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Review

Solgel silica-based biomaterials and bone tissue regeneration

Daniel Arcos, Mara Vallet-Reg *

Departamento de Qumica Inorgnica y Bioinorgnica, Ftad. Farmacia, Universidad Complutense de Madrid and Networking Research Center on Bioengineering,

Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain

a r t i c l e i n f o

Article history:

Received 13 November 2009Received in revised form 2 February 2010

Accepted 4 February 2010

Available online 10 February 2010

Keywords:

Bioactive glasses

Mesoporous materials

Tissue regeneration

Drug delivery

Solgel

a b s t r a c t

The impact of bone diseases and trauma in developed and developing countries has increased

significantly in the last decades. Bioactive glasses, especially silica-based materials, are called to play afundamental role in this field due to their osteoconductive, osteoproductive and osteoinductive proper-

ties. In the last years, solgel processes and supramolecular chemistry of surfactants have been incorpo-

rated to the bioceramics field, allowing the porosity of bioglasses to be controlled at the nanometric scale.

This advance has promoted a new generation of solgel bioactive glasses with applications such as drug

delivery systems, as well as regenerative grafts with improved bioactive behaviour. Besides, the combi-

nation of silica-based glasses with organic components led to new organicinorganic hybrid materials

with improved mechanical properties. Finally, an effort has been made to organize at the macroscopic

level the solgel glass preparation. This effort has resulted in new three-dimensional macroporous scaf-

folds, suitable to be used in tissue engineering techniques or as porous pieces to be implanted in situ. This

review collects the most important advances in the field of silica glasses occurring in the last decade,

which are called to play a lead role in the future of bone regenerative therapies.

2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

1. Introduction

The rise in life expectancy in developed countries has led to an

increased demand for new restoring and augmentation materials,

with application in therapies for bone pathologies. These new com-

positions must tackle the bone repairing therapies in a more

efficient and durable way. The current scenario regarding treat-

ments of musculoskeletal disorders is that over 2.2 million persons

are surgically treated each year as consequence of trauma or tu-

mour extirpation[1]. The gold standard for grafting and repair is

the reconstruction with autograft. However, the limitation of tissue

amount and the morbidity at the extraction site have resulted in a

high interest for artificial materials. An ideal bone graft should be

reabsorbable and guide the patients bone tissue towards a regen-

erative process[2]. Moreover, the graft should exhibit mechanical

properties appropriate to the implantation site, especially when

implanted as a solid piece or as porous scaffolds[3]. Despite the re-

search efforts in the field of ceramics, metals and polymers, the

availability of this ideal material is still far away for clinical

practice.

Silica-based bioactive glasses are a kind of bioceramic material;

these materials have supplied successful solutions to different

bond defects and soft tissue treatments during the last decades

[4]. The high biocompatibility and the positive biological effects

of their reaction products (both leached or formed at the surface)

after implantation[5], have made silica-based glasses one of the

most interesting bioceramics during the last 40 years. In contrast,

the poor mechanical properties of these compounds have seriously

limited the range of clinical applications. Table 1 shows some of

the most important clinical applications of silica bioactive glasses

developed so far.

The story of bioactive glasses began in 1969, when Hench

opened a new research field by using glasses as implant materials

[6]. Since then, this research line has provided very interesting re-

sults in both academic and applied fields through the transforma-

tion of conventional glasses into glasses with biomedical added

value[7]. Bioactive glasses bond to and integrate with living bone

in the body without forming fibrous tissue around them or pro-

moting inflation or toxicity[8]. The high reactivity of these glasses

is the main advantage for their application in periodontal repair

and bone augmentation, since the reaction products obtained from

these types of glasses and the physiological fluids lead to the

crystallization of the apatite-like phase, similar to the inorganic

component of bones in vertebrate species. In addition, degrada-

tion ionic products, especially silica species, have shown osteoin-

ductive properties [9,10]. Summarizing, from a biological and

chemical point of view, silica bioactive glasses exhibit many of

the properties associated with an ideal material for grafting and

scaffolding. This feature promoted new perspectives for SiO2-

based glasses as third-generation biomaterials for bone tissue

regeneration [2].

1742-7061/$ - see front matter 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.actbio.2010.02.012

* Corresponding author. Tel.: +34 913941861.

E-mail address: [email protected](M. Vallet-Reg).

Acta Biomaterialia 6 (2010) 28742888

Contents lists available at ScienceDirect

Acta Biomaterialia

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / a c t a b i o m a t
http://dx.doi.org/10.1016/j.actbio.2010.02.012mailto:[email protected]://www.sciencedirect.com/science/journal/17427061http://www.elsevier.com/locate/actabiomathttp://www.elsevier.com/locate/actabiomathttp://www.sciencedirect.com/science/journal/17427061mailto:[email protected]://dx.doi.org/10.1016/j.actbio.2010.02.012

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In the early 1990s bioactive glasses were for the first time pre-

pared by the solgel process[11]. Porous bioglasses could be pre-

pared from the hydrolysis and polymerization of metal hydroxides,

alkoxides and/or inorganic salts. A wide bibliography, including

excellent reviews, has dealt with this synthesis method and appli-

cation, explaining how solgel chemistry offers a potential pro-

cessing method for molecular and textural tailoring [1217].

Contrarily to melt-derived bioglasses, solgel glasses are not pre-

pared at high processing temperatures. In addition, and due to

the high surface area and porosity derived form the solgel pro-

cess, the range of bioactive compositions is wider, also exhibiting

higher bone bonding rates together with excellent degradation/

resorption properties[18,19].

During the solgel process, the gelling stage occurs around roomtemperature. Gels, aerogels, glasses, dense oxides, etc., can be made

by solgel processing (Fig. 1), thus facilitating the incorporation of

organic and biological molecules within the network[20], or even

cells within silica matrices [2123]. Moreover, solgel processes

can be combined with supramolecular chemistry of surfactants,

resulting in a new generation of highly ordered mesoporous materi-

als for biomedical applications. Mesoporous materials are excellent

candidates for controlled drugdelivery systems,and a great research

efforthas been carried outin this topic duringthe last years [24,25].

One of the most interesting alternatives for bone regenerative

purposes is the association of ostogenic agents with bioactive

glasses, intended to form three-dimensional (3D) scaffolds for bone

tissue engineering[2630]. On the one hand, the bioactive behav-

iour of many compositions involves not only osteoconduction and

osteoproduction, but also osteoinduction processes when im-

planted in living tissue[31]. On the other, this biofunctionalization

provides added values to the implant, since the graft not only fillsand repairs the defect but also acts as a drug delivery system,

which locally supplies osteoregenerative agents.

This review collects and discusses the main advances occurred

during the last decade, regarding new compositions both inor-

ganic and organicinorganic hybrid materials intended for bone

tissue repairing. The potential capability for drug delivery purposes

related with the recent advances in the field of mesoporous mate-

rials is also discussed. Finally, the processing strategies to prepare

biofunctionalized scaffolds, for bone grafting and tissue engineer-

ing from solgel bioactive glasses, are also reviewed.

2. Bioactive glasses: in vitro and in vivo correlation

To date, clinical applications of silica-based bioactive glasses are

limited to those materials synthesized by melting processes. The

bone graft known as Bioglass 45S5 45% SiO2, 24.5% NaO2,

24.5% CaO and 6% P2O5in weight is processed using melting tem-

peratures in the range of 13001450 C [31]. The basis of bone

bonding in these products is the chemical reactivity of the glass

in body fluids. Bonding occurs through a sequence of reactions de-

noted as bioactive process. This sequence starts with the leach-

ing of Na+ and Ca2+ cations to the surrounding fluids, followed by

the formation of silanols (SiOH) at the glass surface. These reac-

tions result in the formation of a silica-gel layer that incorporates

Ca and P from the solution, forming an amorphous calcium phos-

phate layer. Finally, after the subsequent carbonates incorporation

and crystallization, a nanocrystalline carbonate apatite-like phase

(CHA) is formed[32]. These reaction stages do not depend on the

presence of living tissues and can occur when soaking the glassesin simulated body fluids. However, the formation of this nanocrys-

talline apatite layer seems to play an important role in the bone

bonding under in vivo conditions. In fact, there is a close correla-

tion between the apatite forming rate in vitro and the body re-

sponse when implanted in vivo. In the case of melt-derived

compounds, compositions with SiO2 content lower than 53 mol.%,

HCA formation occurs very quickly under in vitro conditions (with-

in 2 h). These materials rapidly bond to both bone and soft tissue

under in vivo conditions; they are osteoproductive and can be clas-

sified as bioactive materials type A [2]. Bioglasses with SiO2 con-

tent ranging between 53 and 58 mol.% develop 2 or 3 days to

develop a CHA layer under in vitro conditions. When implanted,

these materials only exhibit bond bonding and osteoconduction

behaviour. Compositions with SiO2 content of 60% or higher donot develop an HCA layer even after several weeks in simulated

body fluid (SBF) and bond neither to bone or soft tissues.

As mentioned above, the preparation of bioactive glasses by the

solgel method increases the range of compositions showing bioac-

tivebehaviour. For instance, when considering solgel glasses in the

systems SiO2CaOP2O5 and SiO2CaO the most widely studied

bioactive solgel glasses fast in vitro HCA formation has been ob-

served for compositions containing up to 80 mol.% of SiO2[3335].

The in vitro CHA formation also correlates with the in vivo behav-

iour [36], since extensive bone in-growth in rabbit femurs have

been observed when filling an extensive bone defect with solgel

glasses [37]. Comparative in vivo studies of 58S (58% SiO238%

CaO4% P2O5) and 77S (77% SiO219% CaO4%P2O5) solgel glasses

with45S5 melt-derived bioglass, also shows thatsolgel glasses ex-hibit similar cell response with lower degree on environmental

Table 1

Clinical applications of silica-based bioactive glasses.

Material form Clinical application

Solid shapes Ossicle replacement in the middle ear

Cone-shaped devices for jaw defects filling

Curved plates for restoring eye orbit floor

Soft tissue sealing for transdermal implants

Particulates Bone tissue replacement in periodontal diseases

Soft tissue augmentation in paralysis of vocal cords

Particulates and

autologous

bone

Maxillofacial reconstructions

Bone tissue reconstruction in frontal sinus

infections

Chronic pansinusitis

Mucocele

Lower jaw restoring after tumour removal or post-

traumatic injury

Sinus lift operation

Spine

Lumbar radicular syndrome

Particulates by

injection

Urological tissue augmentation

Incontinence derived from decreased ureteral

resistance

Ureteral reflux

Fig. 1. Solgel processing and potential processing methods.

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changes, which is dueto thelower content in Na+ and Ca2+ cations in

the chemical composition. Long term in vivo studies also confirmed

that 58S and 77S solgel glasses exhibited a similar response to

45S5 melt-derived bioglass[19].

In the last decade, a new property of silica-based bioglasses was

discovered. In addition to the osteoconduction (type B glasses) and

osteoproduction (type A glasses), it was observed that type A mate-

rials activate genes that stimulate regeneration of bone tissues.This behaviour, known as osteoinduction, resulted in the third-

generation biomaterials intended to regenerate instead of substi-

tute bone tissue [38]. The mechanism by which silica-based bio-

glasses affect osteoblastic cells is uncertain. However it is clear

that primary osteoblasts show higher phenotype expression as

well as enhanced ability to form mineralized collagen nodules un-

der in vitro conditions[3941]. The osteoinductive properties are

related with the cellmaterial contact surface together with the

ion release. These bioglass byproducts seem to promote the upreg-

ulation of the bone mitogenic growth factor IGF-II[9]. Despite of all

these features, melt-derived glasses such as 45S5 have some

important limitations like high processing temperatures, narrow

range of bioactive compositions and limited textural features.

Solgel glasses exhibit higher rates of apatite phase formation, fas-

ter bone bonding and excellent degradation and resorption proper-

ties [19]. Summarizing, we can state that solgel glasses are at

least as suitable as melt-derived ones, to induce osteoblastic adhe-

sion, proliferation and differentiation, without the textural draw-

backs of melt-derived bioglasses.

3. Chemistry and structural properties of silica-based bioactive

glasses

Knowledge about the bioactive glass structure is mandatory to

understand the role of each component on the bioactive behaviour.

For instance, Bioglass 45S5 is an amorphous structured com-

pound constituted by a covalent bonded network of SiO2, which

is the main network former, together with P2O5. Both components

in the form of [SiO4] and [PO4] tetrahedral units are covalentlybonded through the O atoms at the vertex (bonding oxygen atoms).

On the contrary, CaO and Na2O are named network modifiers. Ca2+

and Na+ cations disrupt the covalent network, establishing ionic

interactions with the O atoms, which become non-bonding oxy-

gen atoms. Whereas network formers provide stability, network

modifiers increase the glass reactivity and, therefore, the bioactive

behaviour[42]. This is clearly reflected in the connectivity param-

eter value (Y). Pure SiO2dense glasses, with all the O atoms bond-

ing [SiO4] and [PO4] tetrahedral, have Yvalues equal to 4. On the

contrary, bioactive glasses exhibit much lower connectivity values.

For instance, Bioglass 45S5 has values of 2.07. Studies extended to

many compositions allowed estimating that SiO2CaONa2OP2O5glasses with Y< 2.3 exhibit in vitro bioactivity[43]. However, the

connectivity parameter of a glass does not necessarily determinethe bioactive behaviour of melt-derived glasses. In fact, the chem-

ical species having a part in the composition as both network form-

ers and modifiers, also determine the glass bioactivity. For

instance, the incorporation of multivalent cations such as Al3+,

Ti4+ or Ta5+ reduces the compositional range for bonding[4447].

After 1991, when the first bioactive solgel glasses were pre-

pared in the CaOP2O5SiO2 system [11], numerous studies were

performed to understand the role of the gel glass constituents on

the surface properties and the in vitro formation of a CHA phase

[4854]. This new layer enhances the osteoblast adhesion when

tested within vitro cell cultures[55]and, in as with melt-derived

glasses, it is supposed to play a fundamental role in bonding to liv-

ing bone under in vivo conditions [5658].

As mentioned above, SiO2is the mayor constituent of the glassand forms a covalently bonded network (network former), thus

providing stability to the material. However, in solgel glasses,

the tetrahedral [SiO4] units condensate as ramified branches or

as 3, 4 or 5 [SiO4] member rings, depending on the stabilization

temperature [59]. This conformation leads to high microporosity

(pore sizes below 2 nm), leading to high surface areas and provid-

ing the characteristic reactivity of these materials [60].

As well as for melt-derived glasses, CaO is also a network mod-

ifier. Ca

2+

cations disrupt the SiO2 covalent network, establishingionic interactions with O atoms, which become non-bonding oxy-

gen atoms. CaO provides reactivity and mesopore volume to glass

and is fundamental to initiating the first stage of the bioactive pro-

cess, i.e. the hydrolysis of SiOCa leaching Ca2+ cations to the sur-

rounding fluid, followed by H+ incorporation to the glass surface by

alkaline earth cation exchange and increasing the interfacial pH.

Thereafter, the reaction sequence follows up to CHA formation as

explained above.

The role of P2O5 in the solgel SiO2CaOP2O5 glasses is more

complex [61]. In fact, amounts over 10 mol.% of this component

lead to non-bioactive compositions, and studies carried out in

1999 demonstrated that SiO2CaO solgel glasses are also bioac-

tive [6264]. Recently, high-resolution transmission electron

microscopy (HRTEM) and solid 31P-nuclear magnetic resonance

(NMR) spectroscopy have shown the presence of orthophosphate

nanocrystalline nuclei in SiO2CaOP2O5 glasses (Fig. 2, see also

Refs.[117,184]). These non-soluble segregated nanocrystals would

decrease the Ca2+H+ ionic exchange, but would facilitate the car-

bonate hydroxyapatite (CHA) formation once a new amorphous

calcium phosphate is previously formed on the glass surface.

4. Compositions, mixtures and added properties in silica-based

solgel glasses

Important research efforts have been made by means of new

cation inclusion or mixtures with other bioceramics, thus provid-

ing novel properties of bioactive solgel glasses. In a common pro-

cedure, new elements are incorporated as network modifiers and

the scientific literature exhibits numerous examples of this. Our re-search team incorporated MgO into SiO2CaOP2O5 solgel sys-

tems, observing the changes induced in the new apatite layer

formed when the glasses were soaked in SBF[6568]. The presence

of Mg2+ cations in the composition slows down the formation rate

of the new biomimetic apatite phase, although the thickness of this

layer is larger compared with that formed in non-containing MgO

glasses. In addition, a whitlockite-like phase appeared together

with the apatite-like phase on the surface, which demonstrates

the influence of the network modifiers on the formed biomimetic

phases. Recently, new investigations have shown that the sol

gel-derived quaternary bioglass system SiO2CaOP2O5MgO has

the ability to support the growth of human fetal osteoblastic cells

(hFOB 1.19). This material has also proved to be non-toxic and

compatible in segmental defects in the goat model in vivo [69].One of the most important aims when adding new components

has been to implement antibacterial properties to the silica solgel

glasses. In this sense, the incorporation of Ag+ as Ag2O (up to

3 wt.%) to the SiO2CaOP2O5solgel systems conferred antimicro-

bial activity againstEscherichia coli, without comprising the bioac-

tivity [70]. Similar studies were later extended to Streptococcus

mutants in the system Na2OCaOSiO2 [71]and also incorporated

into solgel glass scaffolds for bone tissue engineering applications

[72].

Zinc oxide has been also considered as a component of bioactive

solgel glasses. Based on the Zn essentiality involving hard tissue

healing, Zn2+ cations have been introduced as network modifiers.

Zn containing solgel glasses show higher surface area values

increasing the nucleation sites and thus improving the newlyformed calcium phosphate phase, when soaked in SBF. However,

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the glassy network degradation is slowed[73]. This fact could be

due to the lower dissolution rate of Zn2+ compared with Ca2+

[74]as a result of the partially covalent interactions that Zn 2+ cat-

ions exhibit in tetrahedral environments. In vitro studies carried

out with Zn containing 58S solgel glasses and murine macro-

phages as cell cultures, suggest potential prophylactic applications

of these glasses for the prevention of inflammation, based on direct

interaction of zinc, as well as copper ions, in key regulatory path-

ways for the inflammatory response[75].Based on the natural occurrence of strontium as a trace element

in the human body, as well as the reduction of incidence of frac-

tures in osteoporotic patients treated with strontium renalate,

the SiO2CaOSrO ternary system has been proposed [76]. This

system has shown enhanced in vitro bioactivity as well as capabil-

ity to release strontium to the surrounding media under physiolog-

ical conditions.

Bioactive solgel glasses havebeen used to provide bioactivity to

other functional biomaterials through the preparation of intimate

mixtures and composites. For instance, solgel incorporation to

drug delivery systems based on acrylic polymers supplies in vitro

bioactivity, as could be observed for poly(methyl methacrylate)

(PMMA) matrixes [7780]. SiO2CaOP2O5 solgel glasses have

been also considered to ensure the osteointegration of magneticthermoseeds [81,82]. These materials are commonly formed by

magneticiron-oxide-basedbioceramics withlow bioactivity behav-

iour[83]. After surgery extirpation, magnetic glass ceramics are in-

tended for applying magnetic hyperthermia treatment against

potential metastasis and reinforce the bone site. Incorporation of

solgel glasses would facilitate the osteointegrationof these perma-

nentand biocompatible implants[84,85]. Finally,solgel glasses are

used to improve the bioactive behaviour of biocompatible bioce-

ramics such as hydroxyapatite[86,87],as well as precursors to pre-

pare bioactive and mechanically reinforced glass ceramics[8890].

5. Bioactive organically modified silicates (ormosils)

Organically modified silicates (ormosils) provide an alternativeto prepare materials with new properties for several medical and

technological applications[9196]. Ormosils are organicinorganic

hybrid materials that have the unique feature of combining the

properties of traditional materials, such as ceramics and organic

polymers, on the nanoscopic scale. Actually, ormosils are nano-

composites that exhibit properties closely dependent on the chem-

ical nature and relative content of the constitutive inorganic and

organic components. In addition, additives as cations of metal alk-

oxides (Al (III), Ge (IV), Sn (IV), etc.) can also determine the siloxane

structure in terms of loops, length of the chains, or the extent of theinterface between inorganic domains and the siloxane component

[97,98]. In this section, we review and discuss some of the most

important advances in the field of bioactive hybrid materials, spe-

cially those ormosils showing bioactive behaviour and adding new

values to conventional solgel glasses.

The main goal when synthesizing a silicate-containing hybrid

material for any application, including biomedical ones, is to take

advantage from both domains to improve the final properties

[99]. The inorganic component can provide hardness, strength,

thermal stability, density, etc., whereas the organic one provides

elasticity, hydrophobic character, chemical reactivity, etc. How-

ever, the final properties anyway are not only the addition of the

properties of the individual components synergetic effects can

be expected according to the high interfacial area. Accordinglywith the hybrid material classification [100], Ormosils are class II

hybrid materials, that is, materials showing chemical links be-

tween the components and consequently strong interactions.

One of the main drawbacks of silicate-based glasses (both melt-

derived and solgel glasses) is their brittleness. This characteristic

limits their application to fill small bone and periodontal defects

without bearing mechanical loads. Therefore, one of the most

important goals when preparing bioactive ormosils is to achieve

better mechanical performance as well as bone-bonding ability

[101]. The mechanical properties of organicinorganic hybrid

materials are strongly dependent on the micro- and nanostruc-

tures, but also on the intensity of interactions between organic

and inorganic components. Therefore, important efforts have been

made for increasing the interfacial interactions. This aim can be

achieved by combining different polymers and choosing appropri-

Fig. 2. Calcium phosphate clusters within SiO2CaOP2O5 solgel glass. HRTEM image shows two different zones: one corresponding to amorphous SiO 2 and another

nanocrystalline corresponding to calcium phosphate. 31 P-NMR spectra shows that all the phosphate species in the glass are orthophosphates. A schematic model of the local

environment of calcium phosphate clusters is also shown.


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ated inorganic precursors, in such a way that more hydrogen inter-

actions of covalent bonds are formed[102].

In 1997, Tsuru et al. proposed organically modified silicates as

materials able to exhibit bioactive behaviour[95]. The high bioac-

tivity of silicate-based glasses suggests that the incorporation of

silicate as inorganic component would supply bioactivity to the or-

ganic component through the hybrid material synthesis. One of the

first ormosils proposed for dental restorative and bone applicationswas the PMMAsilica system[103]. The chemical bases rely on the

trimethoxysilyl functional groups included in the acrylic mono-

mers, which are reactive in the solgel process. This kind of ormosil

exhibits a very weak in vitro bioactive behaviour, as could be ex-

pected for a calcium-free composition[104], compared with other

Ca-containing and acrylic-based hybrid materials [105]. However,

compared with pure acrylic materials such as PMMA, mouse cal-

varial osteoblast cell cultures showed better biological response

when seeded on PMMASiO2in terms of cell attachment, prolifer-

ation and differentiation. The enhanced biocompatibility of the

PMMASiO2 hybrid can be explained by two possible interrelated

mechanisms: (a) the ability to induce a calcium phosphate layer

formation on the surface of the PMMASiO2in cell culture media,

and (b) the capability to release silica (as silicic acid), which in-

duces osteoblast early mineralization. Other calcium-free hybrid

materials exhibiting a certain degree of in vitro bioactive behaviour

have been obtained by synthesis of polyethilenglycol (PEG)-SiO2ormosils [106]. After being subjected to the biomimetic process

for forming the bone-like apatite layer, it was found that a dense

apatite layer appears on the hybrid materials, indicating that the

formed silanol groups provide the effective sites for the CHA nucle-

ation and growth.

One of the more thoroughly studied organicinorganic hybrid

systems for bone and dental repairing is that including poly-

(dimethylsiloxane) (PDMS) as precursor [107,108]. However, the

in vitro bioactivity of these ormosils was not fully satisfactory until

Ca2+ cations were incorporated into these systems. Chen et al. have

extensively worked on the PDMS-modified CaOSiO2TiO2system

[109], obtaining dense and homogeneous monoliths. These hybridscan be structurally described as a silica and titania network cova-

lently bonded to PDMS and the calcium ion ionically bonded to

the network. The hybrids show relatively large amounts of calcium

in their surfaces and an apatite-like phase is developed on their

surfaces within only 1 or 0.5 day in SBF [110]. Moreover, the Ca2+

amount influences not only the in vitro bioactivity, but also the

presence of the inorganic network (silica and titania) [111113].

From these studies, it was evidenced that apatite formation in-

creases as a function of inorganic component, whereas PDMS sup-

plies better mechanical behaviour.

Although PDMS-derived ormosils show high ductility, the

mechanical strength and Youngs modulus are much lower than

those of human bones. Similar organicinorganic hybrid materials

have been synthesized by replacing PDMS by poly(tetramethyleneoxide) (PTMO), expecting that a ductile bioactive material with

higher mechanical strength could be obtained. In this sense, Kami-

takahara et al. have obtained PTMOTiO2 hybrid materials [114]

that showed mechanical properties analogous to those of human

cancellous bones in bending strength and Youngs modulus. Simi-

larly to that observed for PDMS-based materials, higher presence

of inorganic phase enhances the bioactive behaviour of the hybrids

[115]. The Ca2+ incorporation to hybrid materials promotes the

apatite in vitro formation analogously as it does in bioactive

glasses. The stage 1 of the bioactive process, i.e. SiOCa hydrolysis,

is enhanced and the materials reactivity increases. However, the

higher bioactive behaviour when silica or titania are added must

be explained in terms of the hydrophilic/hydrophobic degree of

the hybrid material. The hydrophilic degree of ormosils is a funda-mental aspect to achieving adequate appropriated features for bio-

medical performance and is commonly supplied by the inorganic

phase. In addition to increasing the silica or titania content, there

are several strategies to control this factor. For instance, the elec-

tion of the organic component and chemical modifications (such

as phosphate groups at molecular level) [116], as well as a deep

knowledge of the inorganic phase nanostructure, is fundamental

[117,118], since the biodegradability and bioactivity of ormosils

also depend on these factors[119]. Moreover, ormosil-based drugdelivery systems can be prepared following these strategies, which

exhibit release profiles without burst effect of premature drug re-

lease[120].

Sometimes the resulting ormosils are not hydrophilic enough to

promote the ionic exchange with the surrounding physiological

fluids. This problem can be tackled by including another less

hydrophobic organic component, for instance 3-methacryloxypro-

pyl-trimethoxysilane (MPS) and HEMA[121,122]. In vitro bioactiv-

ity is achieved for hybrids containing 10 mol.% of MPS and with

calcium ions incorporated into the hydrophilic organic polymer

(pHEMA).

Gelatine has also been used on the assumption that the use of

natural polymers like proteins or polysaccharides as the organic

components should lead to both bioactivity and biodegradability

of the resultant hybrids[123]. This strategy provides inorganicor-

ganic hybrids in which the inorganic component of silicon

chemically bonds to the natural polymer of gelatine with SiO

Si bonds. Bioactive properties of gelatinsiloxane hybrids can be

also improved by adding a calcium source to the gelatine solution

during the synthesis [124]. The pore size distributions range be-

tween 5 and 500 lm and the calcium content makes these hybrids

develop an apatite-like phase in contact with physiological fluids.

For these reasons these materials have been proposed to find appli-

cation as novel bioactive and biodegradable scaffolds in bone tis-

sue engineering [125]. Further studies have demonstrated the

biocompatibility of these hybrids [126]. MC3T3-E1 cell culture

was used to evaluate the potential of scaffolds for bone tissue engi-

neering, demonstrating that the appropriate incorporation of Ca2+

ions stimulates in vitro osteoblast proliferation and differentiation.Biodegradable and biocompatible inorganicorganic hybrid

materials have been prepared by Rhee et al. from tetraethoxysilane

and end-reactive poly(e-caprolactone) (TEOS-PCL) [127]. Poly-

(e-caprolactone) (PCL) is a well-known polymer that shows a

unique set of properties, i.e. biocompatibility, permeability and

biodegradability, that can be also enhanced by calcium addition

[128,129]. In a similar way to the bioactive theory for conventional

glasses, it is suggested that a dense bone-like apatite layer on the

hybrids could be achieved in vitro and in vivo by including an

appropriate calcium salt content.

Star gels are a type of organicinorganic hybrid that present a

singular structure of an organic core surrounded by flexible arms

which are terminated in alcoxysilane groups [130,131]. This char-

acteristic structure allows having precursors with flexibility at amolecular level, which is an important feature when used as im-

plant materials. At the macroscopic level, star gels behave between

conventional glasses and rubbers in terms of material mechanical

behaviour. Similarly to the ormosils described above, star gels

can be upgraded with bioactive properties by Ca2+ cation incorpo-

ration. Our research team has obtained bioactive star gels able to

induce an apatite-like phase after 7 days in SBF [132].

Fracture toughness values of star gels are significantly higher

than conventional solgel glasses and comparable with natural

bone (Fig. 3). It means that star gels are able to absorb more energy

before breaking. A preliminary fatigue test has been carried out by

means of cyclic loading with a nanoindentor. Bone is repeatedly

cyclically stressed and fatigue is one of the causes of bone failure

reported in the literature[133]. Under a 40 MPa stress force, a hu-man femur shows between 100 and 125 cycles to fracture. Star gels


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withstood more than 250 cycles, whereas the conventional solgel

glass, 90Si10Ca, failed after around just 30 cycles. From these re-

sults, star gels are expected to exhibit good long-term fatigue

behaviour.

6. Solgel process and supramolecular chemistry: new trends in

nanostructured silica glasses

The incorporation of supramolecular chemistry to the solgel

processes has provided a new generation of solgel mesoporous

glasses for biomedical applications [134136]. These new glasses

exhibit better bioactivity behaviour due to their outstanding valuesof surface area and porosity, as well as capability to host active

agents that contribute to the tissues healing processes.

In this strategy, the incorporation of structure-directing agents

is essential for obtaining successful structures. Under appropriated

synthesis conditions, these molecules self-organize into micelles.

Micelles link the hydrolyzed silica precursors through the hydro-

philic component and self-assembly to form an ordered mesophase

(Fig. 4).

The mesophase ordering depends on several factors, such as

surfactant chemistry (ionic, non-ionic, polymeric, etc.),

organic:inorganic phase volume ratio, surfactant concentration,

temperature, pH, etc.

Once the product is dried and the surfactant removed (calcined

or extracted with solvents), a mesoporous structure is obtained,exhibiting high surface area and porosity. It is not only bulk or

monolith shapes that can be obtained by this method: inorganic

and hybrid thin films are also obtained, with applications for many

technological purposes as well coatings and membranes in the bio-

materials field. The biodegradability of mesoporous membranes

can be tailored with composition, porosity and calcination temper-

ature, thus controlling the degradation timescale, which is espe-

cially relevant to the culture and growth of cells as well as for

the design of drug delivery systems[137]. An extensive discussion

on the synthesis conditions, processing parameters and methodol-

ogies can be found in Ref.[138]. These characteristics make meso-

porous SiO2 excellent candidates to be used as implantable local

drug delivery systems [139141] and grafting materials for bone

regeneration [142,143]. The following sections will elaborate onthese application fields of SiO2 mesoporous biomaterials.

6.1. Silica mesoporous materials for local drug delivery

Implantable drug delivery systems for local drug release in bone

tissue are one of the most promising therapeutic concepts in ortho-

pedic surgery. Oral administration commonly requires very high,

sometimes also low, effective dosages to reach sufficient drug con-

centrations in the poorly irrigated bone tissue. Antibiotics, growth

factors, chemotherapeutic agents, anti-estrogens, and anti-inflam-

matory drugs are good candidates for the most common bone-re-

lated therapies. In this sense, the possibility of preparing

multifunctional materials able to repair bone tissue, while locally

delivering a drug, is an important milestone in bone diseasetreatments.

Silica mesoporous materials (SMMs) are ordered porous struc-

tures of SiO2, characterized by a high pore volume, narrow pore

size distribution and high surface area. SMMs are synthesized by

self-assembly of silicasurfactant composites, in which inorganic

species (silica precursors) simultaneously condense, giving rise to

mesoscopically ordered composite formation[144].

The first proposal for using these materials as implantable sys-

tems was made by our research team in 2001[145]. Taking into ac-

count the good biocompatibility of SiO2-derived materials with

bone tissue and their porous features, several mesoporous SiO2structures such as MCM-41, MCM-48 and SBA-15 were proposed

as local drug delivery systems to be implanted in bone [146150].

The adsorption of drugs into mesoporous silica is governed bysize selectivity, i.e. the mesopore diameter will determine the size

of the guest drug, as well as the possibility of forming larger enti-

ties by dimmerization [151,152]. The majority of drugs used in

clinical practice fall into the nanometer scale and thus they can

be easily introduced into the pores of mesoporous matrices. The

knowledge of the molecular structure of the therapeutic agent pro-

vides excellent information about the appropriate molecules for

each mesoporous matrix. As an example,Fig. 5shows the most sta-

ble conformation calculated for the alendronate molecule and the

possibility of hosting this drug into a MCM-41 mesoporous mate-

rial. Since the average pore diameter of this SMM is around

2 nm, it can be assumed that the alendronate molecules fit inside

the pore. This information also allows assuming the possible chem-

ical interactions between the drug and the pore wall. In the case of

the alendronate molecule, it can be seen that the phosphate group

Fig. 3. Molecular structure of two different star gels. Fracture toughness of one of these hybrids is compared with human tibia. Images of star gel monoliths are displayedbelow each corresponding structure.


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at the end of the molecule could link to the silanol groups present

at the pore wall.

Pore size depends basically on the chain length of the surfactant

employed in the synthesis, but also on other parameters of the syn-

thesis process. Different methods have been developed to control

the pore size by adding auxiliary organic molecules, which are sol-

ubilized in the hydrophobic region of the micelles, thus increasing

the micellar size[153,154]. This method not only opens the possi-

bility of incorporating larger molecules, but also influences the re-

lease rate of molecules, as it affects the drug diffusion to the

delivery medium [155]. Other factors such as pore ordering

[156], particle morphology[157]and the macroscopic form (films,

monoliths, etc.) [158], can also determine the adsorption and thedrug release kinetics.

The influence of surface area on drug adsorption was also dem-

onstrated when evaluating the alendronate adsorption into MCM-

41 and SBA-15 mesoporous materials[159], which evidenced that

more drug was loaded in the first one (1157 m2 g1 for MCM-41 vs.

719 m2 g1 in SBA-15). For this reason, novel methods to increase

the surface area have been developed. For instance, by adding

phosphoric acid to the reaction media, an important surface area

increase is obtained[160162].

A step forward towards the development of mesoporous silicas

as drug delivery systems (DDS) consists in modifying or function-

alizing the mesopore silica walls with functional groups [163

165]. In this way, the amount of adsorbed drug and the control

of the kinetic release are improved. For instance, amino-function-alized MCM-41 and SBA-15 mesoporous materials have proposed

Fig. 4. Scheme of the steps leading from a micellar solution to a mesoporous silica material.

Fig. 5. HRTEM images of a SiO2-based mesoporous material (up) and conventional solgel glass. Magnification at atomic scale as well as mesoscale allows us to observe the

differences of pore ordering. Schematic representation of alendronate molecule and its interaction with silanol groups at the mesopore are displayed.


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as DDSs for alendronate. After the loading process the amount of

alendronate loaded into amino-modified mesoporous matrices

was almost threefold that of unmodified materials. Therefore, the

organic modification of SBA-15 using different aminopropyl func-

tionalization degrees has been reported as a good strategy to mod-

ulate alendronate dosage [166]. Very recently, the synthesis of

silicazirconia mixed oxides has demonstrated to be a good strat-

egy to control bisphosphonate release. The incorporation of zirco-nium creates a surface with Lewis and Brnsted acid sites, which

complex both alendronate and zolendronate[167].

On the other hand, the functionalization of mesoporous matri-

ces using hydrophobic species aims at impeding drug transport

out of the matrix because the aqueous delivery solution does not

easily penetrate inside the pores. SBA-15 mesoporous matrix has

been functionalized using hydrophobic octyl (C8) and octadecyl

(C18) moieties and adsorption and release tests of erythromycin,

a non-polar antibiotic that belongs to the macrolide family, have

been carried out[168,169]. The organic modification of SBA-15 ex-

ert two actions: firstly it decreases the effective pore size and sur-

face area and, secondly, also decreases the wettability of the

surface by aqueous solutions, thus lowering the amount of erythro-

mycin loaded. However, this strategy allowed a higher control over

the release rate of drug, resulting in a release rate one order of

magnitude lower in the C18-SBA-15 sample compared to unmod-

ified SBA-15. Similar results were reported in the literature with

mesoporous materials modified by silylation. Ibuprofen was incor-

porated into the functionalized mesoporous matrix showing a low-

er drug loading when silylation was carried out [170]. Very

recently, mesoporous silica has been functionalized with macro-

molecular species such as dendrimers, exhibiting excellent charac-

teristics to control the drug delivery kinetics[171].

The importance of the combined action of pore size, surface and

functionalization is clearly envisioned when the confinement of

large molecules, such as proteins and other biologically active mol-

ecules, is pursued. Our first studies in this field began with serum

albumins (BSA) incorporation, one of the major components in

plasma proteins in humans and the upper mammals [172174].However, the real interest when dealing with bone tissue healing

is to incorporate biological agents, which are involved in bone

regeneration processes. A well known protein with osteogenic

capability is the parathyroid hormone-related protein (PTH-rP)

[175]. The C-terminal (107109) region of this protein seems to in-

hibit the osteoclastic bone resorption and to affect the osteoblastic

growth and differentiation. Within the C-terminal region, the 107

111 sequence (ThrArgSerAlaTrp) shows the highest anti-

resorptive activity. Therefore, prior to adsorption of the whole pen-

tapeptide, a model system using L-tryptophan (L-Trp) as the con-

fined molecule in SBA-15 was tested [176]. The amino acid

responsible for the link that produces osteoclastic inhibition is

the Thr position. In this way, by choosing L-Trp (located at the

111 position, far away from Thr) as anchoring site, the biologicalactivity of the pentapeptide should not be modified. The aromatic

indole ring of L-Trp made necessary to modify the silanol-rich wall

of the SBA-15 with quaternary organic amines, since otherwise the

L-Trp adsorption would be very low. Once L-Trp adsorption and re-

lease was effectively modulated through functionalization, this

system was proposed a as previous step to achieve the desired dos-

age of a specific peptide.

Recently, the native C-terminal PTHrP (107111) called osteos-

tatine has been incorporated into SBA-15 with and without func-

tionalization [177]. The results obtained so far demonstrate that

both unmodified and organically modified mesoporous silica

loaded with osteostatine increase cell growth and the expression

of several osteoblastic products, such as alkaline phosphatase,

osteocalcin, collagen, osteoprotegerin, receptor activator of nuclearfactor-kB ligand and vascular endothelia growth factor, in

osteoblastic cells. These findings are the first evidence of the oste-

ogenic features that osteostatine confers to mesoporous silica.

Moreover they also demonstrate the potential of mesoporous silica

for ostegenic protein adsorption as well as appropriated substrate

for cell adhesion and proliferation (Fig. 6).

6.2. Mesoporous bioactive glasses for bone tissue regeneration

Pure silica MCM-41 and SBA-15 mesoporous materials are able

to develop a CHA layer under in vitro conditions [178,179]. How-

ever, the kinetic formation is too slow to consider them as bioac-

tive bone grafts. These experiments helped to draw the future

performance guidelines and the efforts were addressed to prepare

mesoporous materials in the multicomponent SiO2CaOP2O5sys-

tem[180,181]. However, preparing multicomponent systems with

highly ordered mesoporous structures requires a careful selection

of the components, both inorganic precursor and surfactant mole-

cules. For instance, if cetyl trimethylammonium bromide (CTAB),

which is a typical structure-directing agent for MCM family, was

added as structure-directing agent, the mesoporous structure

would be highly defective. This surfactant interferes with Ca2+ cat-

ions, resulting in defective structures through the weakening ofsurfactantsilica interactions, as shown inFig. 7.

The incorporation of non-ionic surfactants such as triblock

copolymers, for instance (EO)(PEO)(EO), opened new possibili-

ties. These structure-directing agents combined with evapora-

tion-induced self-assembly (EISA) process was the keystone for

the successful preparation of this new generation of compounds

(Fig. 8). The EISA process is based on preferential evaporation of

Fig. 6. Schematic representation of the mesopore size, adsorbed proteins and

potential adherent cells.

Fig. 7. Partially impeded interaction between silica species and cationic surfactant(CTAB) when calcium cations are present in the reaction media.


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solvent, which progressively enriches the concentrations of non-

volatile solution constituents and finally ordered mesophase oc-

curs. After gelling, drying and surfactant calcinations, bioactive

mesoporous glasses (MBG) are obtained [182]. Fig. 9 shows the

mesoporous structure obtained for two different compositions:

58SiO236CaO6P2O6 (MBG-58) and 85SiO29CaO6P2O6 (MBG-

85). High CaO contents lead to more hydrophilic phases such as

two-dimensional (2D)-hexagonal p6 m, whereas low contents re-

sult in less hydrophilic mesophases such as 3D-cubic Ia3d struc-

tures [183]. These observations are explained in terms of the

different inorganic phase volume, which increases insofar more

Ca2+ cations are incorporated within the silica network.

The in vitro bioactive behaviour of MBGs is much faster and in-

tense than in conventional solgel glass due to the much higher

surface area and porosity [184,185]. MBG-58 hexagonal material

exhibits a very intense Ca2+ release when soaked in SBF, resultingin a massive growth of amorphous calcium phosphate (aCaP) onto

the MBG surface. Moreover, this material is the first one that pre-

sents a mineral maturation almost equal to that occurred in verte-

brates. Actually, instead of a direct transformation from aCaP to

HCA, MBG-58 exhibits aCaPOCPHCA maturation as can be seen

inFig. 10, in the same way that is accepted to occur in vivo. This

fact can be explained by the intense Ca2+H+ exchange occurring

between MBG-58 and SBF, resulting in a local pH decrease at the

material surface where OCP is temporarily stable.

On the other hand, MBG-85 (3D cubic one) is able to develop

nanocrystalline CHA only 1 h after being soaked in SBF ( Fig. 11),

and exhibit a large amount of serum proteins adsorbed in contactwith vitronectine and fibronectine containing medium. The bio-

degradation products of MBGs are biocompatible and one of the

most exciting aims is preparing scaffolds for bone tissue engineer-

ing or in situ implantation. Recent in vitro biocompatibility tests

demonstrate the good behaviour of osteoblast, fibroblasts and lym-

phocytes in the presence of these materials [186].

Mesoporous silica implants have been also investigated under

in vivo conditions [187]. Healthy and osteoporotic rabbits were

used to test SBA-15 osteostatin loaded and unloaded materials.

The cavitary defects in healthy animals revealed an efficient repar-

ative process, with neoformed bone tissue around the biomaterial

after two weeks. Peptide incorporation into the mesoporous matri-

ces was found to reduce tissue encapsulation, associated with

increased cellularity and appearance of osteoid deposits surround-

ing the biomaterial. Thus, preliminary results have shown that

loading osteostatin into SBA-15 materials promotes the formation

of new bone, especially in osteoporotic animals.

7. Solgel silica glasses as scaffolds for bone tissue engineering

When dealing with ceramics aimed at bone tissue engineering

applications it is essential to keep in mind that the main role will

be played by cells. Pore dimensions of mesoporous materials fall

in the 250 nm range, whereas the dimensions of cells are in the

10200 lm range. That is, mesopores are too small to allow cell

uptake, which needs dimensions in the order of microns. Therefore,

bone porosity, which ranges between 1 and 3500 lm, is necessaryfor several physiological functions [188,189]. In fact, bone tissue

engineering requires the design of hierarchically 3D scaffolds with

interconnected macroporosity, within the 201000lm range

[190192]. Such macroporosity is essential to allow bone cell pen-

etration, adherence, growth and proliferation, leading to bone tis-

sue in-growth and eventually vascularization on implantation. As

described above, mesoporous materials allow controlled release

systems to be designed, with the purpose of loading drugs to be

subsequently released in a localized and controlled way. The role

of these types of molecules is to act as attracting signals for bone

formation cells. These signals must stay at the accessible surface

and not remain inside the mesopores, where osteoblast cannot ac-

cess. However, it is possible to apply all acquired knowledge with

these systems to the fixation of the mentioned peptides or growthfactors onto the external surface or macropores, in the case of 3D

macroporous scaffolds, in order to accelerate the bone formation

rate (Fig. 12).

Several authors have developed 3D macroporous scaffolds

based on bioactive solgel glasses. For instance Zhang et al. pre-

pared 3D-ordered macroporous scaffolds with binary SiO2CaO

and ternary SiO2CaOP2O5compositions[193]. The in vitro bioac-

tivity of these materials has been studied as a function of chemical

composition, microstructure and macrostructure. The formation of

apatite and degradation of the glass were slightly enhanced for the

phosphate-containing composition. In addition, large particles

formed less apatite and degraded less completely compared with

small particles. Lastly, an increase in macropore size slowed down

the glass degradation and apatite-formation processes, an effect re-lated to the decreased internal surface area of the larger pore mate-

Fig. 8. Stages of the evaporation-induced self-assembly EISA process.

Fig. 9. (Up) Hexagonal MBG-58S mesoporous bioactive material. High calcium

content leads to high inorganic volume, thus improving the micellar curvature.

(Down) 3D-cubic MBG-85S mesoporus material with bicontinuous porous struc-

ture. Low curvature results from the low inorganic volume compared with theorganic surfactant.


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rials, although macroporous scaffolds exhibit better in vitro bioac-

tive behaviour than non-3D structured glasses[194].

Solgel glasses can be foamed to produce scaffolds that mimic

cancellous bone macrostructure [195]. Jones and Hench have

developed a method to produce 3D macroporous bioactive scaf-

folds, exhibiting a hierarchical structure, with interconnected mac-

ropore, enhancing the bioactive behaviour as well as the release of

ionic products [196,197]. The foams are produced by including a

surfactant at the sol stage and vigorous stirring. When the foam

is formed, HF acid is added to quench the foam structure by fast

polycondensation of the species. This macroporous glasses have

been tested in osteoblast cultures [198]. Osteoblast proliferation

has shown to be higher in the presence of the foams as well, aswas the collagen secretion. In addition, viable osteoblasts colonize

the foams, suggesting that porous glass foams are promising mate-

rials for bone repair. Recently, the nanoporosity of these foams has

been optimized, improving compressive mechanical properties

[199], although fracture toughness and pore strength are still prob-

lems that must be overcome for future applications.

Several recent research works have been reported concerning

the fabrication of 3D scaffolds using the highly bioactive MBGs as

starting materials. Thus, Yun et al. reported the synthesis of or-

dered giant-, macro- and mesoporous bioactive 3D glass scaffolds

by using a combination of solgel, double polymers templating

and rapid prototyping techniques[200]. The resulting scaffold pre-

sented three lengths of porosity: mesopores (ca. 5 nm) obtained by

using a triblock copolymer template (EO100PO65EO100 (F127)),macropores (1030lm) produced by using methyl cellulose and

Fig. 10.TEM images of S58m after being soaked in SBF at different times: 1 h in SBF; a large amount of ACP is observed next to MBG grain. 4 h in SBF; nanometrical oval nuclei

are observed within the ACP matrix; higher-magnification evidence that these nuclei are nanocrystalline structures constituted by OCP and HA; 8 h in SBF. Needle-shaped

apatite crystallizes within the ACP matrix. Magnified images evidence the microstructural evolution of OCP nuclei to apatite crystallites.

Fig. 11. TEM images of S85 m after being soaked in SBF at different times: 1 h in SBF. Needle-shaped crystallites are observed together with ACP grains. High-magnification

image evidence ordered planes corresponding to (2 1 1) of an apatite phase; 4 h in SBF. Higher amount of polycrystalline apatite is observed on the S85 m surface. FT pattern

and high-magnification image show the planes (1 1 2), (2 1 1), and (0 0 2), corresponding to an apatite phase; 8 h soaked in SBF. Most of the CaP observed correspond to

needle-shaped Ca-deficient apatite. FTIR spectra corresponding to fetal bovine serum (FBS) solution, conventional bioglass (BG), and MBG glasses after 3 days in serum-

supplemented SBF.


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giant-sized pores (301000lm) created by rapid prototyping (RP)

methods [201,202]. The in vitro tests into SBF revealed that the

bioactive behaviour of MBG was preserved because a CHA layer

was formed onto the material surface after 24 h of assay.

Li et al. prepared hierarchically MBG-based scaffolds using P123

surfactant as mesostructure-directing agent and polyurethane

foam (PUF) as template for the macroporous structures [203].

The resulting materials presented hierarchical porosity with inter-

connected macropores of 200400 or 500700lm and uniform

mesopores of 3.7 nm. In vitro bioactivity tests showed that these

MBG-based scaffolds induced the formation of a CHA layer on their

surface after 4 h in SBF.

Other authors have also reported the use of P123 and PUF to

synthesize hierarchically structured 3D MBGs-based scaffolds with

four different chemical compositions and their in vitro bioactivity

and cell adherence evaluation [204]. These scaffolds exhibitedsimilar mesostructural and textural features, exhibiting intercon-

nected macroporous networks with pore diameters in the 200

400lm range and mesopores of 4.9 nm in size. Cell cultures

indicated that primary human-bone-derived cells were able to at-

tach and spread to different degrees on the different scaffolds.

These authors also state that the differences observed in support-

ing cell growth and differentiation observed for different scaffolds

could be related to the CHA formation on the surface of scaffold,

which has been reported to affect cell activity [55,205]. Addition-

ally, the release of calcium and silicon ions may be contributing

to the modulation of cellular attachment[206].

The presence of silanol groups in the external surface of silica

walls would allow the organic modification of the scaffold. The

choosing of the appropriate functional groups could enable the for-mation of strong chemical bonds between the material surface and

different osteoinductive agents, such as certain peptides, proteins

or growth factors, as schematically displayed in Fig. 12. This ap-

proach allows the scaffold to be decorated scaffold by chemically

grafting different active agents, such as certain peptides, proteins

or growth factors, that act as powerful osteoinductive signals able

to promote the appropriate bone cellular functions in the place

where needed [207,208].

8. Conclusions and outlook

The application of the solgel chemistry to the synthesis of bio-

active glasses has opened new perspectives in the chemistry of

these compounds. The higher bioactivity of solgel glasses isattributed to the high surface area and concentration of silanol

groups on the surface of these materials. These features come from

the solgel processing that allows production of glasses and

ceramics at much lower temperatures compared with conven-

tional methods. However, both melt-derived and solgel glasses

present important limitations concerning mechanical properties.

As an attempt to overcome this drawback, organicinorganic hy-

brid materials that exhibit bioactive behaviour have been explored.

Synthesis of silicate-containing hybrids by the solgel method is a

new route to preparing bioactive implants with improved mechan-

ical properties. Moreover, these materials can be degraded by the

physiological environment, which involves the eventual bone col-

onization and full tissue restoring. The future hybrid implants

must be tailored for bone tissue regeneration rather than bone sub-

stitution. Silicate-containing hybrids must promote the osteogenic

performance of the osteoblast-like cells. It can be achieved by

means of the specific species release. These species can be ions in-cluded in the inorganic component such as Ca2+, PO34 , Si(OH)4, etc.,

or by the release of osteogenic agents such as growth factors, hor-

mones or peptides, previously incorporated within the hybrid ma-

trix. In this way, organicinorganic hybrids can be considered as

potential drug delivery systems.The combination of solgel processes and supramolecular

chemistry has produced an outstanding advancement in materials

science, and biomaterials are also involved in it. Bioactive materials

used so far (pieces, powders, coating, self-hardening cements, etc.)

are successfully controlled at the microstructural level, i.e. grain

size, coating thickness, etc. However, the rational design of meso-

porous materials for biomedical applications implies the control at

nanometrical level. By comparing conventional solgel glasses

with mesoporous ones, we can realize how much biomaterials re-search has advanced: the synthesis of conventional solgel glasses

allowed us to obtain bioactive materials with determined surface

area and total pore volume.By overviewing the research on bioceramics over time, we

can realize that their development and advances are, in some

way, related to the decrease in our expectations as materials

researchers. The first generation of inert ceramics was aimed

to substitute natural bone; the second one was aimed just to mi-

mic some biomineralization related-function; finally, with the

third generation of bioceramics we only pretend to help the

bone cells to make their work, by means of supplying appropri-

ated scaffolding. Insofar as we develop more sophisticated sys-

tems by controlling the implanttissue interface, we are

moving back in our artificial purposes giving way to the naturalagents.

Fig. 12. (a) Scheme of macroporous scaffolds with functionalized material surface with PTHrP. (b) Scaffold prepared by foaming processing. (c) Scaffold prepared by rapid

prototyping process.


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The current aims in bioceramic research must be framed in this

field. The development of osteoregenerative ceramics through the

control of their chemical composition, mesoporosity and macropo-

rosity, or by means of osteogenic agent incorporation, should play

a main role in biomaterials science. Finally, the tailoring of scaf-

folds with hierarchical porosity (with different pore size level)

and precise architectures to fit into specific bone defects also will

have a deep impact in the near future. In this sense, rapid prototyp-ing techniques are excellent tools for this purpose and are called to

be fundamental instruments for the development of a new bioce-

ramics generation.

Acknowledgements

Financial support by the CICYT, Spain (Project MAT2008-00736)

and by Comunidad Autnoma de Madrid, Spain (Project S2009/

MAT-1472) is gratefully acknowledged.

Appendix A. Figures with essential colour discrimination

Certain figures in this article, particularly Figures 16 and 812,

are difficult to interpret in black and white. The full colour images

can be found in the on-line version, at doi:10.1016/

j.actbio.2010.02.012.

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