Bionanocomposites: A New Concept of Ecological, Bioinspired, and Functional Hybrid Materials

DOI: 10.1002/adma.200602328

Bionanocomposites: A New Conceptof Ecological, Bioinspired, and FunctionalHybrid Materials**

By Margarita Darder, Pilar Aranda,and Eduardo Ruiz-Hitzky*

1. Introduction

A new generation of hybrid nanostructured materials sig-nifies an emerging field in the frontier between materialsscience, life science, and nanotechnology.[1–3] During the lastfew years, “bionanocomposite” has become a common termto designate those nanocomposites involving a naturally oc-curring polymer (biopolymer) in combination with an inor-ganic moiety, and showing at least one dimension on thenanometer scale.[4,5] Because of their functional properties,

bionanocomposites based on inorganic solids with a layeredarrangement (1D nanoscale materials) are of singular impor-tance, as described in a recent review.[5] Since the develop-ment of nanocomposites two decades ago, materials scientistsare making huge efforts in this research area because of theexcellent features of these nanohybrids as structural or func-tional materials, with interesting applications as componentsin, amongst others, heterogeneous catalysts and optical, mag-netic, and electrochemical devices.[6] A considerable part ofthis effort is now being focused on the development of biopo-lymer-based nanocomposites that display the well-knownproperties of nanocomposites derived from synthetic poly-mers (improved mechanical properties, higher thermal stabil-ity, and gas-barrier properties).[7,8] In addition to these charac-teristics, bionanocomposites show the remarkable advantageof exhibiting biocompatibility, biodegradability and, in somecases, functional properties provided by either the biologicalor inorganic moieties. The great interest towards this researcharea is supported by the strong increase in the number of sci-entific publications according to the Institute for Scientific In-formation (ISI) database (Fig. 1).

Living organisms produce natural nanocomposites thatshow an amazing hierarchical arrangement of their organic

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Bionanocomposites represent an emerging group of nanostructured hybrid materials.They are formed by the combination of natural polymers and inorganic solids andshow at least one dimension on the nanometer scale. Similar to conventional nano-composites, which involve synthetic polymers, these biohybrid materials also exhibitimproved structural and functional properties of great interest for different applications. The properties inherent tothe biopolymers, that is, biocompatibility and biodegradability, open new prospects for these hybrid materials withspecial incidence in regenerative medicine and in environmentally friendly materials (green nanocomposites).Research on bionanocomposites can be regarded as a new interdisciplinary field closely related to significant topicssuch as biomineralization processes, bioinspired materials, and biomimetic systems. The upcoming developmentof novel bionanocomposites introducing multifunctionality represents a promising research topic that takesadvantage of the synergistic assembling of biopolymers with inorganic nanometer-sized solids.

–[*] Prof. E. Ruiz-Hitzky, Dr. M. Darder, Dr. P. Aranda

Instituto de Ciencia de Materiales de Madrid, CSICCantoblanco, 28049 Madrid (Spain)E-mail: [email protected]

[**] This work has been supported by the CICYT, Spain (ProjectsMAT2003-06003-C02-01 and MAT2006-03356), the Junta de Andalu-cía, Spain (Project IFAPA-2002.000890), and the Comunidad deMadrid, Spain (Project S-0505/MAT/000227). We thank Dr. M. A.Camblor for helpful discussions and collaboration in cryogenic tech-niques. Technical support from F. Pinto and A. Valera is gratefullyacknowledged. M.D. thanks the I3P Program of the CSIC for finan-cial support through a postdoctoral contract.

and inorganic components from the nanoscale to the macro-scopic scale. Nacre in pearls and shells,[9] ivory,[10] bones,[11]

and enamel and dentine in teeth[12] are fine examples of bio-nanocomposites found in Nature. Since 1949, more than300 scientific publications on the structure, composition, andmechanical properties of nacre reveal the huge interest of re-searchers in this natural composite, which shows a bricklikestructure of aragonite layers cemented by proteins. As re-viewed by Mann’s group, the understanding of biomineraliza-tion processes has led materials scientists to take inspirationfrom biology for developing new hybrid nanostructured mate-rials.[2] By following this strategy, different research teamshave developed biomaterials that mimic the exceptional fea-tures of natural nanocomposites.[1,2,13–15] New synthetic meth-

ods inspired by Nature are also being explored. For example,Deville et al.[16] have replicated the nacre structure by mim-icking a process that takes place in nature, giving rise to toughand ultra-lightweight materials. The freezing of seawater in-duces a layered structure of crystals of pure ice, forcing saltsand microorganisms to concentrate in the space between theice crystals. In the mentioned work a similar effect is pro-duced by directional freezing of an aqueous hydroxyapatite(HAP) suspension, forcing the arrangement of HAP intowell-defined layers. The result is a porous HAP scaffold witha multilayered structure that resembles nacre. Other inorganicsolids, including layered and fibrous clay minerals, show simi-lar arrangements when using freezing techniques. The ice-templated synthesis of nanocomposites that combine clay

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Eduardo Ruiz-Hitzky is a Senior Research Professor at the National Research Council of Spain(CSIC), and has been Director of the Department of Porous Materials & Intercalation Com-pounds at the Materials Science Institute of Madrid since 1987. He graduated in chemistry fromthe Complutense University of Madrid, and carried out his Ph.D. under the supervision ofProf. J. J. Fripiat at the University of Louvain, Belgium. He was then a post-doctoral fellow atKiel University, Germany, working with Prof. G. Lagaly, before joining the CSIC. His researchwork over the last 30 years has focused on hybrid inorganic–organic and biohybrid systems, withspecial emphasis on intercalation chemistry, the organic functionalization of inorganic solids,and design and preparation of nanocomposites. Currently, his interest in nanostructured materi-als involves biohybrids and bionanocomposite materials based on silicates (clay minerals) andother inorganic solids. He has received awards from the Academie Royale des Sciences, Lettreset Beaux Arts and the Association des Chimistes de Louvain in Belgium, the ICIDC (Ministeriodel Azúcar in Cuba), and by the CSIC in Spain.

Margarita Darder received her Ph.D. from the Autonomous University of Madrid (UAM) in2000, under the supervision of Prof. E. Lorenzo and Prof. F. Pariente. Her doctoral research wascentered on different enzyme immobilization strategies for the development of amperometricbiosensors. In 2001, she joined the group of Prof. Ruiz-Hitzky at the Materials Science Instituteof Madrid, CSIC, as a postdoctoral fellow. She has also worked with Prof. H. D. Abruña atCornell University, USA and with Prof. H. Van Damme at the École Supérieure de Physique etde Chimie Industrielles de Paris, France. Her research activities focus on the synthesis and char-acterization of nanostructured intercalation materials based on the incorporation of polymersand biopolymers in layered solids as well as hybrid organic–inorganic materials prepared viasol–gel procedures, these materials being applied as active phases in electrochemical devices suchas ion-selective sensors and biosensors.

Pilar Aranda has been a Research Scientist at the National Research Council of Spain (CSIC)since 1997. She graduated in chemistry from the Complutense University of Madrid, and thenshe joined the Materials Science Institute of Madrid, CSIC, carrying out her Ph.D. under thesupervision of Prof. Ruiz-Hitzky on nanocomposite materials based on poly(ethylene oxide)/clay intercalations giving rise to a new class of ion conductors. She has worked at the ÉcoleNational Superieur de Chimie de Montpellier, France and at the University of Aberdeen, UK un-der the supervision of Prof. L. Cot and Prof. A. R. West, respectively. She was subsequently apostdoctoral Fellow at the Colorado State University, Fort Collins, CO working with Prof. C. R.Martin before joining the Carlos III University in Madrid as Assistant Professor (1994–1997).Her current research is focused on nanostructured organic–inorganic and bio-inorganic hybridmaterials for electrochemical devices and other applications based on magnetic, optical, and re-activity properties.

minerals and charged biopolymers such as chitosan offers away to prepare biomaterials with a nacrelike structure, as il-lustrated by recent examples investigated in our researchgroup (Fig. 2).

The importance of this class of bioinspired and biomimeticmaterials results from their strong incidence in relevant areas,mainly in regenerative medicine as well as drug vectorizationand delivery, where the employment of biocompatible materi-als is usually required. A large number of biomaterials havebeen reported as implants for tissue regeneration, with a spe-cial emphasis on HAP-based bionanocomposites for bone-re-pair purposes.[17,18] Besides biocompatibility these materialsexhibit other properties such as osteoconductivity, serving asa scaffold that facilitates cell proliferation for the growth ofnew tissue.

The possibility of replacing petroleum-derived syntheticpolymers by natural, abundant, and low-cost biodegradableproducts obtained from renewable sources is also the aim ofnumerous research groups.[19–21] Nature is the source of a widenumber of biomacromolecules that can be involved in thepreparation of these green bionanocomposites, with starch,cellulose (and its derivatives), and poly(lactic acid) (PLA) asthe biopolymers most widely employed for this purpose.[22–25]

Their combination with natural inorganic solids, such as clays,provides reinforced bioplastics that offer the advantages ofnanocomposites as well as biocompatibility and biodegrad-ability. Micro-organisms are able to decompose bionanocom-posites in a fully natural way, giving carbon dioxide that isfixed by plants. Thus, the use of these new green materials inthe food industry, agriculture, or the building industry, amongother areas, will help to reduce the amount of waste productsand to diminish environmental pollution, leading to sustain-able development.

Biopolymers bearing functional groups or biomacromole-cules showing highly specific catalytic properties, such as en-

zymes, have been involved in the development of bionano-composites with the aim of preparing hybrid nanostructuredmaterials with a desired functionality, usually applied forsensing or biosensing purposes. Recently, a wide number ofcharged polysaccharides have been combined with naturalclays and synthetic layered double hydroxides (LDHs), re-sulting in tough bionanocomposites with ion-recognitionability, thereby opening a new field of application in electro-analysis.[26–28] In enzyme-based bionanocomposites the inor-ganic counterpart is commonly envisaged as a protective ma-trix to preserve the immobilized biomacromolecules fromdenaturation, but it can also impart multifunctionality tothe hybrid system.[29,30] The assembly of enzymes with inor-ganic host solids is an alternative to the usual methods forenzyme immobilization, resulting in robust hybrid materialsuseful for the development of biosensors and enzymatic reac-tors.

2. Green Bionanocomposites

Currently, there is a growing tendency to use environmen-tally friendly or “green” materials with the aim of replacing

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Figure 1. Number of publications per year related to polymer-basednanocomposites versus biopolymer-based nanocomposites. Data col-lected from the ISI Web of Knowledge [v3.0]—Web of Science.

Figure 2. Layered arrangement observed in scanning electron microsco-py (SEM) images of A) natural nacre and the clay-systems B) vermicu-lite, imaged by low-temperature SEM, and C) bionanocomposite chito-san–sepiolite, prepared by directional freezing techniques.

nondegradable materials, thereby reducing the environmentalpollution that results from large amounts of plastic waste. En-vironmentally friendly materials with applications in agricul-ture, the building and food industries, or biomedicine are themain objective of many research groups. Petroleum-derivedsynthetic plastics are being replaced by biodegradable naturalpolymers extracted from renewable natural resources, such asstarch, cellulose, PLA, or polycaprolactone, mostly in the pro-duction of bioplastics for packaging applications.[31] Thesenew green materials are composed of nontoxic componentsthat can be easily degraded by micro-organisms. This trendrepresents a huge benefit to the environment and will alsocontribute to a reduced dependence on fossil fuels. Anotherreason that is propelling the production of environmentallyfriendly materials is the great profusion and availability ofbiopolymers in Nature, with starch, cellulose, and chitin beingthe most abundant.

Considering the huge benefits of recyclable environmen-tally friendly materials and their wide range of applications,many research groups are trying to improve the properties ofbioplastics. The aim is to develop complex materials that showthe well-known properties of nanocomposites,[7,8] but consistof biopolymers instead of the usually employed polymers,mainly polyolefins (polypropylene and polyethylene) andpolyamides (nylon). This has led to biodegradable and envir-onmentally friendly bionanocomposites that show betterproperties than nonreinforced bioplastics.[19–21] Neutral poly-saccharides, such as starch derived from corn, wheat, rice orpotato, and cellulose and its derivatives, are the main biopoly-mers employed in the development of green nanocompos-ites.[23–25,32–34] These materials generally incorporate natural orsynthetic clay minerals as inorganic nanofillers as well as orga-nically modified clay minerals, giving intercalation or exfolia-tion compounds. Montmorillonite and cloisite are the usualsilicates used in these studies, acting as nanocharges that canproduce a reinforcing effect in the biopolymer matrix, therebyresulting in improved mechanical properties. Typically, plasti-cizers such as glycerol, tryethylcitrate, or vegetable oils areadded to biopolymers with a melting temperature close totheir decomposition temperature to overcome degradationproblems, transforming them into thermoplastic polymers.These compounds also contribute to a better dispersion of thenanofiller in the biopolymer matrix, resulting in an enhance-ment of the mechanical properties.

The biodegradable thermoplastic polyester PLA, derivedfrom L-lactic acid produced in the fermentation of cornstarch,is another polymer widely used in the development of rein-forced bioplastics, mainly in combination with organicallymodified silicates. Although melt intercalation is the usualmechanism for the preparation of these bionanocompo-sites,[22,35–37] an alternative procedure employs in situ polymer-ization of previously intercalated lactic acid monomers, givingrise to exfoliated systems.[38] Following both procedures, bio-nanocomposites that show improved thermomechanical andgas-barrier properties are achieved. The biodegradability ofreinforced PLA bioplastics strongly depends on the nature of

the layered silicate and the organic modifier, making it possi-ble to tailor the material’s biodegradability by adding an ap-propriate organically modified clay as nanofiller (Fig. 3).[39] Ithas been also stated that a faster hydrolytic degradation takesplace for more hydrophilic fillers.[40] For the same purpose,

the addition of a layered titanate as nanofiller in the PLA ma-trix results in an enhanced rate of biodegradation under solarirradiation because of its photocatalytic reactivity, which iscomparable to that of TiO2.[41] In this context, novel ap-proaches based on clay–TiO2 systems prepared by controlleddeposition of TiO2 nanoparticles on silicate surfaces can beenvisaged.

Although different examples concerning recent research ongreen nanocomposites have been introduced above, the devel-opment of these materials is still in an incipient phase. Newprogresses within this field will require investigations concern-ing the use of alternative biopolymers and also on the meth-odology, to enhance compatibility with the inorganic moieties.Therefore, it can be expected that the controlled modificationof polysaccharides and other polymers of natural origin, aswell as the integration of a wide range of “nonpollutant”nanofillers other than silica and silicate, for example LDHs,would afford new formulations and improve the mechanicaland other properties of the resulting green nanocomposites.

Besides the enhancement of the structural properties, theresulting biopolymer–clay films also exhibit higher thermalstability and improved gas-barrier properties that allow theirapplication in food packaging.[32] Similar to nanocompositesthat involve layered inorganic solids and synthetic polymers,the dispersion of silicate lamellae in the biopolymer matrix

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after 32 days after 50 days after 60 days

Figure 3. Biodegradation of neat PLA and several PLA-based bionano-composites involving organically modified layered silicates. MAE4: di-methyldioctadecyl ammonium cation; ODA4: octadecylammonium cat-ion SBE4: trimethyloctadecylammonium cation. Reproduced from [39].

gives rise to “tortuous” pathways that make gas diffusionthrough the bionanohybrid film difficult.

In addition to the usually employed layered silicates, otherinorganic solids have been incorporated into biopolymer ma-trices as reinforcing agents. For example, the dispersion ofanisotropic particles of sepiolite in natural rubber leads to anenhancement of the mechanical properties of the organic ma-trix.[42] A similar effect was achieved by dispersion of multi-walled carbon nanotubes (MWCNTs) in natural rubber, re-sulting in an improvement of the mechanical, physical, andchemical properties of the biopolymer.[43] It has been alsoconfirmed that the modulus and strength of natural rubberare increased after addition of SiC nanoparticles and single-walled carbon nanotubes (SWCNTs), the mechanical proper-ties of SiC-based nanocomposites being better than those ofSWCNTs-based ones with the same filler content.[44] With re-gard to the nanocomposites’ biodegradability, cellulose andstarch whiskers become a more ecological alternative to inor-ganic nanofillers. For example, waxy maize starch nanocrys-tals ca. 6–8 nm thick, 20–40 nm long, and 15–30 nm wide havebeen tested as nanofillers in both waxy maize starch plasti-cized with glycerol[45] and in natural rubber,[46] leading to anenhancement of the mechanical properties in both cases. Asimilar effect was observed when rodlike cellulose whiskersprepared from cotton linter pulp, with an average length of1.2 lm and a diameter of 90 nm, were employed as reinforc-ing agents in soy protein isolate (SPI) plastics.[47] Increases inboth the tensile strength and the Young modulus were ob-served, most likely caused by crosslinked networks resultingfrom intermolecular hydrogen bonds between the nanofillersand the SPI matrix, as well as an improvement in the water re-sistance. In a recent work, the reinforcing effect of microcrys-talline cellulose (MCC) in a PLA matrix has been comparedto that of commercial bentonite, an organically modifiedlayered silicate.[48] Bentonite offers an improvement in tensilemodulus and yield strength as well as a reduction in the oxy-gen permeability, whereas MCC only shows a better behaviorconcerning the elongation at break. Although superior me-chanical properties seem to be achievable with layered sili-cates as nanofillers, MCC and analogous whiskers should beconsidered for the purpose of preparing fully biodegradablematerials. The interest of many companies in these environ-mentally friendly materials is increasing more and more. Forexample, Fujitsu and NEC have recently begun to commercia-lize environmentally friendly notebook computers and mobilephones based on PLA, either blended with a petroleum-de-rived polymer or reinforced with Kenaf fibers (Fig. 4). Thisapplication will require more studies focused on improvingthe dispersion of biodegradable whiskers in the biopolymermatrix for enhancing mechanical properties.

3. Bionanocomposites in Life Sciences

One of the main applications of bionanocomposites is re-lated to biomedical applications, such as tissue engineering.

This fact has lead to a wide number of scientific publicationson this topic in recent years. However, as recently pointed outby Thomas et al.,[49] the development of biomaterials for re-generative medicine can be still considered an emerging field,with tissue engineering, and especially bone implants, being afast-growing branch of this research area. Biocompatible ma-terials involving biopolymers, such as collagen and PLA, arethe most widely studied materials for the regeneration ofdamaged tissues, acting as artificial supports for cell growth.The requirements for these bioresorbable scaffolds are bio-compatibility, suitable mechanical properties to avoid the col-lapse of the implant, sufficient macroporosity with intercon-nected pores to allow for the transport of nutrients andmetabolic wastes, and controlled biodegradability, becausethe rate of biodegradation needs to be balanced with the rateat which tissue is regenerated.[49,50]

Most of the works found in literature are devoted to bone-repair purposes. A large number of bionanocomposites testedas implants include HAP combined to collagen, a fibrous pro-tein, in order to reproduce the composition, biocompatibility,and mechanical properties of natural bone.[51–53] Other bio-polymers, such as PLA,[54,55] alginate,[56] chitosan,[57] sero-albumin,[58] and silk fibroin[59] have also been combined toHAP with the aim of developing suitable scaffolds for thecreation of new bone. These implants try to mimic the nano-structure, porosity, and surface roughness of natural bone, asthese features seem to facilitate the spreading of osteoblastsand bone regeneration. Different synthetic strategies, suchas fiber bonding, phase separation, solvent casting/particleleaching, gas foaming, and emulsification/freeze-drying, havebeen employed to generate foamlike bionanocompositeswith a suitable porosity and interconnected pores.[49,60] Chito-san-based bionanocomposites prepared recently in our groupby freeze-drying techniques offer such a porous structure,as shown in Figure 5. Unidirectional freezing[53] and super-critical CO2 foaming[55,61] have also come forward as usefulstrategies for the preparation of porous scaffolds. With thislast technique, Ema et al.[61] have prepared superporousPLA–clay nanocomposites with a controlled cellular struc-ture, obtaining pore diameters from nano- to micrometer di-mensions.

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Figure 4. Eco-friendly commercial mobile phone (NEC) and notebookcomputer (Fujitsu) incorporating PLA reinforced bioplastic.

Future improvements within this research line could beaimed towards the replacement of HAP in biopolymer-basedimplants by alternative inorganic, or even organic–inorganic,substrates. Among the few examples that have been studiedso far, sepiolite is a magnesium silicate with a microfibrousmorphology that has been successfully combined with bio-polymers such as collagen, giving rise to hybrid materials witha high degree of organization.[62,63] The high affinity betweencollagen and sepiolite fibers leads to their alignment with thecollagen chains. To reduce the rate of degradation, this bioma-terial can be treated with a crosslinker, such as glutaralde-hyde, that enhances the mechanical properties of the nano-composite, leading to a longer persistence once implanted inthe damaged tissue.[64] Recently, Al2O3–Zr2O nanoparticleshave also been used to reinforce biological matrices such ascollagen, enhancing mechanical and thermal properties andleading to hybrid materials with potential use in biomedicaland bionic applications.[65]

Interestingly, the implant could also act as a drug reservoir,working simultaneously as a scaffold for the growth of newtissue and as a dispenser for the controlled release of bioac-tive compounds. Examples of such innovative applications arethe entrapment of a morphogenetic protein to favor tissue re-generation in an HAP–alginate–collagen system (Fig. 6),[66]

and the incorporation of a vitamin in a Ca-deficient HAP–chi-tosan nanocomposite.[67]

Biocompatibility and reduced dimensions are very usefulproperties for the application of some bionanocomposites asdrug delivery systems. Several examples of this applicationhave been reported in the last years, the use of a DNA-loadedLDH as a nonviral vector for gene therapy being one the firstworks in this topic.[68] Choy’s group confirmed the intercala-tion of DNA in the interlayer space of a magnesium–alumi-num LDH by an ion-exchange mechanism. Analysis by X-raydiffraction revealed an increase of the interlayer distance by2.39 nm, indicative of the arrangement of the DNA chains ina double-helix conformation oriented parallel to the basalplane of the LDH.[69] The mechanism of DNA transfer to thecell nucleus is based on the shielding effect of the DNA’s neg-ative charge by the inorganic matrix. This would facilitate thetransport of the hybrid system through the cell membrane, fol-lowed by dissolution of the LDH at the slightly acidic pH val-ue in the lysosome and the transfer of free DNA to the cellnucleus.[68] Nanometer-scale hybrid particles, suitable for ap-plication as an injectable drug delivery system for intravenousadministration, have been tested in gene therapy for targetedtreatment of diseases such as leukemia and diabetes.[68,70]

Silica-based bionanocomposites processed as nanospheresby means of spray-drying techniques have been also envisagedas a drug delivery system. In this context, the fact that the sili-ca–alginate hybrid nanoparticles are not cytotoxic allows themto enter the intracellular space of fibroblast cells (endocytosis)where they are degraded, being potential carriers for the tar-geted delivery of drugs (Fig. 7).[71] With the same purpose, car-rageenan–silica materials have been synthesized by the CO2 su-percritical drying method to achieve mesoporous aerogels.[72]

It must be remarked that novel multifunctional bionano-composites can simultaneously involve magnetic nanoparti-cles, the selected deliverable drug, and biocompatible and bio-degradable polymers. In this way, materials that include fibersof poly(hydroxyethylmethacrylate) (PHEMA) or PLA havebeen recently prepared by the electrospinning technique.[73]

Their potential significance to various applications in medi-cine, especially for accumulation of the delivered drug in aprecise target area, relies on their superparamagnetic proper-ties and their ability to release the transported drug.

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Figure 5. A) Chitosan porous bionanocomposites based on A) montmo-rillonite and B) chitosan–poly(acryl amide)–sepiolite, prepared by afreeze-drying technique.

Figure 6. A) HAP–alginate–collagen implant, and B) HE section of thewhole implant loaded with a bone morphogenetic protein, showing boneformation throughout almost the entire implant and bonemarrow-like tis-sue (arrows) 5 weeks after implantation. Reproduced with permissionfrom [66]. Copyright 2004 Elsevier.

In the previous paragraphs we have illustrated recent exam-ples of bionanocomposites designed and developed for artifi-cial biological tissue applications, bone implants in particular,frequently involving collagen, PLA, and other related bio-polymers. So far, most efforts were made on HAP and relatedinorganic solids, but it is expected that ongoing research onbiohybrids involving nanoparticulate ceramics of differenttypes, and even metal–ceramic composites, will improve thefracture hardiness and other mechanical properties necessaryin, for example, orthopaedic applications. A future goal wouldinvolve ternary systems, in which the inorganicmoiety is coupled to blends of biopolymers andsynthetic polymers. This appears as an attractiveroute for the preparation of novel bionanocompo-sites showing good strength behaviors and hier-archical porous order introduced by means offreeze-drying techniques. These last characteristicswill receive much attention for the inclusion of liv-ing cells, where the bionanocomposite acts as abiocompatible support facilitating and controllingthe passage of oxygen, CO2, water, and other fluidsthrough the biohybrid materials.

4. Functional Bionanocomposites

Although the bioactive materials used as drugcarriers in regenerative medicine may be also con-sidered functional bionanocomposites, this sectionwill focus on bionanohybrid materials with func-tionalities suited to becoming the active part ofelectrochemical, optical, or photoelectrical devices.This is a very new field in the application of bio-nanocomposites that benefits from the functional-

ity provided by the biopolymer and/or the inorganic host sol-id, with the possibility to develop synergistic interactionsbetween both types of components.

Intercalation compounds, resulting from the combinationof several charged polysaccharides with charged inorganiclayered solids such as clay minerals and LDHs, appear as anew class of hybrid materials that show suitable properties foracting as active phases in electrochemical sensors. This newapplication was first reported in 2003, when a chitosan–mont-morillonite bionanocomposite exhibiting anion-exchangeability was used to build potentiometric sensors.[26] Chitosan isa polysaccharide derived from chitin, one of the main constit-uents of the exoskeleton of crustaceans and some insects.Positively charged chitosan chains can be intercalated in theinterlayer space of montmorillonite by an ion-exchange mech-anism. Depending on the chitosan concentration added to theclay suspension, chitosan chains can be arranged into mono-layer or bilayer configurations between the inorganic layers.In this last arrangement, the excess protonated amino groupsthat do not interact electrostatically with the clay layer remainavailable as anion-exchange sites. Therefore, the cation ex-change behavior of the clay is turned into anion-exchangeability, as shown in Figure 8. This functional bionanocompo-site also possesses excellent mechanical properties that facili-tate its application in the construction of electrochemical sen-sors. The potentiometric evaluation of this device shows amarked selectivity towards monovalent anions, which canoriginate from the special arrangement of the biopolymer inthe clay interlayer space as a nanostructured bidimensionalsystem. The anion-exchange ability of the chitosan–montmo-rillonite nanocomposite has been taken advantage of by re-taining acrylate anions that were subsequently polymerized,

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Figure 7. A) Scanning electron microscopy, and B) transmission electronmicroscopy (TEM) image of spray-dried silica–alginate nanocomposites.C) TEM image showing endocytosis of hybrid nanospheres by fibroblastcells. Reproduced with permission from [71]. Copyright 2006 Royal So-ciety of Chemistry.

Figure 8. Different potentiometric responses in NaCl solutions of chitosan–montmo-rillonite-based sensors as a consequence of the chitosan arrangement in the silicateinterlayer space.

resulting in an improved and photostable water-superabsor-bent material.[74] Using the same biopolymer, chitosan, it hasbeen also possible to reverse the starting cation-exchange be-havior of sepiolite through assembly of chitosan chains by di-rect adsorption.[28]

The opposite effect was observed for bionanocompositesbased on LDHs and negatively charged polysaccharides. Fol-lowing a co-precipitation or co-organized assembly mecha-nism, the biopolymers alginate, pectin, and i-carrageenanwere successfully trapped between the ZnAl LDH layers. Inthis case, the anion-exchange ability of pristine LDH waschanged into a cation-exchange behavior, allowing the appli-cation of these materials as sensing phases in potentiometricsensors. The resulting devices were applied to the determina-tion of calcium ions, given the well-known high affinity ofthese polysaccharides for calcium and other divalent cat-ions.[27]

Multifunctional materials derived from cheap and abundantproducts, such as clay minerals and sucrose, exhibit excellentproperties as electrode materials. A precursor bionanocompo-site prepared by the application of microwave (MW) irradia-tion to a sucrose–sepiolite mixture, giving rise to a caramel–sepiolite material, could be turned into the corresponding car-bonaceous derivative after pyrolysis at 800 °C in a N2 atmo-sphere.[75] The resulting material was functionalized by reac-tion with an appropriate organoalkoxysilane bearing thedesired functional groups, for example protonated aminogroups, to act as anion-exchange sites. Thus, the material cansimultaneously act as electronic collector and sensing phase ina potentiometric sensor, while at the same time showing a re-duced porosity that prevents anions of large volume fromreaching the exchange-sites, making the sensor specific tosmall monovalent anions.[76]

The interactions between gelatin, a fibrous protein resultingfrom the partial denaturation of collagen, and layered silicateswere the object of a deep study carried out in 1950,[77]

which was the basis for the recent synthesis of new gelatin-based nanocomposites derived from zirconium phosphate(a-Zr(HPO4)2 · nH2O, a-ZrP),[78] clay minerals,[79] silica,[80]

and layered perovskite.[81] This last solid gives rise to biohy-brid materials that can be processed as self-supported filmsshowing functionality related to the dielectric behavior of theinorganic moiety. The preparation mechanism requires a priordelamination of the layered calcium niobate with quaternaryammonium salts that results in a colloidal dispersion of theperovskite layers.[81] Further assembly with gelatin leads to re-stacking of the perovskite nanosheets, which are homoge-neously distributed in the biopolymer and highly oriented,with the (a,b) plane parallel to the resulting films (Fig. 9). Ithas been observed that the assembly of this perovskite to gel-atin produces an increase of the dielectric permittivity greaterthan the increase in the dielectric loss values in the biohybridfilms. These materials can easily be handled and conformed asthin films and coatings, suggesting their application in the mi-crowave industry or in high-frequency devices. In a similarway, analogous functional materials could be prepared by

using other perovskites provided with different optical, opto-electronic, superconducting, or ferroelectric properties.

Enzymatic biosensors offer numerous advantages, includinggood sensitivity, high specificity, and long-time stability, thatallow re-use of the device in numerous measurements. Theseparameters are closely related to the stable immobilization ofthe biological agent. It is well-known that the encapsulationof enzymes in a confined space prevents irreversible structuraldeformations, preserving their tertiary structure. Several inor-ganic solids showing 2D structural arrangement have beenemployed as hosts for the entrapment of enzymes: phyllosili-cates, phosphates, triphosphochalcogenides, perovskites, andLDHs. The open framework of these inorganic solids allowstransport of the substrate to the immobilized enzyme as wellas the diffusion of reaction products to the external solution,and at the same time acts as a protective matrix against micro-bial degradation, preserving the enzymatic activity of the bio-logical entity. One of the first approaches was the work byMcLaren and Peterson in 1961, describing the incorporationof lysozyme, lactoglobulin, pepsin, and chymotrypsin into theinterlayer space of the montmorillonite layered silicate, fol-lowing a mechanism of direct intercalation.[82] The aim of thiswork was the use of the silicate as a caliper to determine theenzyme diameter from XRD measurements, but unfortunate-ly these interesting hybrid materials were not tested as biosen-sor devices. More recent works have achieved the immobiliza-tion of different enzymes and globular proteins in otherlayered solids such as zirconium phosphate (a-ZrP),[29]

layered calcium niobate (HCa2Nb3O10, perovskite),[83] man-ganese triphosphochalcogenide (MnPS3),[84] and a syntheticmagnesium phyllosilicate,[85] among other examples. Themechanism followed in the preparation of these bionanocom-posites involves a delamination of the layered solid, usuallyby means of quaternary ammonium salts, followed by the re-

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Figure 9. Schematic representation of the whole process of gelatin-perov-skite bionanocomposite films involving CsCa2Nb3O10 layered perovskite.SEM image shows the lamellar morphology of the bionanocomposite.

stacking of the layers entrapping the biological moiety. In allthese cases the authors confirmed that the immobilized en-zymes retain their activity, which in some cases was evenslightly increased, exemplifying the potential use of these bio-nanocomposites as active phases in biosensor devices. In ouropinion, these works open the way not only to new activephases for biosensors, but also to nanocontainers and nanore-actors using porous solids that entrap this class of functionalbiopolymers. In a similar manner, LDHs also offer an openstructure for the effective immobilization of enzymes betweenthe inorganic layers, allowing the diffusion of substrates andproducts at the same time. Thus, urease has been trappedwithin a ZnAl LDH matrix by following co-precipitation ordelamination-restacking mechanisms (Fig. 10).[30]

The strong association between the enzyme and the LDHlayers achieved with the co-precipitation method makes theuse of glutaraldehyde, a crosslinker commonly employed toincrease the stability in other enzymatic systems, unnecessary.The LDH–urease bionanohybrids were successfully tested asactive phases in capacitance biosensors, where the systemsprepared by delamination-restacking showed the maximumsensitivity.[30]

Silica matrices generated by a mild sol-gel procedure havelong been known as robust networks for the effective immobi-lization of enzymes. One of the most comprehensive reviewson this topic, by Gill and Ballesteros,[86] illustrates the differ-ent organoalkoxy- and alkoxysilanes employed for this pur-pose, as well as the numerous optical and electrochemicalbiosensor devices that incorporate this type of enzymatic sys-tems. In a similar way, a 3D hybrid nanocomposite resultingfrom the assembly of silica and polysaccharides (xanthan, lo-cust bean gum, and cellulose derivatives) appears as an excel-lent network for the immobilization of 1 → 3-b-D-glucanaseand a-D-galactosidase.[87] The porosity of this matrix is enoughto allow the enzymatic substrates to diffuse, but it effectivelyentraps the enzymes, creating a favorable environment tokeep their activity, even increasing their stability by two or-ders of magnitude. It has been also reported that lysozyme isable to precipitate amorphous silica or titania, which entrapthe enzyme, leading to a functional biomaterial with antimi-crobial activity.[88] Nanocrystalline TiO2, prepared by anodic

electrodeposition, is also useful for the entrapment of bacter-ial photosynthetic reaction center proteins, resulting in a func-tional bionanocomposite with potential use as active phase inbiophotoelectric sensors (Fig. 11).[89]

The protective effect of the inorganic matrix and the in-creased long-term stability are the main advantages of en-zyme-based bionanocomposites, which appear as new alterna-tives to the classical methods of immobilization for thedevelopment of improved devices, from biosensors to enzy-matic bioreactors.

In this last section several examples show that certain bio-nanocomposites can act as active phases in different types ofdevices, such as electrochemical sensors and biosensors. Mac-roporous biohybrids synthesized under cryogenic conditionscould be used for immobilizing enzymes in their porous struc-ture for applications other than sensors, for example as robustnanoreactors. Future trends towards the development of mul-tifunctional bionanocomposites may include the combinationof active inorganic counterparts present as nanoparticles, pro-viding new properties to the hybrid systems, with the biopoly-mers providing biocompatibility. An example of this could bethe coupling of biopolymers with magnetic or photoactivenanoparticles to give biocompatible systems amenable tofurther assembling to bioactive species (enzymes or cells),aimed at a new generation of advanced devices.

5. Conclusions and Outlook

Bionanocomposites are hybrid nanostructrured materialsbased on naturally occurring polymers. In the last decade,

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Figure 10. Nanohybrid LDH-urease material showing the arrangement ofthe enzyme between LDH layers with partial preservation of crystal latticeof the host solid. Inspired by data from [30].

Figure 11. Bionanocomposite photoelectrode, composed by bacterialphotosynthetic reaction centers (RCs) entrapped on nanocrystallineTiO2. The photoanode is RC/TiO2 film and the counter-electrode is Pt.The electrolyte is Tris-HCl buffer containing 8 mM sodium dithionite(pH 8.0). P870: bacteriochlorophyll dimer, the primary donor. Cb: con-duction band. Vb: valence band. Reproduced with permission from [89].Copyright 2005 Molecular Diversity Preservation International.

they have been the subject of research in many different areaswith a wide number of applications, from regenerative medi-cine to food packaging. This has lead to an increasing numberof scientific publications that, until now, have focused thestudy of these biohybrid materials from an independent ap-proach. Taking into account their common properties, the aimof the present work was to consider them from an interdisci-plinary point of view. In fact, bionanocomposites can be inte-grated in a new field at the frontier of materials science, lifesciences, and nanotechnology. Two main reasons have pro-pelled the use of biopolymers in the synthesis of nanocompos-ites, replacing the commonly employed petroleum-derivedpolymers. The first one is related to the biodegradability ofthe obtained materials resulting from the incorporation ofthese natural polymers, this property being decisive for thedevelopment of environmentally friendly materials that helpto reduce the pollution caused by plastic waste. On the otherhand, biocompatibility is a crucial property for the applicationof these biohybrids in food packaging or tissue engineering inregenerative medicine. Within this last field, the great effortcurrently devoted to the development of HAP-based bio-nanohybrid implants for bone repair purpose is worth noting.Another interesting biomedical application is the use of bio-nanocomposites as drug delivery systems and, more recentlyas DNA nonviral vectors for the controlled release of DNA ingene therapy. Functional bionanocomposites working as ac-tive phases in electrochemical and optical devices are alsobeing explored. An emerging application is the developmentof bionanohybrid materials incorporating charged biopoly-mers such as chitosan, which exhibit ion-exchange ability andare efficient as active phases of electrochemical sensors. Dif-ferent inorganic solids have been employed as protective ma-trices for the entrapment of enzymes, leading to bioactivenanocomposites that can be integrated in biosensor devicesand bioreactors.

The future development of novel bionanocomposites withimproved properties and multifunctionality can be envisagedas an emerging, open field of research, with plenty of possibil-ities because of the great abundance and diversity of biopoly-mers in Nature, as well as the advantage of their synergisticcombination with inorganic nanosized solids.

Received: October 13, 2006Published online: April 20, 2007

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Bionanocomposites: A New Concept of Ecological, Bioinspired, and Functional Hybrid Materials