141687.1210) were used without

further purification.

Solutions

Dehydrocholic acid sodium salt (NaDHC) solution was

prepared by weighing a quantity of HDHC and by disso-

lution in an appropriate amount of concentrated NaOH

aqueous solution. Stock NaDHC, NaDC, and DDAB

solutions (0.1 mol dm-3) were prepared and diluted as

required for each experiment. Only triplet-distilled water

was used.

Hydrothermal synthesis of porous materials

The siliceous materials (SM) were prepared using a tech-

nique obtained by comparing different literature procedures

[24]: 11.6 mL of TEOS was dissolved in 2 mL of water and

stirred for 10 min at 500 rpm. Then, a solution of 1.1 g of

NaOH in 20 mL of water was added drop-by-drop to the

TEOS solution while stirring. A minute later, 10 mL of the

different BSs-DDAB solutions (CT = 1 9 10-3 mol dm-3)

were poured into the mixture and stirred for 5 min. The

resulting gel was left for 24 h in an autoclave at 100 �C.

The obtained materials were filtered and washed with triplet-

distilled water and left to dry at room temperature. Finally,

it was calcined for 7 h at 640 �C in an air flux. Following

the above descripts procedure, ten different materials were

prepared: M1 (aNaDC = 0.2); M2 (aNaDC = 0.4); M3

(aNaDC = 0.5); M4 (aNaDC = 0.6); M5 (aNaDC = 0.8); M6

(aNaDHC = 0.2); M7 (aNaDHC = 0.4); M8 (aNaDHC = 0.5);

M9 (aNaDHC = 0.6); M10 (aNaDHC = 0.8), where a is the

molar fraction of BSs in the mixture solution used as

templated.

Experimental techniques

Field emission-scanning electron microscopy (FE-SEM) and

energy dispersive X-ray microanalysis (EDX) were per-

formed using a FE-SEM ULTRA PLUS microscope. Reso-

lution: 0.8 nm at 30 kV; accelerating voltage: 0.02 V–30 kV,

continuously adjusted in steps of 10 volts; magnification

range 12–91000000; sizes of openings: 7.5, 10, 20, 30, 60,

and 120 lm. Local compensation of charge, by injecting

nitrogen gas. Microanalysis EDX: resolution 129 eV and

wavelength-dispersive (WD) 8.5 nm.

Transmission electron microscopy (TEM) was per-

formed using a Philips CM-12 transmission electron

microscope equipped with a digital camera MEGA VIEW-

II DOCU and operated at 120 kV with magnification of

9730000. Powdered samples were placed on cooper sup-

ports of 2000 mesh.

Infrared spectra were collected using a Nicolet-Nexus

470 Fourier-Transform infrared Spectrometer (FT-IR)

equipped with a pneumatic motion interferometer. The

spectra is a result of 100 accumulating scans measured

peak to peak with a spectral resolution of 4 cm-1. To avoid

co-adsorbed water, the samples were dried under vacuum

until constant weight was achieved and diluted with KBr

powder before the FT-IR spectra were recorded.

Bioactivity assay

To perform the bioactivity assay, the material was kept

in contact with SBF [25], which has a composition and

ionic concentration similar to that of human plasma, con-

taining NaCl, NaHCO3, KCl, K2HPO4�3H2O, MgCl2�6H2O,

1N-HCl, CaCl2, Na2SO4, and NH2C(CH2OH)3 (trishydrox-

ymethylaminomethane as buffer).

The as-prepared porous materials were soaked in 1.5 SBF

at 37 �C for periods of 5, 10, 15, and 20 days, then they were

removed from SBF, washed with distilled water, and dried.

2838 J Mater Sci (2012) 47:2837–2844

123

Results and discussion

Blank experiments

The synthesis of SM in the absence of DDAB leads to a

very small amount of solid with a non-defined structure.

Only 3% of the silica engaged is recovered. Moreover,

when material was prepared using a pure DDAB solution

as templated, the synthesis causes a lamellar mesoporous

structure [26]. This confirms the need of BSs-DDAB syn-

ergistic influence in generating the sponge porous siliceous

sieves.

Microstructure observation

Figures 1, 2, and 3 show the FE-SEM microphotographs of

the silica materials templated with aqueous BSs-DDAB

mixtures solutions. All materials show a sponge-like

structure whose 3-D pore connectivity in their organized

network depends on the bile salt nature and its proportion

in the reaction mixture. Materials templated with

aNaDC = 0.4; 0.5 and 0.6 mixed systems (Fig. 1) show a

high interconnection of SiO2 channels with a pore size in

the nanometer scale (mesopores). However, those prepared

with aNaDC = 0.2 and 0.8 mixtures (Fig. 2) present also a

sponge-like final structure but the interconnected pore

networks are in the micrometer scale (macropores). In the

particular case of the aNaDC = 0.8 mixture templated sys-

tem (M5), it can be noticed that it is comprised by two

types of morphologies structures. Similar structures were

obtained for the materials templated with aNaDHC = 0.2 and

0.4 mixtures, Fig. 3. Nevertheless, the rest of NaD-

HC:DDAB mixed system did not show materials with a

definite organization. The samples produced a very small

amount of solid. When observed in the electron micro-

scope, the material showed a homogeneous, non-porous

structure. Several runs with varied synthesis procedures

(including acidification with acetic acid after mixing the

surfactant solution with the TEOS one) gave the same

results. However, a hexagonal mesoporous material similar

than MCM-41 was obtaining using NaDHC-CTAB (aNaD-

HC = 0.4) mixed system as template [24]. We were not

able to obtain a mesoporous porous material templated

with pure NaDHC solution [24] or with aNaDHC [ 0.4

mixtures.

At light of the obtained results, it can be inferred that the

material morphology is very sensitive to a subtle difference

in the structure between the BSs isomers. The two bile salts

are very similar to each other except for the presence of

hydroxyl groups, i.e., NaDC has two hydroxyl groups (3

and 12 a-OH) while NaDHC has three carbonyl groups at

positions 3, 7, and 12 of the steroid backbone. This dif-

ference leads to a great divergence in interfacial [21–23]

and solution properties [26–28]. Because the two tested

bile salts differ only in their cholesteric skeleton is pre-

sumed that the hydrophobic effect is a dominant factor in

the formation of these materials. In a previous work, we

studied the interfacial effects of NaDC and NaDHC in a

catanionic mixed adsorbed monolayer at 25 �C and, we

found thermodynamic evidence of the hydrophobic effect

of BSs during it intercalation into interfacial adsorbed

DDAB molecules [23]. The hydrophobic steroid backbone

of NaDHC molecule presents a deep interfacial penetration

than NaDC causing a great disturbance of DDAB palisade

layer. We supposed that a similar effect can cause the

absence of a definite structure in the obtained materials

templated with high content of NaDHC.

Phase transformation during sintering

The DDAB molecule has low water solubility and its

packing parameter, close to unity, dictates a preference to

assemble into bilayer-based structures [29]. The studied

bile salts molecules present a stepwise aggregation to give

Fig. 1 FE-SEM microphotographs of spongy-silica materials tem-

plated with a aNaDC = 0.4, b aNaDC = 0.5, and c aNaDC = 0.6 mixed

systems

J Mater Sci (2012) 47:2837–2844 2839

123

rise to micelles [30, 31]. Mixtures of such surfactants,

micelle-forming with vesicle-forming surfactants, yield the

formation of either micelle or vesicle structures as well as

intermediate structures depending on their architecture and

concentration [32, 33].

The appearance of an L3 phase (see Figs. 1, 2, 3) is

correlated with the presence of a lamellar phase, which

strongly indicates that the aggregate structure is locally of a

bilayer type [34, 35]. This agrees with the fact that at the

select synthesis concentration (CT = 1 9 10-3 M) the

investigated mixed surfactant systems aggregated into

vesicles (see electronic supplementary material, ESM).

The main controlled forces in the vesicular structures

involve hydrophobic affinity on the hydrocarbon–water

interface and hydrophilic repulsion, ionic repulsion, and

steric repulsion of charged head groups. When silica pre-

cursor was added, they form a liquid crystal with molecular

silicate species, and finally, the mesoporous material was

formed through inorganic polymerization and condensation

of the silicate species [34, 35]. Molecules must pack to fill

space and, thus, maximize favorable van der Waals

interactions among the hydrophobic tails while avoiding

high-energy repulsive interactions among the charged or

polar headgroups. Their packing has been quantified

through the packing parameter [36], g = V/a0l, where V is

the total volume of the hydrophobic chains, a0 is the

effective headgroup area per hydrophilic headgroup, and

l is the critical hydrophobic chain length. The a0 parameter

is related to both the size and the charge on the surfactant

headgroup and is affected by the electrostatic environment

around the surfactant headgroup. The driving force for the

vesicle to sponge-like structures phase transformation

seems to be polymerization of silica species during the

synthesis. When silicate condensation proceeds, the alk-

oxide groups produce siloxane bonds and as a result the

charge density is modified. To maintain charge matching in

the interface, the surfactants pack to adjust the surface

curvature. Similar results were obtained by Che et al. [37].

Depending on the circumstances the film can curve toward

the a-polar or toward the polar side. The final mesophases

Fig. 2 FE-SEM microphotographs of spongy-silica materials tem-

plated with a aNaDC = 0.2, b aNaDC = 0.8 mixed systems

Fig. 3 FE-SEM microphotographs of spongy-silica materials tem-

plated with a aNaDHC = 0.2, b aNaDHC = 0.4 mixed systems

2840 J Mater Sci (2012) 47:2837–2844

123

curvature depends of the type and amount of BSs in the

surfactant template mixture leading to different final

material morphologies (Figs. 1, 2, 3).

There are other important effects such as distortion of

hydrophobic-hydrophilic palisade layer due to the insertion

of BSs cholesteric backbone. The surfactant tails play an

implicit role in controlling self-assembly [38]. The role is

implicit in the sense that the tail does not affect the equi-

librium area and the packing parameter, but the tail length

influences the volume of the aqueous cavity. The tail exerts

its controlling influence on the aggregate structure through

its effect on the aqueous core volume. Moreover, it is

considered that ethanol produced from TEOS hydrolysis

tends to reside primarily in the outer shell of surfactant

aggregates, which increases the effective surfactant volume

V in the interface, raising the value of packing parameter

g [36]. In our case, the production of ethanol does not

seems to be very important because the hydrolysis of

TEOS is so rapid that the migration of ethanol was com-

pleted before the phase transformation.

In the specific case of M5 material, the overall the

materials had the form of the bicontinuous sponge phase

that was observed in the M1 sample, however, a deep view

of silica interconnected network revealed the morphology

observed for M2, M3, and M4 samples. Probably one type

of mesophases grew up on the other.

Bioactivity

It was demonstrated that the requirement for an artificial

material to bond to living bone (bioactivity) is the forma-

tion of bonelike apatite (HA) on its surface when implanted

in the living body, and that this in vivo apatite formation

can be reproduced in a SBF with ion concentrations nearly

equal to those of human blood plasma [39]. Successful

osseointegration depends not only on the physical but also

on the chemical properties of the material surface [40]. The

analysis of FT-IR spectra (ESM) of the synthesized mate-

rials does not show many differences on their chemical

surface properties. Nevertheless for those bio-active

materials the FT-IR shows an increase of the asymmetric

Si–O–Si stretching band (1050–1150 cm-1) and a reduc-

tion of the peak associated with structural –OH groups

(622 cm-1). Although the mechanism of apatite layer

formation in a biological environment on implantable bio-

active materials is not completely elucidated, the presence

of silanol groups in the surface seems to be necessary, and

even more the hydrated silica, with a high content of

siloxane bridges, formed afterwards in the body would

induce the nucleation of the apatite [41, 42]. Furthermore,

the existence of a highly porous surface can accelerate the

biomimetic process [42]. In agreements, the apatite depo-

sition was observed only in such specimens prepared from

aNaDC = 0.4; 0.5; 0.6 and 0.8 which content mesopores

and high proportion of siloxane bridges in their structures.

The time evolution of apatite growth on the synthesized

materials was followed by FT-IR measurements (ESM) and

confirmed by scanning electron microscopy. Figures 4 and

5, show the FE-SEM microphotographs of the material

surfaces templated with aNaDC = 0.8 mixture solution after

soaking in 1.5 SBF, similar results were obtained from M2,

M3, and M4 materials. It must be noticed that calcium

phosphate coatings grow not only on the material surface

but also in the pore interior and the progress of this cov-

ering increases as a function of the soaking time, Fig. 4.

Fig. 4 FE-SEM microphotographs showing the time evolution of HA

layer formation on M5 material

J Mater Sci (2012) 47:2837–2844 2841

123

SEM revealed the presence of preformed calcium phos-

phate coatings to be composed entirely of straight plate-

like units with sharp edges, with a change in crystal

geometry as the time of soaking increased, Fig. 5. The

definite crystalline structure is achieved after soaking for

20 days in SBF. The thickness of the apatite-like coating

increases with time and reaches a saturated point after

10 days of soaking, as shown in Fig. 6a. Assuming that the

growth rate of apatite coating is controlled by the calcium

and phosphorous ions diffusion rates from the SBF to the

material surface, the growth kinetics of apatite-like coat-

ings on porous materials can be expressed by an empirical

relationship [43]:

d2 ¼ Kt

where d is the thickness of the coating evaluated from SEM

photos, t is the soaking time for the biomimetic deposition,

and K is the growth rate constant. A plot of the square of

the coating thickness (d2) versus soaking time (t) is shown

to be linear, Fig. 6b. The growth rate constant can then be

obtained from the slope of the plot, K = 2.0208 9

10-18 m2 seg-1.

X-EDS microanalysis (ESM) showed that the Ca/P

atomic ratio of the calcium phosphate coatings was about

1.2. This value is much lower than that of stoichiometric

apatites (Ca/P = 1.67) but closer to the typical values of

the resorbable forms of calcium phosphates such as

brushite (dicalcium phosphate dehydrate, DCPD, Ca/

P = 1.0), octacalcium phosphate (OCP, Ca/P = 1.33) or

even amorphous calcium phosphate (ACP, Ca/P = 1.5)

usually present in human bone [44].

To reveal interactions between HA and living cells,

investigating on surface reactivity of HA nanomaterials

with different organic functions are being a subject of

extensive research. The electronic properties that of HA are

sensible to many variables, such as preparation methods,

defects, size of the nano-crystals, surface reaction with the

atmosphere, etc. Therefore, to investigate the electronic

structure, it is necessary to evaluate the atomic properties

of the constituents in HA material synthesized by a par-

ticular method. Figure 7 shows the FT-IR spectra of sam-

ple M5 before and after soaking in SBF during 20 days.

Silicate absorption bands at 1078 (m), 798 (d), and 460

(m2) cm-1 were observed in the spectrum before soaking in

Fig. 5 HA crystals growth on

M5 material after soaking in

SBF for 10 and 15 days

(a) (b)Fig. 6 a Thickness of apatite-

like coating and b square of

coating thickness versus

soaking time

2842 J Mater Sci (2012) 47:2837–2844

123

SBF. The broad band observed at 1650 and 3440 cm-1

indicate adsorbed water at the materials. The band at

around 3440 cm-1 overlaps with the weak bands at around

3565 cm-1 which is due to structural OH in SiO2 networks.

The band bending due to structural OH also occurs at

around 623 cm-1. After the first days of assay the material

shows phosphate absorption bands at 1036 (m3), 602 (m2),

563 (m4), and 470 (d) cm-1(ESM). Little bands appearing

at wave number values of 1420 and 1480 cm-1 are indic-

ative of the carbonate ion substitution just with a low

intensity peak at 880 cm-1. High intensity peaks at

3000–3700 cm-1 are due to the bending vibration peak of

OH– groups. The analysis of FT-IR spectra indicate that

calcium phosphate coatings are carbonate hydroxyapatites

(CHAs), presumable a mixture of AB substitution type

(A type: CO32- ? OH- substitution and B type:

CO32- ? PO4

3- substitution) with a major proportion of

type A substitution. From the analysis of 3000–3700 cm-1

region it can be recognized almost five peaks related to the

O–H stretch. The band at 3440 cm-1 correspond to

adsorbed water, the others at 3744, 3223, 3100, and

3000 cm-1 may be assigned to different structural OH

groups in HA crystals. Former –OH groups with more or

less hydrogen bond association to phosphate groups, and

others with less or no interactions to the environment.

Similar results have been observed by Panda et al. [45] that

proposed some kind of core shell in the HA structure.

Conclusion

Different bile salts mixed aggregates were used as tem-

plated of spongy-silica materials in an approach to simulate

the trabecular bone organization. The material final struc-

tures take place through a vesicle to sponge-like phase

transformation whose driving force seems to be the

interaction of BS/DDAB and silica species during the

material polymerization synthesis step. Depending of the

type and amount of BS in the template mixture, the film

can curve toward the a-polar or toward the polar side

leading to different final morphologies. The highly

hydrophobic steroid backbone of NaDHC molecule cause a

great disturbance in the templated liquid crystal mixture

and thus only those aNaDHC = 0.2 and 0.4 systems pro-

duced a material with a definite structure.

Those materials prepared from aNaDC = 0.4, 0.5, 0.6,

and 0.8 has a bio-active behavior. Their properties are

supposed related to the mesopores and highly proportion of

siloxane bridges in their structures. Although the thickness

of the apatite-like coating reaches a saturated point after

10 days of soaking, the definite crystalline structure is

achieved after soaking for 20 days in SBF. The analysis of

FT-IR spectra and X-EDS indicate that calcium phosphate

coatings are a mixture of carbonate hydroxyapatites

(CHAs) with a major proportion of type CO32- ? OH-

substitution and a value of Ca/P atomic ratio of 1.2 closer

to the typical resorbable forms of calcium phosphates.

Under specific template conditions (aNaDC = 0.8), it

was possible to synthesized a bio-active open macro-mes-

opore structure material with a 3D-disordered sponge-like

network similar than those existed in trabecular bone.

Acknowledgements The authors acknowledge Universidad Nac-

ional del Sur (PGI 24/ZQ07), Concejo Nacional de Investigaciones

Cientıficas y Tecnicas de la Republica Argentina (CONICET, PIP-

11220100100072), Xunta de Galicia (Project No. PXI20615PN).

MFL and VV have fellowships of CONICET. PM is an adjunct

researcher of CONICET.

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