polymers ha nano composites for bio medical applications

354 MRS BULLETIN • VOLUME 32 • APRIL 2007 • www.mrs.org/bulletin

Introduction and ChallengesBionanocomposites form a fascinating

interdisciplinary area that brings togetherbiology, materials science, and nanotech-nology. New bionanocomposites are impact-ing diverse areas, in particular, biomedicalscience. Generally, polymer nanocompos-ites are the result of the combination ofpolymers and inorganic/organic fillers atthe nanometer scale. The extraordinaryversatility of these new materials springsfrom the large selection of biopolymers andfillers available to researchers. Existingbiopolymers include, but are not limitedto, polysaccharides, aliphatic polyesters,polypeptides and proteins, and polynu-cleic acids, whereas fillers include clays,hydroxyapatite, and metal nanoparticles.1

The interaction between filler compo-nents of nanocomposites at the nanometerscale enables them to act as molecularbridges in the polymer matrix. This is thebasis for enhanced mechanical propertiesof the nanocomposite as compared to con-ventional microcomposites.2 Bionanocom-posites add a new dimension to theseenhanced properties in that they are biocom-patible and/or biodegradable materials.

For the sake of this review, biodegrad-able materials can be described as ma-terials degraded and gradually absorbedand/or eliminated by the body, whether

degradation is caused mainly by hydroly-sis or mediated by metabolic processes.3

Therefore, these nanocomposites are ofimmense interest to biomedical technolo-gies such as tissue engineering, bone re-placement/repair, dental applications,and controlled drug delivery. Table I listssome biopolymers commonly used in bio-medical applications.

Current opportunities for polymernanocomposites in the biomedical arenaarise from the multitude of applicationsand the vastly different functional require-ments for each of these applications. Forexample, the screws and rods that are usedfor internal bone fixation bring the bonesurfaces in close proximity to promote heal-ing. This stabilization must persist for weeksto months without loosening or breaking.3

The modulus of the implant must be closeto that of the bone for efficient load trans-fer.4,5 The screws and rods must be non-corrosive, nontoxic, and easy to remove ifnecessary.6 Thus, a polymer nanocompos-ite implant must meet certain design andfunctional criteria, including biocompati-bility, biodegradability, mechanical proper-ties, and, in some cases, aesthetic demands.The underlying solution to the use ofpolymer nanocomposites in vastly differ-ing applications is the correct choice of

matrix polymer chemistry, filler type, andmatrix–filler interaction. This article dis-cusses current efforts and focuses on keyresearch challenges in the emerging usageof polymer nanocomposites for potentialbiomedical applications.

Hydroxyapatite–PolymerNanocomposites

Producing bionanocomposites basedon biomimetic approaches has been a re-cent focus of researchers. Among thesematerials, hydroxyapatite (HAP)–polymernanocomposites have been used as a bio-compatible and osteoconductive substi-tute for bone repair and implantation.7,8

As the main inorganic component of hardtissue, HAP [Ca10(PO4)6(OH)2] has longbeen used in orthopedic surgery. How-ever, HAP is difficult to shape because ofits brittleness and lack of flexibility. HAPpowders can migrate from implanted sites,thus making them inappropriate for use.Moreover, these powders do not dispersewell and agglomerate easily.9 Therefore,the incorporation of HAP in polymericnanocomposites to overcome processingand dispersion challenges is of great inter-est to the biomedical community. Conse-quently, a desirable material for use inclinical orthopedics would be a biodegrad-able structure that induces and promotesnew bone formation at the required site.

To date, primarily polysaccharide andpolypeptidic matrices have been usedwith HAP nanoparticles for composite for-mation. Yamaguchi and co-workers havesynthesized and studied flexible chitosan–HAP nanocomposites.9 The matrix used forthis study, chitosan (a cationic, biodegrad-able polysaccharide), is flexible and has ahigh resistance upon heating because ofintramolecular hydrogen bonds formedbetween the hydroxyl and amino groups.10,11

The resulting nanocomposite, prepared bythe coprecipitation method, is mechani-cally flexible and can be formed into anydesired shape.9

Nanocomposites formed from gelatinand HAP nanocrystals are conducive tothe attachment, growth, and proliferationof human osteoblast cells.12 Collagen-based,polypeptidic gelatin has a high number offunctional groups and is currently beingused in wound dressings and pharmaceu-tical adhesives in clinics.13 The flexibilityand cost-effectiveness of gelatin can becombined with the bioactivity and osteo-conductivity of HAP to generate potentialengineering biomaterials. The traditionalproblem of HAP aggregation was overcomeby precipitation of the apatite crystalswithin a polymer solution.14,15 The porousscaffold generated by this method exhib-ited well-developed structural features

PolymerNanocomposites for BiomedicalApplications

Rohan A. Hule and Darrin J. Pochan

AbstractBionanocomposites have established themselves as a promising class of hybrid ma-

terials derived from natural and synthetic biodegradable polymers and organic/inorganicfillers. Different chemistries and compositions can lead to applications from tissue engi-neering to load-bearing composites for bone reconstruction. A critical factor underlyingbiomedical nanocomposite properties is interaction between the chosen matrix and thefiller.This article discusses current efforts and key research challenges in the develop-ment of these materials for use in potential biomedical applications.

Polymer Nanocomposites for Biomedical Applications

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and pore configuration to induce bloodcirculation and cell ingrowth. Suchnanocomposites have high potential foruse as hard-tissue scaffolds.12

Three-dimensional porous scaffoldsfrom biomimetic HAP/chitosan–gelatinnetwork composites with microscale por-osity have shown adhesion, proliferation,and expression of osteoblasts.16 A low-magnification scanning electron micro-graph of such a scaffold showing uniformpore sizes and walls is shown in Figure 1.Porosity is critical for tissue-engineeringapplications because it enables the diffu-sion of cellular nutrients and waste, andprovides for cell movement.17

Polysaccharides, such as alginate, pro-vide a natural polymeric sponge structurethat has been used in tissue-engineeringscaffold design. The weak, soft alginate scaf-folds can be strengthened with HAP andhave widespread applications.18 Compos-ite membranes from HAP nanoparticlesand chitosan/collagen sols have also beensynthesized to study connective-tissuereactions.19,20

Studies that target the nucleation of cal-cium phosphates and bone cell signalingwithin the matrix have used acidic macro-molecules as the nanocomposite matrix.21

Specifically, amino acids like aspartic acidand glutamic acid have been used as the

matrix protein. Both of these amino acidsare known to play an important role in in-tercellular communication and osteoblastdifferentiation that increases extracellularmineralization. Related studies have alsohighlighted the significance of aspartic acidin the treatment of osteoporosis and otherbone dysfunctions.22

Aliphatic PolyesterNanocomposites

Aliphatic polyesters have been the pre-dominant choice for materials in degrad-able drug delivery systems. Homopolymersand copolymers derived from glycolicacid or glycolide, lactic acid or lactide, and

Table I: Biopolymers Commonly Used in Biomedical Applications.

Biopolymer Structure



ε-caprolactone form the bulk of this re-search. Most of these polymers degradeby acid- or base-catalyzed hydrolyticcleavage of the backbone or by enzymaticactivity.23

Of the polyesters that show promise inbiomedical fields, poly(L-lactic acid) (PLLA)is the most prevalent. Although reports ofthe use of PLLA can be found in the 1960s,a phenomenal amount of work has beenperformed recently. PLLA has widespreadapplications in sutures, drug delivery de-vices, prosthetics, scaffolds, vascular grafts,bone screws, pins, and plates for tempo-rary internal fixation.24 Good mechanicalproperties and degradation into nontoxicproducts25 are the main reasons for such anarray of applications. Additionally, PLLAis U.S. Food and Drug Administation–approved and available commercially in avariety of grades. As a material, PLLA isrelatively hard and crystalline with a melt-ing point between 170°C–180°C and a glass-transition temperature Tg of �60°C–67°C.Another factor contributing to the use ofPLLA in biomedical applications is itsability to be copolymerized and blendedto obtain a nanocomposite-like productwith desirable properties. The racemicversion of the polymer, poly(D,L-lactide)(PDLLA), sometimes simply called PLA,is amorphous with a Tg of around50°C–60°C.

Studies also have been done to evaluatethe potential of PLLA as a bone reinforce-ment material. The mechanical properties ofneat PLLA might be inadequate for highload-bearing applications.26 This necessi-tates the incorporation of reinforcements

like oriented fibers, HAP, or clays to formnanocomposites. Such studies report anincrease in the flexural modulus, strength,and moduli values commensurate withbone replacement implants.27

“Self-reinforced” composites have alsobeen synthesized by incorporation of ori-ented PLA fibers in a matrix of the samematerial.28 Past work in our group29 in-volved the synthesis of PLLA–organoclaynanocomposites via the exfoliation adsorp-tion film-casting technique, in which boththe matrix and the filler are sonicated sep-arately in a common solvent. The two solu-tions are then mixed and cast on a substrateunder controlled evaporation conditions,resulting in a film.

Exfoliation in the case of Cloisite 30B claywas ascribed to favorable enthalpic inter-actions between the diols of the organicmodifier and carbonyl bonds of the PLLAbackbone with polymer crystallinity beingsuppressed at complete exfoliation.29 Thisunusual phenomenon necessitated in-depthstudies that revealed lower crystallinityand crystallization rates and higher radialspherulitic growth rates resulting from theaddition of highly miscible organoclay inPLLA.30 Subsequent time-lapsed Fouriertransform infrared (FTIR) studies attributedthis behavior to the precedence of intra-chain interactions, specifically, PLA 103 helixformation and backbone reorientation,over interchain interactions, as opposed toneat PLLA.31–33

Poly(glycolic acid) (PGA) is anotheraliphatic polyester with applicability forbiomedical use. However, unlike PLLA,PGA is readily soluble in water. Mechani-cal properties of self-reinforced PGA havebeen investigated and are found to worsenon exposure to distilled water.23 Thus, watersolubility and its high melting point limitthe use of PGA in bionanocomposites.

Another biodegradable and nontoxicaliphatic polyester discussed in the bio-medical nanocomposite literature is poly(ε-caprolactone) (PCL). Synthesized bythe ring-opening polymerization of ε-caprolactone, it has a melting temperatureof 61°C and a Tg of �60°C. The rubberystate permits the diffusion of low-molecular-weight species at body temperature, thusmaking PCL a promising candidate forcontrolled release and soft-tissue engineer-ing. The range of properties can be furtheredby copolymerization with other lactonessuch as glycolide, lactide, and poly(ethyl-ene oxide) (PEO) or by nanofiller incorpo-ration. Both techniques have been adoptedand have shown great potential for bio-medical applications.23 Nanocompositepolymer–clay hydrogels have also beenstudied extensively by microscopy and scat-tering techniques.34

Recently, electrospinning has been usedas an alternative scaffold fabrication tech-nique in soft-tissue transplantation andhard-tissue regeneration. This method pro-vides woven mats with individual fiberdiameters ranging from 50 nm to a few mi-crons. The interconnected, porous networkso formed is desirable for drug delivery aswell as biomedical substrates for tissue re-generation, wound dressing, artificial bloodvessels, and other uses. Electrospinninghelps tailor the mechanical, biological, andkinetic properties of the scaffolds by vary-ing parameters such as polymer solutionproperties and processing conditions (e.g.,electrical force, the distance between theelectrospinning needle and the oppositelycharged surface acting as ground, spinneretgeometry, and solution flow rate).35 How-ever, some of the restrictions of this method,like controlling the pore size and softnessof the electrospun mat, currently preventsit from being used for hard-tissue applica-tions. Studies incorporating montmorilloniteclay36 (MMT) in a PLLA solution that wassubsequently electrospun into a mat foundimproved mechanical and biodegradationcharacteristics and ideal pore sizes (mi-crons) for cell growth, blood vessel inva-sion, and nano-sized pores for nutrient/waste transfer.37

Polypeptide-BasedNanocomposites

Polypeptides as matrices provide an ad-ditional array of opportunities in materialsdesign and application in terms of a uniqueability to adopt specific secondary, tertiary,and quaternary structures, a feature notavailable with synthetic polymers. Func-tionality can also be incorporated by theuse of natural and non-natural amino acidswith desired activity at specific sites alongthe polypeptide backbone. Our group hasbeen investigating the incorporation ofpolypeptides, particularly, poly(L-lysine)(PLL), as the matrix polypeptide and MMTas the filler.38 Initial work39 producednanocomposites from PLL and MMT thatexhibited enhanced mechanical propertiesand thermal properties comparable to otherwidely explored biomaterials and engineer-ing thermoplastics. A transmission electronmicrograph showing the intercalated MMTlayers in a PLL–MMT nanocomposite isshown in Figure 2.

The potential applicability of these ma-terials was further investigated by study-ing the effect of the molecular weight of thepolypeptide on the secondary conformationof the final nanocomposite matrix. PLL isa good choice for such a study because itcan display a variety of secondary struc-tures: the random coil, α-helix, or β-sheetin aqueous solution. Moreover, transitions

Figure 1. Low-magnification scanningelectron micrograph of a hydroxyapatite(HAP)–polymer/chitosan–gelatin scaffoldprepared from HAP/chitosan–gelatin/acetic acid mixture. The uniform porosityobserved in the micrograph is advanta-geous for tissue-engineering applications.The chitosan–gelatin concentration usedwas 2.5 wt%; HAP/chitosan–gelatin,30/70 parts by weight. (Reproducedfrom Reference 16.)


MRS BULLETIN • VOLUME 32 • APRIL 2007 • www.mrs.org/bulletin 357

between conformations can be easilyachieved using pH, temperature, saltconcentration, or alcohol content as an en-vironmental stimulus. The secondarystructure transitions in the liquid as wellas the solid state and related thermody-namics have been accurately mappedusing circular dichroism (CD), FTIR, andRaman spectroscopy. PLL folds preferen-tially in the β-sheet structure at the highconcentrations relevant to nanocompositefilm formation regardless of solution con-formation from which films were cast. Thetransition from α-helix to β-sheet is di-rectly dependent on molecular weight, withhigh-molecular-weight films showing aconsistent β-sheet conformation and exhib-iting a kinetic dependence on temperature.We hope this insight into the mechanismof secondary structural control inpolypeptides will foster the design of newpeptidic nanomaterials for specific desiredapplications in the biomedical arena.38

Efforts in our group40 have also been di-rected at responsive hydrogels con-structed via self-assembly of short20-residue peptides. These synthetic pep-tides are designed to intramolecularly foldunder desired aqueous conditions andsubsequently intermolecularly self-assemble into supramolecular networks.40

The network scaffold is comprised of stiff,fibrillar structures that exhibit varied mor-phology, including twisted or untwistedsingle fibrils and fibril laminates.

Materials like these, in addition to pro-teins, introduce the possibility of fibrilincorporation into nanocomposites as re-inforcement with biodegradable matrices.

Such unique nanocomposites combine thedegradability and strength of the gel matrixwith control over functionality and mor-phology of the fibrillar fillers. Potential ap-plications of such nanomaterials includedrug delivery matrices, tissue-engineeringscaffolds, and bioengineering materials, toname a few.

Nanocomposites from OtherPolymers and Fillers

Nanocomposites from bioactive mole-cules and clays have also been reported.One such example is smectite nanocom-posites that use the ability of smectites toinduce specific cointercalation of purinesand pyrimidines. Thus, thymine and uracilare absorbed on MMT appreciably if solu-tions also contain coabsorbed adenine.41

Layered double hydroxides (LDHs) pres-ent a layered structure comprised of di- andtrivalent metal cations [M(II) and M(III)]coordinated by six oxygen anions. The sub-stitution of M(III) cations induces an over-all positive charge that is counterbalancedby exchangeable interlayer anions. Thus,LDHs can serve as hosts for polymeric in-tercalation. An attractive, potential appli-cation of LDHs is controlled drug releasecarriers. Several bioactive compounds likeDNA and pharmaceuticals have been in-corporated within LDH hosts.42

Poly(urethane urea) (PUU) segmentedblock copolymers are common in ventric-ular assist devices and total artificial heartsas blood sacs. One of the main disadvan-tages of PUUs in these devices is their rel-atively high permeability to air and watervapor, a result of the diffusion through thepoly(tetramethylene oxide) soft segmentsthat are present as the majority componentof the copolymer. The use of organicallymodified layered silicates seems particu-larly attractive among the variety of ap-proaches taken to reduce permeability whilemaintaining desired biocompatibility andmechanical properties. This can be ascribedto the dramatic increase of barrier proper-ties because of intercalated or exfoliatedhigh-aspect-ratio (�1000) clay layers in thepolymer matrix. Studies on the PUU–claysystem have shown increases in the mod-ulus and strength of the nanocomposite.However, in contrast to conventional com-posite systems, this enhancement does notcome at the expense of ductility. In fact, itis reported that the ductility increases withclay loading.43 A convincing explanationfor this remarkable behavior has not yetemerged. Nonetheless, a significant reduc-tion in gas permeability with an increasein mechanical properties has been shown.

Just as nanocomposites used for variousbiomedical applications have different re-quirements, nanocomposites used for dental

applications have unique necessities. Ther-moset methacrylate-based composites areused commonly as dental restorative ma-terials, because of a relatively high cureefficiency by free-radical polymerizationand excellent aesthetic qualities. How-ever, the demands of the oral environmentand the masticatory loads encountered bydental restoratives require further propertyimprovements in these materials. Specifi-cally, nanocomposites with improved mod-ulus, better efficiency of the free-radicalpolymerization, low water sorption, im-proved processability, and low shrinkageare needed. Selective functionalization ofthe filler can lead to better interactions at thefiller–matrix interphase and has been usedin studies in which silica nanoparticles weresilanized to varying extents using two dif-ferent modifiers and then mixed with adimethacrylate resin. A few practical ad-vantages of the dual silanization are im-proved workability of the composite paste,higher filler loadings leading to better mod-ulus values, and nanocomposites with lowerpolymer shrinkage.44

The design of cardiovascular interfacesnecessitates a combination of amphiphilic-ity and antithrombogenicity. Amphiphilicityensures optimal endothelial cell responseat the vascular interface. Thrombogenicityrefers to blood clot formation and can lead toearly graft occlusion. Using reports of poly-hedral oligomeric silsequioxanes (POSS)acting as an amphiphile at the water–air in-terface, researchers have studied the possi-bility of using POSS at the vascular interface.The strong intermolecular forces betweenconstituent molecules and neighbors andthe robust framework of shorter bondlengths make POSS nanocomposites moreresistant to degradation. Initial work hasshown that POSS nanocomposites are cyto-compatible, making them potentially suit-able for tissue engineering.45 Future effortsin this field are directed at assessing thethrombogenic potential of these nanocom-posites, which would be critical in their ap-plication as cardiovascular interfaces.

Concluding RemarksWe have discussed an emerging group

of hybrid materials based on various poly-mers and nanofillers that are either usedextensively or show promise in the area ofbiomedical materials. These novel materialsvary from inorganic/ceramic-reinforcednanocomposites for mechanical enhance-ment to peptide-based nanomaterials inwhich peptides are both the filler and thematrix, with the chemistry designed to ren-der the entire material biocompatible. In-terest in these nanocomposites varies fromapplication-oriented design to understand-ing a multitude of structure–property

Figure 2. Bright-field transmissionelectron micrograph of a 5 wt%poly(L-lysine)-montmorillonite clay nano-composite film, showing intercalatedregions. The image was obtained on amicrotomed film (�80 nm) at 200 kV.(Reproduced from Reference 38.)



relations. Requisite functional criteria in-clude mechanical strength, biocompatibil-ity, biodegradability, morphology, and ahost of other parameters, depending onend use. However, at the basis of the per-formance of these nanocomposites are in-teractions between the biopolymer orsynthetic polymer and the filler, which canbe tuned and perfected to suit specificneeds. We hope that further research intothese interactions will prove valuable incontemplating the design of novel bionano-composites for biomedical applications.

AcknowledgmentsThis work was partially funded by the

National Science Foundation Career AwardDMR-0348147 and the DuPont Young Fac-ulty Award.

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polymers ha nano composites for bio medical applications

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