Aerosol Route to Functional Nanostructured Inorganic and Hybrid Porous Materials

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Aerosol Route to Functional Nanostructured Inorganic and Hybrid Porous Materials

Cedric Boissiere , David Grosso , Alexandra Chaumonnot , Lionel Nicole , and Clement Sanchez *

The major advances in the fi eld of the designed construction of hierarchi-cally structured porous inorganic or hybrid materials wherein multiscale texturation is obtained via the combination of aerosol or spray processing with sol–gel chemistry, self-assembly and multiple templating are the topic of this review. The available materials span a very large set of structures and chemical compositions (silicates, aluminates, transition metal oxides, nanocomposites including metallic or chalcogenides nanoparticles, hybrid organic–inorganic, biohybrids ). The resulting materials are manifested as powders or smart coatings via aerosol-directed writing combine the intrinsic physical and chemical properties of the inorganic or hybrid matrices with defi ned multiscale porous networks having a tunable pore size and connec-tivity, high surface area and accessibility. Indeed the combination of soft chemical routes and spray processing provides “a wind of change” in the fi eld of “advanced materials”. These strategies give birth to a prom-ising family of innovative materials with many actual and future potential applications in various domains such as catalysis, sensing, photonic and microelectronic devices, nano-ionics and energy, functional coatings, biomaterials, multifunctional therapeutic carriers, and microfl uidics, among others.

1. Introduction

Materials found in nature combine many wonderful smart features such as sophistication, miniaturization, hierarchical organizations, hybridization, resistance and adaptability. [ 1–4 ] This optimized effi ciency is often associated to their hier-archical constructions at multiple length scales, commonly ranging from the nanometer to millimeters, that introduce the capacity to address the physical or chemical demands occurring at these different levels. [ 1–4 ] Elucidating the basic

© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimAdv. Mater. 2011, 23, 599–623

Dr. C. Boissiere , Prof. D. Grosso , Dr. L. Nicole , Dr. C. Sanchez UPMC Univ. Paris 06, CNRS, UMR 7574 Laboratoire Chimie de la Matière Condensée de Paris Collège de France 11 place Marcelin Berthelot, 75005 Paris (France) F-75005, Paris, France E-mail: [email protected] Dr. A. Chaumonnot IFP-Lyon, Rond-point de l’échangeur de Solaize 69390 Vernaison, France

DOI: 10.1002/adma.201001410

components and building principles selected by evolution to propose more reliable, effi cient, and environment respecting materials requires a multidis-ciplinary approach. Since the beginning of the last decade, materials chemists have demonstrated that materials with complex hierarchical structures can be constructed with high control through “bioinspired” chemical strategies. [ 5–9 ] This important scientifi c and technolog-ical challenge can be addressed via the tuning of hybrid organic-inorganic inter-faces. In particular, the combination of sol–gel chemistry termed ‘‘soft matter’’, and modern processing methods has proven to be highly effi cient as a result of their fair versatility and adaptability without disrupting their own function. These new “integrative chemistry” [ 5 , 6 , 10–12 ] approaches, where chemistry and process are strongly coupled, provide the ability to design condensed matter at several length scales, taking care of the nano-scopic to macroscopic morphologies.

In general, main approaches envis-
aged for multiscale texturation of materials use and com-bine: nanocasting, cooperative self-assembly (molecular and polymeric surfactants), [ 13 ] multiple templating with discrete condensed objects (latex, [ 14–16 ] organogelators, [ 17 , 18 ] biotem-plates (bacteria, viruses, etc. [ 19–22 ] )) or dynamic templates (breath fi gures, [ 23 , 24 ] phase separation [ 25 , 26 ] ). The use of all these various templating strategies, combined with sol–gel chemistry and smart processing methods such as multilayers deposition (via dip-, spin- spray-coating), [ 27–30 ] dip-pen lithog-raphy, [ 31 ] TPA lithography, [ 32 ] ink jet printing, [ 31 , 33–35 ] elec-trospinning, [ 36 , 37 ] foaming [ 38–40 ] and aerosol processing, [ 41–45 ] contributes to a very attractive fi eld of research. Obviously, the development of such a virtually infi nite number of com-binations, is motivated by the easy fabrication of hierarchical materials with more and more complex structures, that will play an important role in many application fi elds such as catalysis, optics, photonics, sensors, separation, sorption, electrochemical devices, controlled release, and therapeutic carriers.
In particular, materials presenting multimodal or multiscale porosity are of major interest, for catalysis, fuel cells and bat-teries, and separation processes, for which optimization of

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the diffusion and confi nement regimes is required. Although, excellent progresses have been made in the investigation of a wide variety of nanoporous materials in the past 20 years, conventional templating procedures used to process nano-structured materials (catalysts for example) present several drawbacks from the standpoint of advanced nanotechnologies. Indeed, most of these procedures are still conducted in time-consuming batch operations, resulting in materials having lim-ited functionality.

The coupling of template-directed-sol–gel-chemistry with a low-cost, scalable, and environmentally benign aerosol process, allows to produce hierarchically structured inor-ganic and hybrid, particles exhibiting periodically organized organic and inorganic nanodomains and bearing a mes-ostructure at different levels. In addition, polymers, latex beads, biomolecules, drugs, or nanoparticles can be easily dispersed within mesoporous inorganic or hybrid micronic, or submicronic, spheres by the spray-drying method in a “one-pot” preparation process. These materials exhibit func-tional hierarchical structures composed of several compo-nents with tuneable sizes. The control of particle localiza-tion can be achieved through an adequate functionalization of nanoparticles and accurate control of the spray-drying processing parameters.

In contrast to the classical solution precipitation pathway, the aerosol process involves a very limited number of prepara-tion steps, produces material continuously, allows for a simple continuous collection of the powder and generates very low waste. Moreover, the physico-chemical quenching associated with droplet formation allows the “freezing” of materials into metastable states, which are hardly achievable by the usual precipitation method, because condensation/dissolution equi-librium usually favours the formation of the thermodynami-cally stable product. [ 46 ] This “freezing” strategy is not solely limited to the synthesis of supports for catalysts but is already employed for the synthesis of new bioceramics and therapeutic vectors, carrying several independent or complementary func-tions such as enhanced contrast MRI, hyperthermia, and con-trolled drug delivery. [ 47–51 ] Moreover, the recent development of robotic engineered aerosol writing allows the micro patterning of inorganic, organic or nanocomposite “inks” materials on arbitrary surfaces. Wherein it opens a land of new possibilities for the design of hierarchically patterned porous coatings and membranes. [ 42 , 43 , 52 ]

This short review presents the major advances in the fi eld of the designed construction of hierarchically structured porous inorganic or hybrid materials for which multiscale texturation is obtained via the combination of aerosol or spray processing with the combination of sol–gel chemistry with self-assembly and/or multiple templating. In addition, the characterization and properties of the resulting materials are also discussed. In particular, for aerosol based synthesis, the dynamic coupling between chemical and processing conditions is an important factor that controls materials on both the micro and nanostruc-tures. The basic understanding of this coupling dictates a more systematic use of in situ characterization techniques [ 53 , 54 ] that follow, in real time, aerosol droplets formation and structura-tion from the molecular precursor solutions to the fi nal stabi-lized powder.

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2. Aerosols: An Obvious Example of Strong Coupling Between Colloidal Chemistry and Process

2.1. General Strategies to Produce Porous Materials Via Aerosol Processing

Aerosol or spray drying methods are low-cost and environ-mentally benign processes which involve a limited number of preparation steps that are compatible with on-line continuous production. As a consequence, they are extensively used in food processing technology, pharmaceutical industries and overall recently in materials processing. [ 44 , 55 , 56 ] In its more simple form, the method consists of atomizing chemical solu-tions into droplets dispersed inside a carrier gas. This colloidal dispersion of liquid droplets is properly termed “aerosol”. The latter undergoes the evaporation of the solvent and condensa-tion of the non volatile solute into solid particles, both being thermally induced in most cases. Droplets can be generated using different atomization methods, all associated with the mechanical destabilization of the solution/atmosphere inter-face, such as by allowing the liquid to meet rotary disks or a powerful air jet, or the use of ultrasonic nebulizers. Powders composed of solid particles are usually obtained, however aer-osol systems can be used as complex “inks” if combined with robot controlled deposition technologies, allowing for instance direct writing of metal oxides on various substrates (e.g. silicon wafers, glass slides, polymeric, curved glass) with micrometer resolution ( Figure 1 ). [ 42 ]

The fi rst important condition for effi cient aerosol processing is to use a “stable” colloidal dispersion (i.e a sol) as the initial solution. The precursor sol must be kinetically stable for the whole duration for the full batch to be processed (from at least a few minutes to one hour depending on the equipment). Indeed a sol precursor can be composed of dispersed dense or porous nanoparticles together with sol–gel inorganic or hybrid polymers and surfactants. More complex colloidal dispersions can result from an ingenious mixing of components. Therefore aerosol processing of such a large variety of systems is a truly a versatile, simple and rapid method to generate nanostructured porous materials. Initially, the different aerosol derived strate-gies can be schematically divided into three general routes that are pictured in Figure 2 .

Route A corresponds to the use of colloidal dispersions of porous or dense submicronic or even nanoparticles that can be organic beads as latex, dense or mesoporous inorganic powders (as Stöber or fume silica nanoparticles, MCM silicas) or a mix-ture of latex and inorganic particles, etc. In that case, after aer-osol processing and subsequent thermal treatment, the porosity of the fi nal materials results from the interstitial volume between the close packed particles (route A1), [ 57 ] the pores are created by the removal of latex, a sacrifi cial template (route A2), [ 58 ] and a bimodal porosity is obtained from the intrinsic mesoporosity of the precursor particles (for example MCM41 silica particles) coupled with a second porosity resulting from interparticle voids (route A3). [ 59 ]

Route B corresponds to the use of a colloidal bath in which reactive sol–gel systems combined with molecular surfactants

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Figure 1 . (A) Schematic representation of EISA mechanism via spray-drying processes. (B) General diagram of an aerosol set-up. (C) Examples of the resulting materials obtained via aerosol process: various patterns printed by an aerosol robocaster [ 42 ] and mesoporous microspheres. Reproduced with permission from [42].

or amphiphilic block co-polymers allow to generate mesoporous microspheres via evaporation-induced self-assembly (EISA) [ 41 ] or evaporation- induced micelle packing (EIMP) [ 60 , 61 ] Aerosol particle sizes can be tuned between 100 nm and 20 μ m through an adequate selection of the aerosol set-up.

Route C corresponds to a complex system where components of route A and B can be mixed, “aerosol cocktail”, in different ratios to yield multifunctional materials with hierarchically structured porous networks. [ 45 , 49 , 62 , 63 ] For example, latex beads can be combined with a sol–gel-surfactant diluted dispersions containing small Inorganic NanoParticles (i.e., INPs of metallic oxides, metals, etc.) to produce micronic porous spheres with a control of size at four different levels after EISA. In this case, the aerosol approach allows for all dimensions to be independ-ently adjusted.

The present review will mainly focus on porous materials obtained along routes B and C. Therefore the background concerning sol–gel chemistry and the main chemical and processing parameters that control the formation of mesopo-rous microspheres in the presence of surfactants will be dis-cussed shortly.

© 2011 WILEY-VCH Verlag GmAdv. Mater. 2011, 23, 599–623

2.2. Sol–Gel Chemistry Background

The chemistry involved in the sol–gel process is based on inor-ganic polymerization reactions. [ 64 , 65 ] Precursors are usually metallo-organic compounds such as alkoxides : M(OR) n (M = Si, Ti, Zr, Al, etc.; OR = OC n H 2n + 1 ), chelated alkoxides [ 66 , 67 ] or metallic salts as metal chlorides, nitrates, sulfates, etc. [ 68 ] The reaction proceeds fi rst through the hydroxylation of metal alkoxides or metallic salts which occurs upon the hydrolysis of alkoxy groups or deprotonation of coordinated water molecules. As soon as reactive hydroxy groups are generated, the formation of branched oligomers, polymers, nuclei with a metal oxo based skeleton and reactive residual hydroxo and alkoxy groups occurs through polycondensation processes (oxolation, olation). [ 65 , 69 , 70 ] These three reactions (hydrolysis, oxolation, olation) can be involved in the transformation of a molecular precursor into a metal oxo-macromolecular network or oxide nanoparticles. The structure and the morphology of the resulting network strongly depends on the nature of the precursors, the water content, the pH, the temperature, the solvent and on the relative contribu-tion of each of these reactions over the allowed reaction time.

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Figure 2 . Chemical strategies for the synthesis of inorganic and hybrid mesoporous particles.

The percolation of these metal-oxo polymers can produce bushy extended structures, percolating through the whole volume and yielding a gel that traps the solvent, the reaction by-products and the added organics. Other fi nal states, such as precipitates of aggregate, dense structures or sols (colloidal dispersion of smaller macromonomers or nanoparticles that did not reach macroscopic sizes) may also be reached. [ 69 ] This latter state is well appropriated to aerosol processing since the control of the colloidal dispersion is achieved through changes in the chem-ical reactivity of each system. The hydrolysis ratio, the use of catalysts, the use of complexing ligands or nucleophilic rea-gents, the steric hindrance of the alkoxy groups, the nature of solvents, the temperature and the pH are the main chemical parameters that must be mastered by the sol–gel chemist in order to be able to achieve the formation of stable sols. Because the size and condensation degree of many sol–gel-derived metal oxo polymers are time-dependent, the ageing time of the pre-cursor solution can have drastic infl uence on the texture of the resulting spay-dried materials, for a given set of chemical and physical parameters.

The various characteristics of sol–gel chemistry (metallo-organic precursors, organic solvents, low processing tempera-tures) allow introducing heat-sensitive organic molecules at the nanometer scale inside an inorganic network, [ 2 , 70–73 ] which role is to bring an additional peculiar physical or chemical property to the material. They can create entirely new properties (optical,


electrical, electrochemical, chemical or biochemical) [ 74 , 75 ] and/or infl uence the growth of the inorganic extending phase to form nanostructured inorganic or hybrid mesomaterials. [ 5 , 76–79 ]

It is now well-known that amphiphilic molecules have the ability to “organize” structures at the micro-, meso-, and nano-scales if present during sol–gel condensation. [ 5 , 12 , 80 ] It has been a signifi cant breakthrough since the discovery that micellar and lyotropic liquid-crystal phases can act as templates for the designed synthesis of periodically organized mesoporous mate-rials. [ 76 , 81 , 82 ] They constitute a challenging domain in materials chemistry that is experiencing explosive growth. In the past 20 years, an increasing quantity of mesostructured and mes-oporous materials with very diverse chemical compositions (oxides, metals, carbons, chalcogenides, semiconductors, etc.) shaped as powders, monoliths, thin fi lms, membranes, or fi bers have been reported. A few selected reviews could help the reader to evaluate the state-of-the-art in this rapidly expanding fi eld. [ 5–7 , 12 , 13 , 28 , 78 , 79 , 83–91 ]

2.3. From Self-Assembly Directed Mesostructuration to Aerosol-Processed Mesoporous Powders

Indeed, by combining the sol–gel growth of inorganic or hybrid networks with self-assembled surfactant mesophases and aerosol processing (routes B and C in Figure 2 ) innovative mesoporous



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materials having complex and diverse architectures can be obtained. Up to now, the preferential way of aerosol assisted mesoporous materials synthesis is the evaporation induced self-assembly (EISA) approach fi rst reported by Brinker et al. (for more detailed information about mesoporous materials the following extensive reviews are recommended [ 28 , 92 , 93 ] ). Briefl y, EISA process (Figure 1 ) implies fi rst the development of a stable isotropic dilute solution containing mainly inorganic (or hybrid) precursors, solvents, catalysts and molecular or macro-molecular templating agents.

The latter solution is then nebulized as droplets which are subsequently carried by air into a drying tube heated to a tem-perature above the vaporization temperatures of volatile species (typically ethanol, THF, HCl, H 2 O). This fast evaporation trig-gers the self-assembly process by concentrating progressively the system in inorganic precursors and surfactant. For given heating time and gradient, which depend on chamber geom-etry, carrier gas fl ow rate, temperature and pressure , the critical micellar concentration is locally reached, driving the micelles to form and self-arrange within the surrounding of the still fl ex-ible inorganic phase. When block copolymers with very poor solubility are used (i.e., high-molecular-weight PB-PEO, PS- b -PEO, etc.) micelles readily form in the solution previous to aerosoling wherein the self-assembly mechanism follows. The evaporation-induced micellar packing (EIMP) mode [ 60 , 61 , 94 ] is particularly useful to create well-organized mesoporous pow-ders or fi lms with systems that are delicate to structure such as mesoporous alumina and transition metal oxides. [ 60 , 61 , 94 , 95 ]

Depending on the processing conditions, i.e., temperature, water, and solvent relative pressures, the micelles could self-organize on a large scale leading to a liquid-crystalline phase before the extended condensation of inorganic species are “locked” in the system. The last step is dedicated to the removal of the surfactant, the stiffening of the inorganic network and eventually the crystallization of the inorganic walls.

2.4. Main Chemical and Processing Parameters Controlling Structure and Texture of the Mesoporous Microspheres

The EISA and EIMP approaches are not always straightforward to optimize since they both imply at least three competitive proc-esses: inorganic condensation versus organic meso-organization and extended phase separation. All of them are infl uenced by the evolution of the local concentrations in non-volatile and volatile species during the aerosol process. The latter governs the polarity fl uctuation and the viscosity change in the droplet depth profi le. As a result, diffusion of the volatile species inside the particles, as well as through the solid/gas interface, plays a key role in the particles’ structure. Because such diffusion is a critically important phenomenon, related parameters such as droplet size, concentration, and residence time in the tube, together with carrier gas relative pressures in volatile species, temperature and fl ux have to be controlled and adjusted. [ 44 ] With respect to the latter statement, optimization of the properties of these mesoporous materials requires a deeper understanding of the governing formation mechanisms, in addition to a sound knowledge of their structure-property relationships. The specia-tion, the nature (hydrophilic/hydrophobic balance, charge, etc.)


and the mean size of the metal-oxo polymers present in the sols before spraying are very critical parameters that infl uence the quality of the resulting meso-porosity. They can be determined by NMR ( 29 Si, 1 H, 13 C, 17 O, etc.), [ 64 , 96–102 ] FTIR, [ 103 , 104 ] light or X-ray scattering. [ 69 , 105–108 ] Among the relevant characterization techniques, the great potential of ex situ or in situ SAXS meas-urements [ 53 , 54 ] combined with HRTEM, 3D HRTEM tomog-raphy [ 109 , 110 ] for the mesostructure determination and with gas adsorption isotherms for determining pores size, pore accessi-bility, surface area has clearly been demonstrated. [ 111 ]

Sol–gel aerosol assisted self-assembly can be divided in sev-eral critical mechanisms: (i) condensation of the species during sol ageing, (ii) fast evaporation of solvent(s), (iii) formation and stabilization of the hybrid mesophase and (iv) chemical and thermal solidifi cation of the network by extended condensation. In the following paragraph, we will emphasize some specifi c aspects of these critical mechanisms.

The solvent evaporation during the drying step strongly infl uences the fi nal morphology of the spray-dried micro-spheres. The solidifi cation of the droplet has to be slow enough to ensure the formation of a dense material but fast enough to avoid coalescence and agglomeration. The whole process is under kinetic control , wherein the properties and structures developed at different length scales are determined by the relative rates of each phenomenon. This is the main reason that renders it diffi cult to obtain simultaneously a microsphere with a high degree of meso-organisation and a high degree of sphericity. This step is often critical when complex systems are assembled since the evaporation creates a radial gradient of species (gradient of precursors concentra-tions but also a gradient in medium polarity) , which induces the radial diffusion of different species contained in a droplet. This effect is responsible for many organizational effects such as core–shell, hydrophobic nanoparticles rejections at the periphery of the particles, depletion of highly polar self-interacting moieties (such as NaCl) or even massive phase separations.

The morphology and texture of the resulting mesoporous micro-ranged particles depend on the relative rates of solvent evaporation and solid formation. In hydro-alcoholic media , the evaporation of volatile species tends to be faster than the forma-tion of a continuous solid network. [ 41 , 53 , 105 , 106 ] When solidifi ca-tion occurs in a time short enough to avoid agglomeration , well separated microspheres are obtained. However , if this time is too short (i.e., the temperature of the droplet is too high T > 150 ° C) poorly textur e d spheres are obtained. Moderate evapo-ration temperatures (80 ° C < T < 130 ° C) are usually needed to perform a good control of both textural and dispersion of the microspheres. In this range of temperature, the resulting mor-phology and texture are sensitive to the extent of condensation of the inorganic oligomers. For a given surfactant, the degree of condensation, the shape and charge, and the chemical com-position of the backbone of the sol–gel promote metal-oxo oli-gomers mostly carrying hydrophilic oxo and hydroxo groups or partly hydrophobic hybrid backbone due to the presence of residual alkoxy groups or grafted organic functions. This variable philicity is an important parameter that strongly infl u-ences the texture and microstructure of the resulting porous materials. [ 105–107 , 112 , 113 ]



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For silica, organosilica, alumina, aluminosilicates, titania based mesoporous materials these chemical and processing parameters have been extensively studied through the use of both ex situ and in situ characterization techniques. [ 53 , 54 ] Indeed, Boissiere et al. [ 53 ] have demonstrated for the fi rst time through in situ SAXS measurements that meso-organisation of spray dried SiO 2 and TiO 2 microparticles is determined by both chemical (concentration, hydrolysis ratio, ageing time) and processing parameters (drying time). The temperature start of the organisation is strongly dependant on these parameters, since droplet concentration and gas temperature governs the evaporation/diffusion and thus the time realated system local composition.

For the silicates-CTAB systems grown in acidic media, the extension of siloxane condensation in the precursor sols strongly infl uence the resulting morphology. In particular, Alonso et al. [ 105–107 , 112 , 113 ] have demonstrated that mesoporous organisation of silica and organosilicas can be optimized when the 29 Si NMR measured condensation degree (C) of the siloxane oligomers ranges between (0.6 < C < 0.75). The resulting oli-gomers have mean gyration radius of 4 to 9 Å. Moreover, the number of residual alkoxy groups should be lower than 0.4 OR/Si to allow facile mesophase organisation. These chemical con-ditions seem to be optimal to generate silicatropic species that favour a fast self-assembly process. In such conditions, when most of the solvent has evaporated a liquid - crystal - like media is formed where the concentration and acidity of the medium allow condensation of the siloxane oligomers without inhib-iting the self-assembly process. Then, depending on the rate of extended solidifi cation , well separated or agglomerated mesos-tuctured microdroplets are obtained. Moreover the presence of remaining alkoxy groups or grafted organic functions modify, via interfacial interactions with the head groups of the sur-factants, the size and morphology of the micellar aggregates. As an example it has been shown for CTAB-silica aqueous solutions that the presence of residual alkoxy groups induces a decrease of the radius of the rods that constitute the hexagonal mesophases and consequently a decrease of the reticular dis-tances measured by SAXS. [ 105 ]

In basic media , the aerosol processing of mesostructured microspheres from surfactant-silica or surfactant-alumino-silicate sols is not straightforward for several reasons: i) the low time window stability for CTAB-Silica sols, ii) the interac-tions misfi t between the polar heads of non ionic surfactants such as Brij and Pluronic derivatives and the negatively charged metal-oxo oligomers which yield a rapid spinoidal decomposition [ 114 ] that drives down the more delicate self-assembly driven meso-organisation process. However, very recently a strategy using an alkyl ammonium (TPAOH) assisted pluronic (F127) templating and the control of the kinetics of condensation through the tuning of pH and Al/Si ratio led to new mesoporous aluminosilicates labelled as Large pore size Aluminosilicates performed in Basic medium, (LAB) with excellent catalytic acidic properties. [ 46 ] For a tuned condensation rate, the favorable interactions between organic cations (TPA + ) and hydrophilic PEO blocks are likely respon-sible for the successful self-assembly process that bypasses the typically obtained spinoidal phase decomposition even in such a basic medium.


3. Silica-Based Mesostructured Materials Prepared Without Surfactant

Many aerosol powders applications (separation, heterogeneous catalysis or drug delivery for example) are dependent on their size but also on their porous structure. As shortly described in the introduction, several nano-structuring strategies have been recently developed for tuning particles porosity at different scales, with mesopores to macropores.

3.1. Spray Drying of Monodisperse Colloids

The simplest strategy is probably the spray drying of solutions containing already made colloids of controlled size. [ 44 , 115 ] Upon evaporation, dense colloids tend spontaneously to aglomerate leading to locally closely-packed structures. Since the mean pore size corresponds to the inter-particle intersticial void, it can simply be tuned by adjusting the initial colloid size (reported dimensions are between 4 and 100 nm). The resulting porosity is a 3D interconnected network with high tortuosity. Such a net-work is, in principle, very effi cient for a homogeneous diffu-sion of chemical species and may be advantageously used for heterogeneous catalysis supports or as solid phase in HPLC columns. [ 116 ]

However simple, this approach produces powders with limited functionality due to the fact that the constitutive col-loids have to connect with each other in order to maintain the mechanical cohesion of the micrometric powders produced. Such cohesion is obtained by thermal sintering which con-solidates the particle junctions. Due to the latter fi nal treat-ment, one-pot synthesis of organic functionalised materials is forbidden, and post functionalisation of the surface will have to be applied if required. Finally, this strategy imposes a direct correlation between the size of colloids and the devel-oped surface area of the fi nal particles (with spherical col-loids for example, Surface < 6/(colloid density × colloid diam-eter)). As a consequence, as soon as an application requires pore size larger than 5 nm (which is usually obtained for a colloid diameter of around 15 nm) the obtained surface area will not exceed 200 to 300 m 2 g − 1 for SiO 2 materials, which is low when compared with surfactant-templated powders (vide infra). Hence, a compromise must be found between surface area and porous network accessibility. This last point was addressed by mixing colloids of different sizes and structures.

3.2. Spray Drying of Polymodal Colloids

The hierarchical porous structure directly stemming from col-loids packing is the bimodal colloid packing. This strategy con-sists of mixing colloids of different sizes, the bigger playing the role of structuring agent for the smaller. In literature, this approach has mainly been investigated for templating small silica colloids with larger PolyStyrene Latexes (PSL) parti-cles. [ 58 , 117 , 118 ] By mixing SiO 2 colloids ranging from 5 to 25 nm and PSLs with size on the order of 42 to 178 nm, Okuyama’s group proved that a critical ratio of SiO 2 /PSL diameter had to



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be maintained to allow the spontaneous self-packing of small colloids around densely packed PSLs. In this case, the max-imum diameter d of silica colloid able to fi ll the space between the PSLs of diameter D is:

d =

(2√

33

− 1)

D

An example of such a hierarchical powder is shown in Figure 3 . From a processing point of view, the spray apparatus consisted of two or three heating zones tube for fi rstly dry the liquid droplets containing suspended colloids at 150–200 ° C, secondly calcine PSLs at 450–500 ° C and a third part as hot as 1500 ° C to sinter the silica structure (the ideal temperature having been found at 900 ° C). As can be seen on SEM pictures, the mac-roscopic order of latex particles is decreased while decreasing the fi nal particle size due to the increasing curvature of small droplets which induces packing defaults of PSLs and a faster drying. A specifi c investigation proved that slow drying in the drying zone was crucial for promoting good quality ordering of the macroporosity. Recently, such a strategy was extended to multimodal porous systems by mixing PSLs of different sizes. [ 119 ]

From a functionality point of view, this approach presents the same limitations as the spray drying of monodisperse col-loids. If the tunable macroporosity obtained by this method is perfectly calibrated and the global porosity is high (70%), the resulting powders are still exhibiting only a moderate surface area.

3.3. Using Salt as an Inexpensive Template

In order to develop the synthesis of nano/macroporous and high surface area silica particles using an inexpensive recyclable template, Zachariah’s group developed an original strategy mixing sol–gel chemistry of molecular silica precursors (tetrae-thoxysilane) in water/ethanol solvent and an inorganic NaCl salt as nearly no-cost template. [ 120 ] By carefully adjusting the water addition into the acidic precursors solutions and waiting for the slow growth of silica oligomers (10 to 50 h), the spray-drying of


Figure 3 . SEM image of a) a power and b) its surface morphology obtainepermission. [ 117 ] Copyright 2002, American Chemical Society.

the aerosolized solution droplets gave birth to nearly spherical particles containing thermally stable NaCl nanocrystals trapped in a condensed silica matrix. The washing of salts with water revealed hollow like porous particles. At this point, the ageing of the solution was determining the capacity of the sol–gel matrix to trap nanocrystals nucleating at the liquid/air interface during the drying. The longer the solution’s aging time, the higher the surface area of the resulting powder (from 230 to 700 m 2 g − 1 for 10 to 50 h of rest). TEM characterization revealed a gradient of porosity with nanopores from 2 to 10 nm localised near the surface of the particles. Larger pores (diameters higher than 20 nm) were observed in the central part of the particles due to the accumulation of salt promoted by the solvent concentration gradient appearing during the evaporation of the solvent at the droplet/air interface in the drying chamber.

3.4. Spray Drying of Mesoporous Colloids

A double-step preparation of mesostructured micron sized particles was reported by Lind et al. in 2003. [ 59 ] The synthetic strategy described consisted in preparing submicron size particles by precipitation in basic hydroalcoholic solution in the presence of a quartenary alkylammonium surfactant CTAB. After calcinations, the resulting mesostructured pow-ders exhibited either 2D hexagonal or 3D Ia3d cubic organ-ized porous domains characteristic of MCM-41 and MCM-48 materials respectively (the obtained particle size ranged from 400–1000 nm and 200–700 nm, respectively).

In a second step, these powders were redispersed in water to form a 3 wt% particle solution and agglomerated at 120 ° C to form 10 to 25 μ m particles using a LabPlant SD05 spray dryer. The resulting spherical objects exhibited a well-calibrated mesopo-rosity (intra-colloidal) with a high surface area (1220–1588 m 2 g − 1 ), a well calibrated small macroporosity due to the inter-colloidal voids, and fi nally a large macroporosity coming from the inter-particular voids (cf. Figure 4 ). Such a hierarchical structure theoretically allows the fast diffusion of chemical species from any external medium to the mesoporosity, thus becoming a very good candidate for any heterogeneous catalysis or HPLC application.


d from a mix of 178 nm PSLs and 5nm SiO 2 colloids. Reproduced with


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Figure 4 . Scheme of composite micron-size hierarchical particles prepared by spray-drying of submicron size MCM-41 and MCM-48 mesostructured colloids.

4. Mesostructured Powders Prepared by Evaporation Induced Self Assembly (EISA)

4.1. Use of a Single Structuring Agent

The fi rst strategy reported for preparing one-pot high sur-face area particles with narrow mesopore size distribution is through the use of the self-assembly properties of amphiphilic molecules in presence of inorganic molecular precursors. The fi rst and most widely used inorganic precursor is the TEOS which, once hydrolyzed in an acidic medium, forms elongated and fl exible silica oligomers able to trap the surfactant mes-ostructure forming upon evaporation of the solution. Early in 1997, Bruinsma et al., reported the preparation of such a structure using CTAC (cethyltrimethylammonium chloride) surfactant in water. [ 121 ] The resulting particles exhibited either a hollow or collapsed macrostructure (prepared with drying temperatures of 76 or 120 ° C, respectively) with inorganic mesostructured shell presenting 2D hexagonal porosity and a

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Figure 5 . TEM images of aerosol-generated particles. a) Faceted, calcined particles exhibitingb) Calcined particles exhibiting cubic mesophase, prepared from the nonionic surfactant Brij-58. prepared from the ethylene oxide/propylene oxide/ethylene oxide tri-block copolymer P123. [ 27 ,

Panel (C) Copyright 1999, Nature Publishing Group.

very high surface area ( > 1000 m 2 g − 1 ), which is characteristic of surfactant templated materials. Although the resulting ill-defi ned shaped powders were far from a perfect spherical shape (hollow cavity was prob-ably due to a too long hydrolysis time and the water concentration gradients appearing during the solvent evaporation), this pio-neering work opened the way for the design of many new inorganic, hybrid organic/inor-ganic and nanocomposite materials that will be described in the following sections of this review. This work was soon after improved by Brinker’s group which replaced a large part of the water solution by ethanol and diluted the precursors in order to obtain solution with surfactant concentration below the critical micellar concentration (CMC). The majority of the solvent having to be evaporated before reaching the CMC, this adaptation allowed the production of homogeneous mesostruc-tured spheres with various amphiphilic structuring agents ( Figure 5 ). [ 27 , 41 ] These

ed at the same time that the low temperature
early works showprocessing of such materials could be used for trapping gold colloids and organic dyes. From this point, several research groups explored the many possibilities given by this fl exible process for producing porous materials with various structures, compositions and applications.
By screening chemical and processing conditions, they achieved a good comprehension of structuration EISA mech-anisms during spray drying (cf. structuration mechanisms in section 2). A complete family of simple structures was achieved: cylindrical pores forming locally 2D hexagonal mesostructure were obtained with quaternary ammonium surfactant (mainly CTAB), [ 27 , 122–124 ] vesicular-like particles exhibiting lamellar mes-ostructure were prepared with bloc copolymers (Pluronic P123 and P104), [ 27 , 124 ] spherical pores of various size and connectivity could be achieved with Brij family surfactants and Pluronic F127 block copolymers. [ 27 , 41 , 122 , 124 , 125 ]

Interestingly, fi nal structures observed after spray drying process were sometimes different from mesostructures obtained with similar solution processed as thin fi lms. [ 28 ]

heim Adv. Mater. 2011, 23, 599–623

1D hexagonal mesophase, prepared using CTAB. c) Calcined particles exhibiting vesicular mesophase, 41 ] Panels (A) and (B), Copyright 1999, Wiley-VCH.


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Figure 6 . TEM image of calcined spray-dried mesoporous silica parti-cles synthesized in the presence of two surfactants. Note the thin mem-brane layer with a different symmetry as compared to the inner part of the particles. Reproduced with permission from The Royal Society of Chemistry. [ 126 ]

Particles obtained by spray drying with CTAB for example exhibit systematically cylindrical pores with 2D hexagonal mes-ostructure in whatever range of the CTAB/TEOS molar ratio of 0.1 to 0.25 used. When fi lms prepared by dip or spin coating at ambient temperature adopt 2D hexagonal, 3D hexagonal, 3D cubic or lamellar structures depending on the solution composition and the humidity of the evaporation atmosphere. This difference is likely to come from the evaporation condi-tions of spray drying which is achieved in a hot and dry atmos-phere (structuration takes place at temperature near the boiling point of the solvent and is very fast if compared with fi lms structuration conditions) [ 53 ] and modifi es the thermodynamic pseudoequilibrium of the formed mesostructure. As a gen-eral trend, the EISA process starts at the droplet/air interface where inorganic and surfactant concentrations are the highest. As a result, the arising inorganic/organic mesophase co-align with this curved interface. As the mesostructuration progresses through the centre of a particle, the mesophase tries to grow epitaxially with this interface, up to the point where it can no longer adapt to the increasing curvature of the drying interface. As a consequence, the mesostructure is very often found having some packing defaults which are responsible for a lower struc-turation quality than the one observed for particles produced by hydrothermal precipitation with similar structuring agents. The larger is the (organic domain diameter)/(particle diameter) ratio, the more packing faults will be obtained. In a similar way, the spray-drying process promotes at times the appearance of a non-structured silica shell at the surface of the particles. This shell, which thickness ranges from 5 to 15 nm usually is almost systematically found when block copolymers (P123, F127, or P104) are used as structuring agents. [ 122 , 124 ] Gas physisorption analyses proved that this shell is semi permeable to small gas molecules such as nitrogen but contains only small mesopores (smaller than 3.8 nm) or micropores, as attested by the sys-tematic presence of catastrophic nitrogen desorption between 0.47 and 0.42 P/Po. Although thin, such a shell is thus an effi cient membrane limiting the diffusion of chemical species between the particle mesostructure and the environment. This can either be an advantage, for drug delivery applications for example, or a drawback if the particles have to be used as hetero-geneous catalysis substrates. This phenomenon has not been explained yet, but it is very likely coming from the high CMC of copolymers structuring agents, which delays the appearance of the fi rst mesostructured layer after the formation of a thin unstructured silica shell. As a consequence, removing this shell will require to mix a part of low CMC structuring agent with block copolymers or to modify the sol–gel transition kinetic of inorganic oligomers.

4.2. Hierarchical Structures Obtained by EISA

The direct EISA of hierarchically structured silica particles with two well calibrated porosity was obtained by a dual templating strategy consisting in mixing two partially miscible structuring agents presenting very different CMC. The fi rst example of this strategy was reported by Areva et al. in 2004 [ 126 ] and allowed the synthesis of mesoporous core-shell with a bimodal porosity. Based on the known phase separation appearing between


hydrocarbon and fl uorocarbon based surfactants, [ 127 ] the pre-cursor solution was made of a mix of Pluronic F127 (a high CMC structuring agent) and a very surface active cationic fl uorosurfactant IC-11 (C 8 F 17 CH 2 NH(C 2 H 5 ) 2 Cl), with IC-11/F127 molar ratio of 25 and IC-11/TEOS molar ratio of 0.014. The structure of the inner part of the particles is similar to that previously reported for aerosol-generated F127–silica particles, as shown in Figure 6 . The inner pore diameter as estimated from the TEM image is about 8 nm. However, in addition to the pores in the inner parts of the particles, a thin porous membrane with an organized structure of periodicity 4 nm is clearly visible close to the particle surface. The presence of two types of structures was confi rmed by XRD, producing a corre-lation peak at low angle being characteristic of the F127 large porosity and another at higher angle characteristic of the shell periodicity. Yet, the absence of higher order peaks did not allow the structural determination of the particles shell. A combina-tion of the higher surface activity of the fl uorocarbon surfactant microphase separation and solvent concentration gradient asso-ciated to the evaporation at the droplet interface may therefore be responsible for the enrichment of fl uorocarbon-surfactant at the particle periphery. The structure directing agents for the pores in the core is probably a mix of IC-11 and F127 micelles, but here the longer F127 surfactant will determine the micellar diameter. However, the driving force for phase separation decreases rapidly with increasing temperature, and the absence of a bimodal porosity in the inner part of the particle can there-fore be rationalized. A similar experiment performed with IC-11 and cetyltrimethylammoniumbromide, CTAB, (50 : 50 molar ratio) did not, however, lead to a similar core–shell structure as that observed for IC-11–F127.

The other leading strategy early developed for the one-pot EISA processing of hierarchical porous particles was to add a soluble polymer into the surfactant and inorganic precursor solution. The drying of such solution promoted phase separations



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of different types, depending on polymers loadings, molec-ular weights, and polarities. Several polymers have been tested: some more hydrophobic such as polypropylene oxide (PPO-Mw 425, 2000, and 3000 or polypropyleneglycol dimethy-lacrylate -Mw 425), and some hydrophilic such as polyacrylic acid (PAA-Mw 5000 and 240000). PPO polymers were used as non volatile alternatives to alkanes or trimethylbenzene (TMB) employed as micelles swelling agents in usual preparations of mesostructured materials obtained by precipitation. [ 128–130 ] Unsurprisingly, when used without surfactant, PPO-silicate precursors weak attractive interactions promotes uncontrolled phase separation leading to unstructured particles with a broad pore size distribution ranging from 20 to 200 nm and small surface areas ( < 100 m 2 g − 1 ). When added in presence of surfactant (either CTAB or non-ionic PEO surfactant or block copolymers), two parameters were found to control the fi nal material porous structure. The fi rst one was the molecular weight of PPO, the second being the weight fraction of PPO incorporated as a swelling agent. Globally, two types of behav-iours have been found. (i) If the Mw of PPO is small enough (that is no more than a few times the Mw of the hydrophobic tail of the amphiphilic structuring agent) and a small weight fraction is added in the surfactant/silicate solution, evaporation of droplets leads to the homogeneous incorporation of PPO into the hydrophobic core of each micelle. This approach leads thus to the tunable control of the mesopore size by the in situ formation of PPO swelled mesostructures ( Figure 7 ). One has to notice that swelled mesostructures may be different from the non swelled ones as a result of the evolution the g packing parameter [ 131 ] (ii) If the Mw of PPO is too large or its weight fraction is too high, the mesostructure incorporation capacity is exceeded and PPO microemulsion like droplets form spontane-ously during solvent evaporation. A complete range of hierar-chical structures can be obtained by this way. Indeed, it leads to multimodal particles retaining some mesostructured domains cohabitating with large meso or macroporous voids. Particles still exhibit high surface area, very much like particles formed by the incorporation of latex particles into a surfactant/silicate solution. [ 128 ] On the other hand, foam-like particles with very thin pore walls and large mesoporous of macroporous porosity can also be created (this latter are the equivalent of Mesocellular Foams obtained by swelling P123 micelles with TMB already reported in literature). [ 132 ] Although, one has to point out that the fast incorporation kinetic of PPO of the spray-drying process

© 2011 WILEY-VCH Verlag Gwileyonlinelibrary.com

Figure 7 . TEM images of aerosol-generated mesoporous silica particles tem10 wt% PPGA. Reproduced with permission. [ 128 ] Copyright 2001, Elsevier.

makes the pore size distribution of such mesocellular particles diffi cult to reproduce. [ 130 ]

On the other hand, when hydrophilic PAA is incorporated into a CTAB/silicate precursor solution, both surfactant mes-ostructuration and phase separation were found coexisting in a large composition range, forming, by this way, hierarchical porous particles with different structures, from hollow mes-ostructured particles to mesoporous-mesocellular particles. [ 133 ] In this case, the main PAA aggregation factors were found to be the gelation kinetic of silica domains and the radial polarity gradient appearing during droplets drying which drives the hydrophilic PAA to migrate towards the center of the particle. This strategy seems to be a very attractive and robust method for producing spacially engineered particles for drug delivery, for example.

5. Inorganic Silica-Based Mesostructured Materials

It is very important for the tailoring of functional mesostruc-tured particles to understand and control the incorporation of heteroelements into the mesostructured materials. When using the spray-drying process, both precursor solution chemistry and fast drying conditions infl uences greatly the fi nal locali-zation, structure and properties of the fi nal particles. To keep this reciex concise, we have reviewed only one-pot incorpora-tion of salts and preformed metal or metaloxide nanoparticles (MOx NPs).

5.1. “ne-Pot”incorporation of NPS into Silica Matrix

Only a few reports can be found on the one-pot incorporation of preformed NPs. If one excludes reports on the incorpo-ration of latex beads, one sees that, in a general trend, spray drying is a fl exible process allowing the introduction of large amounts (sometimes more than 10 wt%) of very different NPs such as gold, [ 41 ] TiO 2 , [ 134 ] CeO 2 , [ 62 ] or magnetic γ -Fe 2 O 3 [ 49 , 135 ] or γ -Fe 3 O 4 [ 63 ] ( Figure 8 ).

The homogeneous dispersion of NPs into the mesostructured silica matrix depends mainly on two parameters, the homo-geneity of the NPs dispersion into the precursor silica/surfactant solution, and the NPs’_surface/silica/surfactant interactions.

mbH & Co. KGaA, Weinheim Adv. Mater. 2011, 23, 599–623

plate by a) 3wt% P123, b) 3wt% P123 + 3.5 wt% PPGA, c) 3wt% P123 +


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Figure 8 . TEM images of microtomed mesostructured powders embedding a) bare b) phenyl and c) amino functionnalized CeO 2 NPs, [ 62 ] and d) dodecanethiol stabilized gold NPs. [ 41 ] Copyright 2008, Springer Netherlands. Copyright 1999, Nature Publishing Group.

The stability of the NPs suspension is obviously infl uencing the homogeneity of the incorporation. Whenever the dispersion is not stable enough, either due to insuffi cient surface charge or hydrophobic character of NPs, spontaneous aggregation of NPs in solution leads to the incorporation of aggregated NPs domains within fi nal particles. [ 49 , 62 , 134 ] This may lead to a lower NPs content than what is introduced into the precursor solu-tion. The NPs’surface functionalization was found to be of par-amount importance during the evaporation step since it con-trols in a large part the NPs/environment interactions. Several types of surfaces have been investigated. In this case, the best study found was the comparison of positively charged amino-functionalized, phenyl functionnalized and bare-surface 3 nm CeO 2 NPs in CTAB-silica or Brij58-silica solutions. It revealed that reasonably attractive interactions between NPs’ surface and either silica or surfactant was needed to avoid a NPs phase separation. [ 62 ]

Although homogeneously dispersed into the solution, the positive charge CTA + surfactant was found to reject amino-functionalized NPs at the surface of the fi nal particles. In a dif-ferent way, phenyl-functionalized NPs, dispersed via the addi-tion of a fraction of THF into CTAB/silica precursor solution, were found to aggregate within the fi nal particles. This phase


segregation was probably promoted by the preferential evapora-tion of THF, leading to the fast increase of the droplet polarity, and thus to the related hydrophobic fl occulation of NPs during the process. None of these phase separations was evidenced when Brij-58 surfactant was used, which is probably due to both the nonionic character and the higher viscosity of drying drop-lets observed with this structuring agent. In a different way, Lu et al. successfully dispersed 1–3 nm dodecanethiol-stabilized gold NPs into CTAB structured silica particles. In this case, pure water solvent was used for promoting the incorporation of NPs into CTAB micelles via dodecane-cethyl hydrophobic stabilisation. This work is remarkable since it is the only one reporting the incorporation of NPs into the hexagonal mes-ophase of the particles as attested by the increase of d-spacing observed by XRD (d 100 = 6 nm of 3.2 nm with or without gold NPs respectively). [ 41 ]

5.2. One Pot Incorporation of Mixed Metaloxides-Silica Matrices

The main advantage of the production of powders by EISA is that one retains a priori in the fi nal powder the initial stoichi-ometry of the solution. Indeed, at the difference of precipitation



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methods in which the fi nal powder composition is determined by the sol–gel condensation thermodynamic, by EISA, the dif-ferent inorganic precursors don’t necessarily have to interact attractively with each other to be incorporated into the fi nal material. Spray-drying is thus a very convenient way to syn-thesise powders with high loading of heteroelements, leading thus to a very large range of properties such as improved hydro-thermal stability (Al or Zr incorporation), bioactivity (Ca and/or Phosphate incorporation), catalytic activity (Pt, Au, Zr and Al incorporation), thermal stability (Zr incorporation), electrical conductivity (Ru-doped Nb 2 O 5 ) etc. By spray-drying, the locali-zation of heteroelements, introduced in the pristine solution as molecular or salt precursors, is very sensitive to both the chemistry of precursors in solution and his reactivity and inter-actions with structuring agent and silica oligomers. In literature, the following heteroelements have always been incorporated into acidic conditions, which is needed for the structuration of powders by EISA: aluminium, [ 46 , 136–141 ] zirconium, [ 48 , 139 , 142 ] cal-cium, [ 47 ] iron, [ 143 ] phosphate ions, [ 144 ] palladium, [ 145 ] etc.

As heteroelement concentration increases in the solution, the trapping capacity of the structuring agent and silica oligomers play a crucial role in the fi nal localization of metallic centres. At low concentration, heteroelements are usually found homoge-neously distributed within the fi nal particles. Most of the time, the mesostructures obtained with pure silica are not affected by the incorporation of small amounts of heteroelements. How-ever, they tend to reorganize with increasing content. [ 47 , 140 , 141 ] The trapping limit of one heteroelement is conditioned by its attractive interactions with silica oligomers or with the struc-turing agent. Such interactions avoid inorganic-inorganic or inorganic-organic phase separation as long as the radial con-centration gradient promoted by droplet drying is active. If, attractive interactions are weak, or the trapping capacity of silica oligomers and/or surfactant is overwhelmed, (with high heteroelement loading for example), “free to diffuse” hetero-centres may then migrate faster than silica oligomers along the radial concentration gradient and a heteroelement concen-tration gradient or a phase separation may take place at the centre of the particles. [ 140 , 141 ] This concentration gradient may be a drawback for some applications but also has been smartly used for promoting the one-pot formation of core-shell particles with specifi c properties: for controlled drug-delivery [ 146 ] or for the nucleation of a functional nanoparticle at the centre of the particle such as magnetite. [ 143 ]

5.3. Large Pore Alumino-Silicate Prepared from Basic Media (LAB) by EISA

As described precedently, solutions used for the preparation of spray-dried silica-based mesostructured particles are always prepared in acidic media for, at such a pH, silica oligomers are small and stable for long periods and permit mesostruc-ture formation with a broad range of structuring agents. In parallel, synthesis of large-pore aluminosilicates acid catalysts, combining mesostructured porosity with improved catalytic activity and hydrothermal resistance, is usually achieved by precipitation in basic conditions. [ 147 , 148 ] In most cases, zeo-lite “seeds” are pre-formed in sodium ion-containing alkaline


solution before they precipitate in presence of a surfactant. How-ever, only long-chain-containing ammonium ions or amines can be directly used in basic media, leading to maximum pore size of 3.5 nm. The use of amphiphilic block copolymers, such as [EO] x -[PO] y -[EO] x Pluronic P123 or F127, leads to larger pore sizes but necessitates a careful acidifi cation step of the zeolite precursor. This acidifi cation step is needed in basic medium to favor strong interactions between silica and PEO-based copoly-mers and effi cient silica mesostructuration. [ 149 , 150 ]

In a recent report, Pega et al. [ 46 ] showed that EISA could be used to directly promote the micro and mesostructuration of very acidic and large mesopores aluminosilicates directly from a basic solution by using a dual templating approach. The spray-dried solution used is free of sodium ions and cati-onic surfactant, that promote the rapid gelation of the pre-cursor solution, and contains clear aluminosilicate precursors. Pluronic F127 and tetrapropylammonium hydroxide (TPAOH) are used as meso and microstructure-directing agent (SDA). High Si/Al molar ratios, as high as 6, could be achieved with a homogeneous repartition of tetraedrally coordinate aluminum centers. The batch precipitation process, classically used for industrial production, can here be signifi cantly improved by spray-drying which eliminates time-consuming and expen-sive steps such as fi ltration, sodium ion exchange, purifi ca-tion, and produces no solvent waste. One has to highlight here that EISA is, so far, the only process available to produce silica-based mesostructure of pores larger than 4 nm with PEO-based structuring agents directly from basic solutions. Upon drying, evaporation promotes the rapid precursor con-centration leading to a quasi-liquid crystalline phase formation at the air-droplet interface. In this case, silico-aluminate pre-cursors are confi ned within the aqueous phase between F127 micelles. No inorganic-organic strongly attractive interactions are needed to mesostructure the fi nal powder, the kinetic con-fi ning of precursors and a rapid condensation of the system are self-suffi cient (very much like observed in the preparation of metallic thin fi lms by electrochemical reduction of salts con-fi ned in a liquid crystal). [ 151 ] The exploration of structuration mechanisms showed that TPA + species are partitioned between the inorganic walls (wherein it plays the role of microstructure template) and the F127 micelles domains (where it plays the role of swelling agent). [ 152 ] As a result, mesoporous and micro-porous volumes could be almost separately tuned by tuning F127, TPAOH and TPABr contents as shown in Figure 9 (pri-vate communication). Some of the powders exhibit surface area higher than 1000 m 2 g − 1 and microporous volume higher than 0.2 cm 3 g − 1 . The Figure 10 is showing the infl uence of struc-turing agents on the fi nal porous structure obtained. When the amount of TPAOH is too high (that is a higher pH and a higher volume of TPA + ), the system condensation kinetic of inorganic precursors is slowed down and the system cannot be stabilize in an ordered mesostructure. The constituents tend to phase separate, forming after calcinations a dual micro-macro-porous structure very well-appropriated for rapid molecule dif-fusion. The tunable hierarchical porous network and zeolitic aluminosilicate precursors promoted excellent catalytic proper-ties in metaxylene isomerization with higher activity than the zeolite-based industrial reference catalyst. The deactivation of LAB materials was found much slower (fi ve times) than that



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Figure 9 . Scheme of the relation structure/composition of LABs materials. TEM images of some microtomed powders prepared with different TPAOH/(Si + Al) and aluminum contents. [ 152 ]

of the standard reference. All these qualities and the cheap, continuous and rapid production of LAB materials make them exceptional candidates for the future generation of heteroge-neous acidic catalysts.


Figure 10 . N 2 adsorption-desorption isotherms of different LAB materials easy modulation of mesoporous volume, B) TPAOH/Metal ratio allows an increasing the microporous volume.

5.4. Non-Silicate Mesostructured Ceramics

By contrast with the numerous developments of silica-based mesostructured materials, only few reports can be found for the


prepared with different compositions. A) F127 concentration allows the easy control of the mesopores size, and C) the addition of TPABr allows


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preparation of non silica powders. The fi rst works on transition metal oxides were published in 2003 by Grosso et al. [ 53 , 153 ] This fundamental work proved that the general strategy consisting in preparing mesostructured transition metal oxide fi lms via EISA could be fully extended to the preparation of mesostructured powders via spray-drying. Yet, silicate and non-silicate precur-sors exhibit often very different sol–gel condensation kinetics. The in situ SAXS study of silica and titania aerosolsproved that a small increase of drying chamber temperature (from 80 to 130 ° C for ethanol-rich acidic solutions of silica structured with CTAB and titania structured with Brij 58, respectively) associ-ated with the fast concentration of precursors is enough to com-pensate this sol–gel reactivity gap. As a consequence, several chemical strategies can be used for stabilizing inorganic pre-cursors in solution and produce via aerosol process mesostruc-tured materials (either (i) metal-chloride precursors [ 153 ] or (ii) complexing agent (acetic acid or acethylacetonate)/hydrochloric acid/metal alkoxide mix [ 154 , 155 ] are described in literature).

The fi rst works described in literature were dedicated to TiO 2 , ZrO 2 , CeO 2 and mixed metal oxides such as Zr x Ti (1 − x) O 2 and Zr x Ce (1 − x) O 2 . [ 153 ] Similar work was reported much later with an additional mesostructured materials composition: 10%CuO/TiO 2 , [ 154 ] Nb 2 O 5 and Ru-doped Nb 2 O 5 . [ 156 ]

Structuring agents used were quasi-systematically PEO-based copolymers. F127 was mainly used for producing mes-opores ranging from 4 to 6 nm. Crystallizations of transition metal oxide matrices could be thermally activated for reaching interesting additional properties such as the photo-catalytic activity of TiO 2 anatase crystals, or the acidity of γ -alumina. The critical nucleation and collapsing temperatures were found very similar with those reported for mesostructured fi lms of similar composition (for example 350 ° C and 700 ° C for ana-tase). [ 98 ] Surface areas of mesostructured transition metal-oxide materials and alumina prepared with F127 were always lower than 250 m 2 g − 1 . However, the preparation of small pores mes-ostructured amorphous alumina using CTAB structuring agent in the presence of urea was recently reported by Kim et al. for producing powders with surfaces higher than 320 m 2 g − 1 . [ 157 ]


Figure 11 . TEM pictures of a) Al 2 O 3 [ 60 ] and b) ZrO 2 [ 154 ] mesostructured powdChemical Society. [ 154 ] Copyright 2008, Wiley-VCH.

By contrast, the successful preparation of large mesopores γ -alumina mesostructured powder was reported in 2006 by using a [E(B) 75 ]-[EO] 86 block copolymer called KLE which hydrophobic block is stable up to 300 ° C. [ 60 ] In this latter case, the use of thermally stable structuring agents allowed limiting the massive contraction of inorganic matrix observed during the dehydration of AlOOH in Al 2 O 3 . [ 158 ] As a con-sequence, after calcinations at 700 ° C, the produced Al 2 O 3 materials (cf. Figure 11 a) keep a perfect mesostructure with pores having diameters of 12 nm yielding high surface area of 403 m 2 g − 1 (when at similar temperature, F127 produces materials of less than 150 m 2 g − 1 ). At such temperature, the alumina network is still amorphous, due to the presence of a large amount (45–50%) of AlO 5 centers. Temperature has to be raised up to 800 ° C (for several hours) or 900 ° C (for few tens of minutes) for promoting the γ –alumina crystallization. The formed materials still exhibits a highly 3D ordered of mesopores together with a high thermal stability.

6. Hybrid Organic-Inorganic and Bio-Hybrids

As hybrid thin fi lms developed via EISA process, [ 28 , 159 ] the incor-poration of (bio)-organic components in aerosol-assisted micro-spheres were preferentially done via a “one-pot” procedure (all the chemical components are mixed together in the starting solution) leading to hybrid organic-inorganic materials of class I or II depending on the strength of bonds between the organic part and inorganic counterpart (weak interactions for class I materials and strong interactions for class II). [ 70 ] It is inter-esting to notice that all the materials involving hybrid organic-inorganic microparticles are silica-based materials with two mixed oxides SiO 2 -ZrO 2 [ 48 ] and SiO 2 -CaO-P 2 O 5 [ 47 ] matrices only.

Following the one-pot procedure, four main types of organic or hybrid components were introduced in mesostructured microparticles: (i) fl uorescent dyes (rhodamine B, [ 41 ] phen-anthroline Eu 3 + /Tb 3 + complexes, [ 63 ] photoacid generator and the pH-sensitive dye dimethyl yellow, [ 63 ] photochromic dyes


ers calcined at 700 ° C and 500 ° C respectively. [ 60 ] Copyright 2006, American


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spiropyran and spirooxazine [ 160 ] ) (ii) macromolecules (oligomers to polymers) (poly(propylene glycol dimethylacrylate), [ 41 ] poly-propylene oxide (PPO), [ 129 , 130 ] poly(acrylic acid), [ 133 ] phenolic oligomer or resol, [ 161 , 162 ] (iii) functional surfactants (polymeriz-able diacetylene surfactant, [ 163 ] alkyloligosiloxane precursors, [ 164 ] block copolymers silylated [ 165 ] ), and (iv) organosilanes bearing a methyl, [ 106 , 107 , 112 , 146 , 166 ] mercapto, [ 49 , 113 , 167 ] amino, [ 49 , 50 ] phenyl, [ 49 ] fl uoro, [ 166 ] vinyl, [ 166 ] methacrylate, [ 166 ] fl uorescein [ 50 , 168 ] group or bridged silsesquioxanes (phenyl-bridged, [ 169 , 170 ] butylene-bridged, [ 169 ] and ethyl-bridged. [ 43 , 170 , 171 ] It is worth mentioning that very recently living cells were also encapsulated in mes-ostructured microspheres. [ 172 ]

Examples of post-synthesis modifi cations (i.e., modifi cations done after spray-drying and surfactant removal) are scarce. This route was mainly used for developing multifunctional vec-tors for diagnosis and therapy with the incorporation of drugs (ibuprofen, [ 51 , 135 ] triclosan, [ 47 ] doxorubicin, [ 50 ] alendronate, [ 48 ] zoledronate [ 48 ] ), fl uorescent dyes (calcein, [ 50 , 168 ] fl uorescein, [ 173 ] rhodamine R6G [ 173 ] ), and bio-components (phospholipids-liposomes, [ 50 , 168 , 173 ] transmembrane protein (ICAM-1), [ 173 ] bioreceptor-functionalized phospholipid, [ 173 ] fl uorescein-labeled phospholipid, [ 173 ] Texas Red-labeled phospholipid [ 50 , 168 ] ) and also mesoporous carbon particles by a well-known sucrose infi ltration/carbonization, [ 174 ] mesoporous siliaon oxycarbide by carbonization of pure bissylil-ethane hybrid particles, [ 171 ] or synthesis of supported gold nanoparticles catalysts. [ 140 , 175 ]

6.1. Infl uence of Organic Species on Formation of Mesoporous Particles

A mesostructured hybrid thin-fi lm mesostructure is very sen-sitive to the one-pot incorporation of organic species. Because of a very high ordering of the starting mesostructure, mes-ophase transitions are easily detected. Many examples have been reported such as the cubic to 2D-hexagonal and then to lamellar transitions induced by the incorporation of an increasing amount of hydrophobic bulky organic species, [ 176 , 177 ] the increase of the lattice parameters with hydrophilic organic compounds, [ 178 , 179 ] or the very common loss of meso-ordering leading to a wormlike structure. The infl uence of the one-pot incorporation of organic species on the mesostructuration of aerosol-assisted microspheres is not so obvious to determine. Indeed, it was previously stressed that mesostructuring should take place in a confi ned volume of high curvature interface (micrometer-sized droplets) in a few seconds (often less than 5 s), implying then an intense competition between micelles formation, mesostructuration and inorganic condensation. [ 41 ] As a consequence, the mesophases transition usually observed for thin fi lms when the surfactant content increases (for example with CTAB: disordered → 3D-hexagonal → cubic → 2D-hexagonal or Lamellar) [ 180 ] is rarely observed for aerosol-assisted particles wherein limit phase transitions to the worm-like → 2D-hexagonal → lamellar sequence. [ 41 , 123 ] To this date the only one example showing the following sequence dis-ordered cubic → 2D-hexagonal → lamellar was reported by Andersson et al. [ 124 ] with P104 block copolymers. In addition to that, well-oriented domains remain mainly at the periphery of particles while a disordered domain (worm-like type) appears


in the core, excepted for the lamellar mesophase, which gives an onion-like structure throughout the particle. Determining the infl uence of organics on mesostructuration process is thus a diffi cult task which requires the use of complementary char-acterization techniques allowing: (i) the characterization of the sol (liquid-state 29 Si and SAXS) [ 105–107 ] (ii) the characteriza-tion of powders (solid-state 1 H, 13 C, 14 N, and 29 Si NMR, SAXS, XRD, TEM with microtomy preparation preferentially, SEM, nitrogen adsorption-desorption) [ 105–107 , 12 , 113 ] and (iii) in situ SAXS experiments. [ 53 ]

The incorporation of hydrophilic or hydrophobic macromol-ecules induces two different phenomena depending on their molecular weight and/or their concentration. With oligomers, i.e. phenolic oligomers [ 161 ] or PPO of low molecular weight, [ 129 ] a mesophase transition from 2D-hexagonal to disordered [ 161 ] or lamellar [ 129 ] phases is observed, and might be preceded by a slight increase of pore size. [ 129 ] With macromolecules of higher molec-ular weight (MW = 2000–240 000), a phase separation is usually observed leading to a foam structure and a mixture of foam and large vesicles at higher polymer content. [ 129 , 130 , 133 ] With polymers of highest molecular weight (PPA of 240 000), hollow particles were obtained. [ 133 ] Phase separation can also be promoted by the addition of small molecule as sorbitan monooleate surfactant (Span 80). [ 162 ] Foam structure and puckered vesicular mesostruc-ture were also synthesized by in situ thermally initiated polym-erization of poly(propylene glycol dimethylacrylate). [ 41 ]

As previously mentioned, class II-functionalized microparticles were mainly elaborated via a “one-pot” procedure which involved a co-condensation step between a functional organosilane and the inorganic precursor (TEOS) in the presence of templating agents. This procedure generally leads to a more homogeneous distribution of organic functionalities into mesoporous matrices with a high control of the stoichiometry. Final materials exhibit a small decrease of the pore sizes and pore volume, only. How-ever, the synthesis could be more delicate because of different effects of organic functions on the mesostructuring process. The amount of organosilanes incorporated inside microparticles was generally comprised between 10 and 30 mol% (organic/Si molar ratio). However, organosilanes loadings of 100% in microparti-cles were achieved by using either hybrid bridged silsesquiox-anes [ 43 , 169 , 171 ] or silylated surfactants only (alkyloligosiloxane pre-cursors, [ 164 ] block copolymers silylated [ 165 ] ).

Studies dealing with the infl uence of organosilanes on the mesostructuration mechanism are scarce compared to those on mesostructured thin fi lms. It is then diffi cult to depict a general trend in function of the characteristics of organosilane mole-cules (size, hydrophobic/hydrophilic, ionic, etc.) as it was the case for hybrid thin fi lms obtained with EISA. [ 28 ] Spray-drying is a highly kinetics-dependent process. Final structure type, quality and reproducibility will greatly depend on both chemical parameters (such as dilution, alcoholic or aqueous medium, cosolvents, ageing time, inorganic condensation degree) and processing conditions (such as the composition and tempera-ture of the gas fl ow, the temperature of the heating zone, and the resident time of particles in the heating zone).

Several studies have been reported in literature. The incor-poration of organosilanes induced a decrease of meso-ordering. This loss of ordering could be done without signifi cant phase changes, [ 112 , 166 , 169 ] which was explained by a decrease in the



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size of organized domains. One might also observe phase transition; starting with a pure 2D-hexagonal, a mixed 2D-hexagonal (outer part)/wormlike (inner part) or a lamellar phase, a wormlike mesophase is fi nally obtained. [ 166 , 181 ] With highly hydrophobic fl uoro-silanes, a localized phase transi-tion was only observed at the surface circumference (from a 2D-hexagonal phase to a dimpled lamellar phase). [ 166 ] It was shown for thin fi lms that fl uoro-silanes act as amphiphilic mol-ecules allowing their co-assembly with a low fraction of CTAB surfactant. [ 182 ] As it was pointed out by Brinker et al. [ 41 , 146 ] a radial concentration gradient occurs in drying droplets with an enrichment of droplet surface in water (due to the preferential evaporation of ethanol). One could then postulate a preferential co-assembly of fl uoro-silanes and CTAB at the particles surface (rich in water) which causes a decrease of the micelles curva-ture leading to a lamellar phase while the core of the particles remains 2D-hexagonal due to fl uoro-silanes microphase separa-tion. [ 126 ] It is also interesting to notice that instead of a lamellar phase expected, a mixed 2D-hexagonal (outer part)/wormlike (inner part) was synthesized by using a phenylene-bridged silsesquioxane in place of TEOS. [ 169 ] The presence of salt (NaCl) in a methyltriethoxysilane/TEOS-CTAB system favored a higher mesophase ordering with the increase of methyltriethoxysilane content (excepted for the higher molar ratio: 40/60). [ 146 ] The increase of ionic strength screens electrostatic interactions, reducing then the optimal CTAB headgroup area. Up to a point, this may allow greater accommodation of amphiphilic hydro-lyzed methyltriethoxysilane at the surfactant/silica interface, while maintaining appropriate charge density matching.

While the majority of class II functionalized micropar-ticles were synthesized via a “one-pot” procedure, Alonso et al. [ 106 , 107 , 112 , 113 ] demonstrated that a “delayed” procedure often leads to more organized hybrid microparticles. This “delayed” procedure, already investigated for hybrid mesostructured thin fi lms, [ 31 , 176 , 177 , 183–185 ] consists in the formation of silica oli-gomers from hydrolysis-condensation reactions of TEOS fol-lowed by their functionalization with organosilanes bearing methyl, phenyl, mercaptopropyl, cyanopropyl groups. From SAXS measurements on sols, the authors shown that an optimal silica oligomers size (radius of gyration around 0.5–1.0 nm) allowed producing non agglomerated microparticles with a high degree of textural ordering. This size range was found to be close to the wall thickness of CTAB-based mesoporous mate-rials. Moreover, they stressed the important function of pending groups (residual alkoxy groups or organic part of organosilanes) which are spatially close to the surfactant headgroups and then might disturb the aggregation properties of surfactants. This location of functional organosilanes at the pores surface was demonstrated by Ag + sorption experiments. It was proved that mercapto functions were homogeneously dispersed in the whole volume of particles and fully accessible to external analytes. [ 113 ]

6.2. Complex Multifunctional Systems

6.2.1. Optical and Filler Properties

In 1999, the fi rst hybrid aerosol-assisted microparticles with optical properties were reported by Brinker et al. [ 41 ] Although


these mesostructured microparticles could be regarded as a simple system ioncorporating either a fl uorescent dye, rhod-amine B, or gold nanoparticles well-dispersed into mesostruc-tured microparticles, they opened a way ten years ago for multifunctional platforms, following a very simple, fast, and effi cient “one-pot” procedure.

Soon after, photochromic mesostructured silica pigments were synthesized via a “one-pot” incorporation of photochromic dyes, such as spiropyran (SP) and spirooxazine (SO), into mes-ostructured silica microparticles. [ 160 ] It was shown that these spherical microparticles provide a mechanically and chemically rigid framework, pretecting dyes without hindering confor-mational transformation. The optical characteristics of photo-chromic dyes, fast rate constants for the thermal fading and position of absorption peaks, indicate that dyes are solubilized within the micellar phase of these microparticles. Additionally, silica-encapsulated pigments were easily dispersed in latex fi lms without any addition of dispersing agents providing transparent photochromic fi lms with transmissions of 97–100%.

Rare earth ion-phenanthroline fl uorescent complexes were also introduced in such mesostructured microspheres. Starting with a solution containing all the precursors needed for the synthesis of mesostructured microspheres plus phenanthroline and EuCl 3 /TbCl 3 , the authors obtained, in one step, lumines-cent vesicular mesostructured silica microparticles. [ 63 ] Under the same excitation wavelength (330 nm), these microspheres displayed the characteristic simultaneous emission of Eu 3 + and Tb 3 + . Moreover, the luminescence intensity ratio of Eu 3 + to Tb 3 + could be precisely tuned by just adjusting the initial molar ratio of Eu 3 + to Tb 3 + in the initial solution. In addition, the lumines-cence spectra of these microspheres remain almost unchanged after 10 days immersed in an aqueous medium. This quasi-lack of leaching phenomenon could be linked to the vesicular structure of microspheres which may limit diffusion process. The simple addition of magnetic nanoparticles (magnetite) in the solution previously described led to the production of bifunctional magnetic and luminescent microspheres. [ 63 ] The presence of magnetic nanoparticles disturbs neither photolumi-nescence properties of the rare earth ion-phenanthroline com-plexes nor the mesostructurating process since the same vesic-ular mesophase was obtained. On thye other hand, the spray-drying process does not alter the crystalline characteristics of the magnetite nanoparticles. To demonstrate the versatility of this approach, magnetic microspheres containing a photoacid generator ((4-phenoxyphenyl)diphenylsulfonium trifl ate) and microspheres containing the photoacid generator and a pH-sensitive dye (dimethyl yellow) were also synthesized, both of them displaying photoacid generation under UV irradiation (254 nm) in air and in apolar liquid media. [ 63 ]

Another interesting property was reported by Lu et al. [ 181 ] They synthesized, via the “one-pot” procedure, a wormlike hybrid mesoporous microspheres functionalized with (3-tri-methoxylsilyl)propyl methacrylate (TMSPMA) molecules which present C = C bond suitable for free radical polymerization and alkoxy groups allowing the formation of a tridimensional silica network. These functionalized microspheres after surfactants extraction in ethanol were dispersed in mixture of TMSPMA monomers and thermal initiator. After monomer infi ltration and subsequent polymerization, organic/inorganic nanocomposites



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were formed. They observed that the incorporation of such functionalized microspheres induces an improvement of both thermal and mechanical properties of nanocomposites. Mechanical tests remonstrated that nanocomposites showed a signifi cant increase in tensile strength, modulus, and tough-ness with a little sacrifi ce on the elongation compared to the bulk polymer.

6.2.2. Multifunctional Vectors for Diagnosis and Therapy

The most important application of hybrid mesoporous particles concerns the development of multifunctional vectors. Although this fi eld has been intensively investigated since 2001 [ 186–192 ] with mesoporous materials obtained via precipitation method, the fi rst attempts concerning the use of aerosol-based parti-cles as biomedical carriers are actually recent. [ 49 , 51 , 173 ] As it was already mentioned, spray-drying offers several features which could be advantageously used in this fi eld: (i) this technique is widely used in the pharmaceutical industry, (ii) the spherical morphology of micro-particles obtained via an aerosol-assisted method is more suitable for their incorporation within fl uids or injectable pastes than irregular and diffi cult to control bulky particles obtained via conventional method, (iii) it is a green, fast and low-cost process that can easily be scaled up, (iv) the dimension and structure of spherical particles could be tuned by adjusting the chemical composition of the starting solu-tion and the set-up conditions, (v) the composition of the fi nal microspheres corresponds to the stoichiometry in non-volatile species of the initial solution, and (vi) it provides mild synthesis conditions compatible with the incorporation of (bio) organic components.

The versatility of the spray-drying technique combined with the EISA process allowed the development of hybrid microspheres which present generally two different prop-erties (or more) amongst the followings: (i) magnetic reso-nance imaging (MRI), [ 49 ] (ii) hyperthermia, [ 49 ] (iii) controlled drug delivery, [ 47 , 48 , 50 , 51 , 135 , 168 ] (iv) targeting, [ 50 , 168 , 173 ] (v) (poten-tially) bone tissue regeneration and dental reconstruction. [ 47 ] It is noteworthy that in vitro tests involving cells were per-formed for controlled drug delivery and targeting properties only. [ 50 , 168 ] These properties were achieved by the addition of specifi c chemical compounds during the mesoporous parti-cles synthesis or after: (i) superparamagnetic nanoparticles of maghemite ( γ -Fe 2 O 3 ) [ 49 , 51 , 135 ] for MRI and hyperthermia, [ 49 ] (ii) functional organosilanes (coupling agents) leading to tar-geted drug delivery after further bio-modifi cations, [ 49 ] (iii) mixed oxides allowing delayed drug release due to strong iono-covalent interactions between ZrO 2 matrix content and phosphonated drugs [ 48 ] or formation of bio-compatible apatite-like phase in simulated body fl uid (SBF) [ 47 ] (iv) drug loading (ibuprofen, [ 51 , 135 ] triclosan, [ 47 ] alendronate, [ 48 ] zolendronate, [ 48 ] doxorubicin [ 50 ] ), (v) liposomes fusion on mesoporous particles and subsequent modifi cations of these supported phospholi-pids bilayers (bilayers charge tuning) which both hinders drug release and favors the endocytosis process, [ 50 , 168 ] (vi) incorpora-tion of transmembrane proteins, bioreceptors and fl uorophore-labeled lipids into these supported phospholipids bilayers. [ 173 ]

Synthesis : From a chemical point of view, all the multifunc-tional vectors reported in the literature are silica-based materials


(pure SiO 2 , [ 49–51 , 135 , 168 , 173 ] SiO 2 -ZrO 2 [ 48 ] or SiO 2 -CaO-P 2 O 5 [ 47 ] mixed oxides, SiO 2 functionalized with phenyl-, aminopropyl-, mercaptopropyl-, [ 49 , 50 ] or fl uorescein- organosilanes [ 50 , 168 ] ) synthesized with various templating agents: CTAB, [ 47 , 49 , 50 , 168 ] Brij-58 [ 173 ] or pluronic block copolymers (F127 [ 47 , 48 ] and P123 [ 47 , 49 , 51 , 135 ] ).

Functionalization of silica matrices with organosilanes was created via a “one-pot” procedure leading to the incorporation of organic functional groups between 10 and 20 mol% (func-tional organosilanes/TEOS molar ratio) in matrices without sig-nifi cant loss of mesostructure ordering. [ 49 , 50 ]

Encapsulation of maghemite nanoparticles (8 nm) was also done by a “one-pot” procedure from a colloidal γ -Fe 2 O 3 suspen-sion. [ 49 , 51 , 135 ] Julian-Lopez et al. [ 49 ] pointed out that the order of addition of the different chemical compounds constituting the initial solution was crucial for avoiding maghemite nano-particles aggregation since one of the main requirements of the EISA process is to work with a homogeneous stable solu-tion. Ruiz-Hernandez et al. [ 51 ] observed that the incorporation of maghemite nanoparticles into mesoporous microspheres induces a decrease of mesopores ordering at high nanoparticles loading only ( γ -Fe 2 O 3 /SiO 2 = 46 wt%) but has no infl uence on the morphology and size of mesoporous particles. It appeared that maghemite nanoparticles are well-dispersed in fi nal mesoporous microspheres and more interestingly that their integrity (size, composition, cristallinity and then magnetic properties) is unaffected through the whole synthesis process (spray-drying, surfactant removal). [ 49 , 51 , 135 ]

Temperatures of the heating zone in the aerosol process was between 350 and 500 ° C (mostly 400 ° C) with an average residence time of a few seconds. This short residence time is insuffi cient to induce any decomposition/damaging of organic components due to a too low heat transfer to the particles. [ 50 ]

Depending on the composition of matrices (fully inorganic or hybrid i.e. silica functionalized with organosilanes cited above), two different procedures were applied for the sur-factant removal: a calcination step (350–700 ° C during several hours in air) [ 47–49 , 51 , 135 , 173 ] or a more organic compatible proce-dure: a solvent extraction with ethanol at 70 ° C. [ 49 , 50 , 168 ] Finally, drug loading and liposomes fusion were performed on mes-oporous microspheres obtained after surfactant removal in solution. [ 47 , 48 , 50 , 51 , 135 , 168 , 173 ]

Magnetic Resonance Imaging and Hyperthermia : The MRI con-trast agents properties of maghemite-encapsulated mesoporous microspheres were demonstrated by Julian-Lopez et al. [ 49 ] By comparing recorded T 2 -weighted images of γ -Fe 2 O 3 -SiO 2 micro-spheres with those of three references: water, mesoporous microspheres and pure γ -Fe 2 O 3 nanoparticles, they observed that the contrast displayed by γ -Fe 2 O 3 -SiO 2 microspheres revealed a good behavior as a T 2 contrast agent (even if it was slightly weaker than those of pure γ -Fe 2 O 3 nanoparticles). It should also be noted that pure silica spheres present a slight T 2 effect, which can be associated with air (O 2 being paramagnetic species) entrapped in the pores after surfactant removal by cal-cinations. ( Figure 12 ).

The superparamagnetic properties of maghemite nanocrys-tals could also be useful for hyperthermia. The application of a radio frequency magnetic fi eld to maghemite nanoparticles could generate heat as a result of Néel and Brown relaxations. [ 193 ]



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Figure 12 . Hyperthermia and T2 contrast agent properties of mesoporous microspheres. [ 49 ] (A) Hyperthermia: temperature increases due to the heating of γ -Fe 2 O 3 nanoparticles by a rf fi eld in an aqueous solution, the same solution in 2 wt% agarose gel (98% water), and in P123-templated γ -Fe 2 O 3 (5 wt%)–silica microspheres (after surfactant removal) retained in agarose gel. (B) T 2 -Weighted MR image of four test tubes containing an agarose gel loaded with (A) an aqueous dispersion of functionalized γ -Fe 2 O 3 –SiO 2 spray-dried spheres, (B) water (note: an air bubble entrapped in the gel is responsible for the black spot); (C) an aqueous dispersion of Phenyl-functionalized SiO 2 sprayed spheres and (D) an aqueous dispersion of γ -Fe 2 O 3 MNCs. [ 49 ] Reproduced by permission of The Royal Society of Chemistry.

The authors compared the response of bare maghemite nano-particles dispersed into two different media: an aqueous solu-tion and a passively conductive 2% aragose gel (which has bone-like thermal properties [ 194 , 195 ] ). A signifi cant reduction of the thermal effect was observed for maghemite nanoparticles immobilized in the aragose gel, wherein Brownian motion is hindered. They also showed that the heating effect of γ -Fe 2 O 3 -SiO 2 microspheres and bare γ -Fe 2 O 3 nanoparticles both embedded in the agarose gel were similar, confi rming that the magnetic properties of maghemite nanoparticles are well pre-served when encapsulated into mesoporous microspheres.

Drug Loading/Release: an in vitro Investigation in Simulated Physiological Medium : Drug loading was generally performed by a simple thermodynamic adsorption process. [ 47 , 48 , 51 , 135 ] Briefl y, a certain amount of mesoporous microspheres where added into a solution of drug and stirred between 5–20 min, [ 50 , 168 ] up to 24–48 h [ 47 , 48 , 51 , 135 ] at room temperature without solvent evap-oration. The amount of drug loaded depends on both textural properties of the mesoporous microspheres and the strength of interactions between the matrices and drug molecules (since


the adsorption is an equilibrium-based process). The drug content in pure silica mesoporous microspheres after adsorp-tion/washing cycles was between 3 and 25%wt. The in vitro drug release assays were done in buffered aqueous solution of physiological pH of 7.4 at 37 ° C during 50–200 h. A gen-eral trend can be observed with pure silica mesoporous micro-spheres. [ 47 , 48 , 51 , 135 ] During the fi rst hours, an important and fast release is observed corresponding to 50–70% of the drug loaded which is followed by a slower release until the end of the experiment. This two-step release behavior was attributed to the adsorption of drugs at two different sites: drug molecules adsorbed either at the outer surface of mesoporous micro-spheres or inside the pores, the former ones leading to a fast release and the latter ones to the slower release due to diffu-sion from the mesoporous network to the environmental fl uid. It has been reported that mesoporous silica materials (thin fi lms and powders) exposed to biological conditions could be (partially) degraded in several hours. [ 196 , 197 ] This degradation is highly dependent on composition, porosity, and calcination temperature, [ 196 ] and may fi nally lead to the loss of drugs activity



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before reaching the target. In order to overcome this problem, Collila et al. [ 48 ] synthesized SiO 2 –ZrO 2 mesoporous microparti-cles presenting various compositions (ZrO 2 content comprised between 0 and 20 mol%). Indeed, it has been demonstrated that mesoporous silica-zirconia mixed oxides matrices were signifi cantly more stable in relevant biological conditions than pure silica materials. [ 196 ] In addition to that, the presence of zir-conia may be interesting in drug delivery applications since it may induce a delay of drugs release due to the complexation of drugs with zirconia species present at the pores surface. In this work, the authors investigated the infl uence of both the zirconia content and hydrophilic/hydrophobic character of bisphospho-nates drugs on the loading and release properties in respect to textural characteristics of mesoporous microparticles. The two drugs studied presented the same phosphonate complexing heads [ 198 ] but with different chemical tails, one being hydro-phobic (possessing an imidazole ring) in the case of zoledro-nate and the other one being hydrophilic with a propyl chain terminated by an amino group in the case of alendronate. As a consequence, regarding the drug loading, a general tendency was observed: independently of the drug adsorbed (determined via experiments involving pure silica matrices), the amount of drug intake increases with the zirconia content in the silica matrix except for the microparticles having the highest zirconia content (20 mol%) which exhibits the lowest textural character-istics ( i.e. surface area, porous volume and pores size). It was also noticed that the drug loading is more important (up to 3.5 times) for hydrophilic species (alendronate) than for hydro-phobic drugs (zoledronate). This result could be explained by the hydrophilic environment of microparticles surface provided


Figure 13 . Simultaneous loading and encapsulation of drugs through liposoimages of the FITC-labeled mesoporous core, Texas Red-labeled lipid, andAmerican Chemical Society.

by the Si-OH and Zr-OH groups. On the other hand, this hydro-phobic/hydrophilic character of drugs also has an infl uence on the release behavior. While the release profi le of alendronate is similar to those described previously (i.e., a fast release fol-lowed by a more controlled one), the release profi le of zoledro-nate is sigmoidal and could be decomposed into three phases: lag phase, burst phase and saturation phase. This sigmoidal profi le was explained by the hydrophobic property of zoledro-nate which impedes the diffusion of the aqueous physiological medium inside the porosity inducing then the lag phase. Once a part of zoledronate was released, the hydrophilic/hydrophobic balance of surface became more hydrophilic favoring then the diffusion of solvent into the pores and the normal release could take place with burst and saturation phases. It is interesting to notice that, as expected, the amount of drugs release is much lower (especially in the case of zoledronate) when drugs are strongly attached to the surface (silica-zirconia mixed oxides) than simply adsorbed to the surface (pure silica).

Brinker’s group investigated another way to control the drug release via liposomes fusion on mesoporous microparticles ( Figure 13 – 15 ). [ 50 , 168 ] This biomimetic approach leading to a cell-like structure or “protocells” is undoubtedly one of the most elegant way to create advanced biocompatible drug delivery multiplatform. It is based on the ability of the lipidic behavior of membranes in cells to control materials exchange, and in par-ticular to hinder the diffusion of ions and charged hydrophilic molecules. These studies are based on the electrostatic inter-actions at neutral pH between the silica-based microparticles which could be anionic, in the case of bare silica, or cationic once functionalized with 3-[2-(2-aminoethylamino)ethylamino]


me fusion on mesoporous silica nanoparticles with confocal fl uorescence merged image confi rming the postulated construct. [ 168 ] Copyright 2009,


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propyltrimethoxysilane (AEPTMS), fl uorescent drugs (calcein: a model drug negatively charged and a positively charged drug, doxorubicin), and phospholipids/lipids (positively charged DOTAP: 1,2-dioleoyl-3-trimethylammonium-propane–chloride salt–zwitterionic DOPC: 1,2-dioleoyl-sn-glycero-3-phospho-choline–negatively charged DOPS: 1,2-dioleoyl-sn-glycero-3-[phospho-L-serine] sodium salt).

The authors observed neither liposomes fusion nor drug loadings when silica-based microparticles present the same charge than phospholipids or drugs. For example, liposomes fusion or calcein loading were not observed when DOPS and anionic microparticles are involved. In contrast, a synergistic system was observed when the loading of negatively charged calcein occurred during the fusion of positively charged lipo-some (DOTAP) with the negatively charged silica microparti-cles. [ 168 ] It could even lead to an important calcein uptake with a calcein concentration inside protocells 110 times greater than those in the remaining solution. In term of release properties, 90% of calcein contained in a DOTAP protocell are released within 18 days. It is worth mentioning that the loading and release for the protocells are qualitatively different than those of conventional liposomes, since the calcein concentration in liposomes is approximately that of the solution (no enrichment) and the release is practically instantaneous. Since loading and release processes are governed by electrostatic interactions, cal-cein loading was also performed with cationic silica particles, leading to an uptake of around 25 wt% with saturated calcein solution. [ 50 ] However, in the complex biological F-12K medium, within 20 minutes, the negatively charged calcein was displaced into solution by anions (phosphate, sulfate, carbonate, chloride) present in the F-12K medium. To overcome this premature fast release, an initial fusion with an anionic DOPS was performed,


Figure 14 . Confocal fl uorescence images of protocells incubated with CHOincubated with free calcein in media. (C) CHO incubated with calcein enChemical Society.

thereby causing a reduction by 55% of the calcein’s release. To further improve drug sealing, DOPS protocells were mixed with free cationic DOTAP liposomes. This procedure led to a partial lipid exchange which allowed the decreasing of defects in the phospholipids bilayers and then reduced the calcein release by 75%. Liposomes fused on microspheres present a third advantage in addition to drug encapsulation promoter and drug leaching inhibitor: it could favor an endocytosis process leading then to a better targeting of drugs.

Endocytosis and targeting: an in vitro cells investigation : In vitro cells experiments were performed on mammalian cells (Chinese hamster ovary cells–CHO) with two fl uorescent mol-ecules, followed by confocal fl uorescence microscopy. Calcein which is a negatively charged (at neutral pH) model drug is membrane impermeable and displays a green fl uorescence and doxorubicin which is positively charged (at neutral pH) chemotherapeutic drug is membrane permeable and presents a red fl uorescence. Moreover depending on the experiments, mesoporous silica microparticles were labeled with fl uorescein silylated derivatives (FTIC) and liposomes with Texas Red-mod-ifi ed phospholipids.

First endocytosis of protocells was demonstrated with protocells formed by the fusion of Texas Red-labeled ( + ) DOTAP liposomes on FTIC-labeled ( − ) mesoporous silica particles ( Figure 14 ). [ 168 ] During the endocytosis process, the loss of a part of the fused liposomes was observed and attributed to either a lipid exchange or membrane fusion. This implies then that drugs encapsulated in mesoporous particles and retained by the phos-pholipids bilayers could be delivered inside the cells. This was verifi ed with incubation experiments of calcein-loaded proto-cells (anionic microparticles and ( + ) DOTAP bilayers). CHO cells displayed the green fl uorescence of calcein while when


cells. (A) FITC-labeled core and Texas Red-labeled DOTAP shell. (B) CHO capsulated in supported DOTAP bilayers. [ 168 ] Copyright 2009, American


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Figure 15 . A negatively charged drug (green dots) is adsorbed into the pores of a cationic mesoporous silica nanoparticle. Other anions that are adsorbed more strongly (red dots) can displace the loaded drugs (pathway 1). Fusion with a negatively charged liposome reduces the displacement (pathway 2), and further lipid exchange/fusion with cationic liposomes reduces it even more (pathway 3). [ 50 ] Copyright 2009, American Chemical Society.

free calcein was incubated, no cellular uptake was observed. Calcein release inside CHO cells was not homogeneous and cells displayed dimmer and brighter regions. By in vitro experi-ments in simulated body fl uids, the authors determined that calcein release depended on the pH (much faster for pH < 6) and brighter regions were attributed to calcein release in endosomal compartments (pH 5) while dimmer regions were ascribed to calcein release into the cytosol.

To stress the important function of phospholipids bilayers in drug delivery and targeting, two sets of experiments could be reported ( Figure 15 ). [ 50 ] First, calcein loaded cationic mes-oporous microparticles (without liposomes) cited previously were unable to deliver calcein inside cells despite the endo-cytosis of microparticles. As it was previously mentioned, calcein molecules were progressively displaced into the surrounding biological F-12K medium by anions. The ( − ) DOPS liposomes fusion on these particles limited the calcein displacement by 55%, however due to the negative charge of protocells provided by the DOPS liposomes which is repelled by the negatively charged cells surface, the cellular uptake of cal-cein was only slightly improved. In order to favor cells uptake, a partial exchange of ( − ) DOPS by ( + ) DOTAP was realized by a simple mixing of free DOTAP with DOPS calcein-loaded pro-tocells. By tuning the charged surface of protocells, the author signifi cantly improved the calcein delivery to CHO cells. The second set of experiments involved ( + ) doxorubicin-loaded ani-onic silica microparticles fused successively with three lipo-somes (( + ) DOTAP/( − ) DOPS/( + ) DOTAP). It was observed that free membrane-permeable doxorubicin and doxorubicin-loaded anionic silica microparticles showed the same cellular uptake i.e. a relatively uniform red fl uorescence. In contrast,

© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, WeinhAdv. Mater. 2011, 23, 599–623

doxorubicin-loaded protocells produced a very bright punctuated pattern typical of micro-particles endocytosis suggesting that at least a fraction of the doxorubicin was delivered by the protocells. Moreover, the amount of doxorubicin delivered by protocells is 3 times greater than those delivered by anionic silica microparticles. Finally, to improve both the targeting and the endocytosis processes, spe-cifi c biocomponents as transmembrane pro-tein, phospholipids receptor could be added during the formation of liposomes and their fusion on microparticles. [ 173 ] Concerning the toxicity of silica microparticles and protocells, the authors observed a very high cell viability of > 97%.

Conclusion

Aerosol processing coupled with soft matter chemistry is an easy to scale up process, involving a limited number of preparation steps. Moreover, this process is compatible with a continuous production of materials. Moreover, it generates the strict minimal wastes and allows the preparation of novel materials with chemical compositions, dis-

persion and structures which are hardly achievable by the usual precipitation methods, as a result of the fast evaporation that forces precursors to co-arrange inside very confi ned domains and under metastable state. Indeed, aerosol processing cou-pled with sol–gel chemistry, self-assembly, and nanoparticles is a smart strategy that allows to tailor hierarchically structured porous inorganic or hybrid materials with the possibility to tune the pore size, connectivity, surface area, etc. The multitude of multifunctional materials span a very large set of structures and chemical compositions. Therefore, they are serious candidates for numerous applications such as catalysis, sensing, photonic and microelectronic devices, nanoionics and energy, functional coatings, biomaterials, multifunctional therapeutic carriers, and microfl uidics. However, [ 11 ] one of the key parameters to obtain reproducible aerosol derived functional materials is the design and control of hybrid organic-inorganic interfaces. This synergistic time dependent interaction between the organic and inorganic components is crucial. It can yield tailored mesostruc-tured networks with periodic, or non periodic, organizations, with submicronic (50–100 nm) or extended phase separations, with composition gradients, with aggregation or dispersion of additionally introduced nano-objets, or with core-shell morphol-ogies etc. It should be also mentioned that the kinetics at which the interface develops and stabilize also control the course of heterogeneous reactions in the gel state, including problems such as exchange fl uxes, boundary-controlled reactions, inter-face morphology, nonlinear phenomena connected with inter-faces and reactions at boundaries.

Even if a few in situ experiments have been successfully carried out, currently, the general approaches of these nano-structured porous materials often rely on trying and testing

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procedures due to the limits of the knowledge of in situ para-meters during experimentation of these dynamic structures, variable chemical compositions, interface modifi cations, etc. A few main limits have been identifi ed and breakthroughs as well as a better prediction of material design are expected when a better understanding is reached via: (i) systematic in situ SAXS experiments with a perfect control of the carrier gas composi-tion and the temperature inside and outside the droplet, cou-pled with mass spectrometry to evaluate the fl ow and composi-tion of the vaporized solvent. (ii) In situ Raman and IR to char-acterized condensation or speciation of the growing inorganic or hybrid oligomers.

On the other hand, these phenomena are complex and there is a real need for the understanding simulation of the organic-inorganic interaction processes, in particular for the characterization of the real time local evolution of the inter-face between the different components that are responsible for the self-assembly driven structuring. The characterization of the intimate nature of the interface to better design surface affi ni-ties is still not satisfactory. Both strong interactions between organic and inorganic components, as well as interfacial mor-phologies could be better scrutinized working on the inter-species distances, chain mobility and generated free volume in the hybrid mesophases. These basic studies do need to be carry out because they will lead to the complete control of these proc-esses, giving to the aerosol synthesis of mesoporous materials a whole maturity needed for its development at the industrial scale.

Acronyms list:

AEPTMS 3-[2-(2-aminoethylamino)ethylamino]propyltrimethoxysilane

CHO Chinese hamster ovary cells CMC Critical Micellar Concentration CTAB Cethyltrimethylammonium bromide CTAC Cethyltrimethylammonium chloride DOPC 1,2-dioleoyl-sn-glycero-3-phosphocholine DOPS 1,2-dioleoyl-sn-glycero-3-[phospho-L-serine]

sodium salt DOTAP 1,2-dioleoyl-3-trimethylammonium-propane–

chloride salt EIMP Evaporation Induced Micelles Packing EISA Evaporation Induced Self Assembly FTIC Fluorescein silylated INP Inorganic Nano Particles LAB Large pore size Aluminosilicates prepared in

Basic medium MNC Magnetic Nano crystal MRI Magnetic Resonance Imaging NPs Nano Particles PAA Polyacrylic acid PB polybutadiene PEO Polyethyleneoxide PPO Polypropyleneoxide PS polystyrene PSL PolyStyrene Latexes SBF Simulated Body Fluid


SDA Structure Directing Agent SDS Sodium Dodecyl Sulphate TEOS Tetraethylorthosilicate TMB Trimethylbenzen TMSPMA (3-trimethoxylsilyl)propyl methacrylate TPA lithography Two Photon Absortion Lithography TPA + Tetrapropyl ammonium cation TPABr Tetrapropyl ammonium bromide TPAOH tetrapropylammonium hydroxide

Acknowledgements The authors would like to acknowledge all PhD students and postdoctoral researchers who worked with the hybrid materials group of the LCMCP for their contribution and effi ciency to spray-drying developements, namely: A. Coupé, S. Péga, N. Baccile, B. Julián-López, F. Colbeau-Justin, B. Louis, and Institut Français du Pétrole, CNRS, and UPMC for their funding.

Received: April 19, 2010 Published online: October 20, 2010

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