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Bioinspired nanoscale materials for biomedical and energy applications Priyanka Bhattacharya1, Dan Du2,3 and Yuehe Lin1,3


Pacific Northwest National Laboratory, 902 Battelle Boulevard, PO Box 999, Richland, WA 99352, USA Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, People’s Republic of China 3 School of Mechanical and Materials Engineering, Washington State University, PO Box 642920, Pullman, WA 99164-2920, USA 2

Review Cite this article: Bhattacharya P, Du D, Lin Y. 2014 Bioinspired nanoscale materials for biomedical and energy applications. J. R. Soc. Interface 11: 20131067.

Received: 17 November 2013 Accepted: 25 March 2014

Subject Areas: biomaterials, nanotechnology, bioengineering Keywords: bioinspired, dendrimers, protein cages, biobatteries, tissue engineering, biomineralization

Authors for correspondence: Priyanka Bhattacharya e-mail: [email protected] Dan Du e-mail: [email protected] Yuehe Lin e-mail: [email protected]

The demand for green, affordable and environmentally sustainable materials has encouraged scientists in different fields to draw inspiration from nature in developing materials with unique properties such as miniaturization, hierarchical organization and adaptability. Together with the exceptional properties of nanomaterials, over the past century, the field of bioinspired nanomaterials has taken huge leaps. While on the one hand, the sophistication of hierarchical structures endows biological systems with multi-functionality, the synthetic control on the creation of nanomaterials enables the design of materials with specific functionalities. The aim of this review is to provide a comprehensive, up-to-date overview of the field of bioinspired nanomaterials, which we have broadly categorized into biotemplates and biomimics. We discuss the application of bioinspired nanomaterials as biotemplates in catalysis, nanomedicine, immunoassays and in energy, drawing attention to novel materials such as protein cages. Furthermore, the applications of bioinspired materials in tissue engineering and biomineralization are also discussed.

1. Introduction Advances in nanoscience and nanotechnology have profoundly led to the development of functional materials in recent years, which have found applications ranging from biomedical to environmental engineering and high-energy storage as well as garnered interests in fundamental science [1– 6]. Among these functional nanomaterials are carbon nanotubes (CNTs), graphene, fullerenes, soft, polymeric nanoparticles, metal organic nanomaterials, self-assembled and supramolecular nanostructures, and their derivatives to name a few. Their unique physico-chemical properties such as catalytic, dielectric, optical and mechanical give rise to their distinctive applications in sensors, drug delivery, proteomics and biomolecular electronics. In particular, their biological applications have furthered fundamental understanding of biomolecular systems such as vesicles, viruses and cells as well as stimulated the design of nanomaterials with biological functions. The last ones have been commonly called bioinspired nanomaterials [7]. Research on the interactions of nanomaterials with biological systems in recent years has largely focused on their therapeutic applications and in elucidating their potential adverse effects [8,9]. The former takes advantage of the similarity in size between nanoparticles and typical cellular components such as proteins, which permit their entry into cellular compartments, both by energydriven endocytosis as well as through mechanical damage. The physico-chemical properties of the nanoparticles such as size, shape, surface charge and surface chemical composition largely dictate their entry into cells. Here, we review the development in the field of bioinspired nanomaterials, wherein we divide this broad class of materials into two subclasses: biotemplates and biomimics. Inspired by nature’s extraordinary finesse, researchers have been designing nanomaterials with a variety of applications in biomedicine. The primary reason for the extraordinary functions of these bioinspired nanomaterials stems from the fact that the human biological system is made up of nanoscale

& 2014 The Author(s) Published by the Royal Society. All rights reserved.

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protein cage




interface exterior exterior

self-assembly of biological molecules. There has been tremendous progress in the past decades in the area of biomimics and bioinspired materials such as organs-on-chips, smart robotic devices, a new class of materials that mimic the homeostatic abilities of living organisms to adapt and selfregulate, and nanomaterials for tissue engineering and orthopaedic implants ( In this review, we thus discuss the latest developments in the field of bioinspired nanomaterials and their applications in biomedicine and energy harvesting and storage.

uniform chemical modification of the cage interior under physiological conditions, and demonstrate the primary role of conserved hydrogen-bonding interactions in providing geometrical specificity for cage assembly. Mann and co-workers [16–18] artificially synthesized Fe3O4 nanoparticles within empty ferritin cages, called apoferritins. The homogeneous diameters of the nanoparticles formed were determined by the interior diameter of ferritin, which is 8 nm.

2.1. Protein cage

2. Bioinspired nanomaterials as biotemplates Biological templates are architectures that behave as containers such as viral capsids. Specifically, these biological containers can function as carriers for DNA assays and immunoassays, drugs, catalysts, and be used in novel material synthesis [10]. In recent times, researchers have also used biological macromolecular assemblies as templates for the construction of novel functional nanomaterials [11]. Recently, our group and others have conducted extensive research on protein cages—synthetic, highly symmetrical, multi-functional protein architectures with three distinct interfaces—interior, exterior and the interface between subunits [12,13] (figure 1). These subunits can be modified both chemically and genetically, thus imparting a single cage with multi-functionality and with a wide range of applications from electronics to biomedical. Ferritins, a family of proteins whose function is to primarily store and sequester iron (Fe) [14], were the first protein cages to be used in the synthesis of inorganic nanoparticles. Several studies focused on the self-assembly of these protein architectures. One of the recent studies by Huard et al. [15] introduces a new engineering strategy—reverse metal-templated interface redesign (rMeTIR)—that transforms a natural protein –protein interface into one that only engages in selective response to a metal ion. They applied this technique to the self-assembly of ferritin protein cage controlled by divalent copper binding. Here, copper behaves as a structural template for ferritin assembly in a similar way as RNA sequences that template virus capsid formation. This method of engineering protein cages allows one to fundamentally understand the structure and stability of the isolated ferritin monomer as well as the

The major applications of protein cages range from nucleic acid storage, biomineralization, sequestration, the transport and delivery of nucleic acids between diverse chemical environments to development of anode materials for lithium ion batteries [12,19]. Following Mann and co-workers, several researchers used the biomineralization approach of preparing inorganic as well as metallic nanoparticles within the apoferritin structure [20 –27]. Some of these approaches proceed via a sequential sequestration of ions, such as in the synthesis of ZnSe nanoparticles [27]. Here, the formation of the nanoparticles occurs only if Zn2þ is added prior to Se22, owing to a directing electrostatic influence of the protein concentrating cations in the interior of the cage.

2.1.1. Protein cage template nanoparticles for catalysis Metallic nanoparticles are synthesized within the cage by preincubating metal salts within the cage followed by chemical reduction with NaBH4. Kramer et al. [28] synthesized ferritin-encapsulated silver nanoparticles by genetically introducing silver-binding peptides within the ferritin cage and then chemically reducing the silver ions bound to the peptides to silver nanoparticles in situ. We have shown the synthesis of homogeneous Au–Ag alloy nanoparticles ranging in size from 5.6 to 6.3 nm in the cavity of horse spleen apoferritin (HSAF) by a diffusion technique (figure 2) [29]. These nanoparticles were further applied for the reduction of 4-nitrophenol in the presence of NaBH4. It was observed that as the Au content was increased in the caged nanoparticles, the rate constant of the reaction was exponentially increased. Such bimetallic nanoparticles will be further applicable in catalysis, sensing and biomedical areas.

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Figure 1. (a) Cryo-electron microscopy imaging reconstruction of sulfolobus turreted icosahedral virus (diameter: 75 nm) isolated from a boiling, acidic environment in Yellowstone National Park. (b) Schematic of the three interfaces in a protein cage architecture available for chemical or genetic modification. Adapted from Uchida et al. [12]. (Online version in colour.)





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Figure 3. Schematic of the synthesis of DENs. Adapted from Myers et al. [32]. Metal ions (M2þ, red, small ellipsoids in centre panel) complex with interior tertiary amines of the dendrimer (blue, porous branched macromolecule) and are reduced by BH4  to form a DEN. (Online version in colour.) Recent developments in the field of macromolecular science have opened gates to the synthesis of three-dimensional molecules with exceptional physico-chemical and mechanical properties. A class of these macromolecules—dendrimers—is highly branched, symmetrical and monodispersed with a well-defined number of end groups which can be functionalized to exhibit unique applications [30]. The vast flexibility in dendritic synthesis, rich physico-chemistry and selfassembly have inspired engineering of novel applications for gene and drug delivery. Among this class of dendrimers are poly(amidoamine) (PAMAM) dendrimers whose topology match those of biomacromolecules and hence mimic globular proteins. However, the subtle but important differences between proteins and dendrimers make the latter more robust for biomedical applications. For example, globular proteins are essentially folded structures formed from linear polypeptides and hence are susceptible to denaturation by temperature, pH and light. Additionally, the protein interiors are densely packed and their surfaces more heterogeneous, with a mixture of hydrophobic and hydrophilic domains. By contrast, the globular nature of dendrimers is covalently fixed and their homogeneous surfaces with well-defined interiors afford a structural integrity for precise and robust biological functions. Like apoferritins, PAMAM dendrimers are particularly attractive in forming monodispersed metallic nanoparticles. Crook et al. [31] were the first to synthesize copper nanoparticles in a PAMAM dendrimer scaffold. Since then, several groups of authors have synthesized a plethora of metallic and bimetallic nanoparticles encapsulated within a dendrimer [32]. Dendrimer-encapsulated metallic nanoparticles (DENs) are stable and hence do not agglomerate. Much of

the surface of DENs is available for catalysis because they are enclosed within the dendrimer while their surfaces are still unpassivized. By contrast, pristine metallic nanoparticles have to be surface-coated with stabilizing agents such as polymers to render them soluble in solvents, thus reducing their effective surface area available for catalysis. The branched structure of dendrimers also allows for small molecules to enter their core to gain access to the metallic nanoparticles. Such DENs were used in the catalysis of hydrogenation of allylic alcohol and N-isopropylacrylamide in water [33]. The tertiary nitrogen atoms of the PAMAM dendrimer interior serve as perfect heteroatom ligands for metal ions. These dendrimer–metal complexes can be reduced chemically, for example, by NaBH4 to form metal nanoparticles (figure 3). The monodispersity of the formed nanoparticles arises from the limited growth of the metallic clusters within the dendrimer, resulting from steric hindrance by the dendrimer branches. Only the amines present in the dendrimer’s interior are capable of complexing with transition metal cations such as Cu(II), Agþ, Pt2þ, Pd2þ, Ru3þ and Ni2þ. Indeed, such complexation processes can be easily observed spectroscopically. We showed that Cu(II) complexed with the interior amines of a trifunctionalized dendrimer at high pH to yield a broadened absorbance peak at 300 nm (290–340 nm) [34]. Such peak broadening was induced by the ligand-to-metal charge-transfer (LMCT) between Cu(II) and the ligand groups of the dendrimer. Crooks & Zhao [35] showed the encapsulation of Pt nanoparticles by hydroxyl-terminated PAMAM dendrimers; instead of LMCT coordination between the dendrimer amines and Pt2þ, a slow ligand-exchange occurred between one chloride ion from PtCl4 2 and one tertiary amine of the

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Figure 2. Schematic of the apoferritin-templated synthesis of Au – Ag – HSAF nanoparticles. Agþ and AuCl4  ions competitively diffuse into the HSAF cavity, which is negatively charged, through the threefold channels at pH 8.3. After dialysis against aqueous NH4OH solution to remove outer surface-bound metal ions, the metal ion mixture in the cavity is reduced upon adding NaBH4. Once a metal atom or metal ion mixture that acts as a nucleation centre is formed, it also acts as a catalyst for the reduction of the remaining metal ions present in the solution. The micro Au2Ag alloy particles produced at the initial stage of colloid formation subsequently agglomerate until they fully grow up to the HSAF cavity size [29]. (Online version in colour.)


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cellular uptake Cyt C


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Figure 4. Schematic of intracellular glutathione (GSH)-triggered release of anti-cancer drugs (blue circles) loaded within dendrimer-encapsulated gold nanoparticles (DEGNPs; yellow ellipsoid within branched dendrimer). Adapted from Wang et al. [36]. (Online version in colour.) dendrimer. These synthetic DENs serve as drug carriers into human cells as well as display enhanced detection towards proteins. Recently, Wang et al. [36] used dendrimer-encapsulated gold nanoparticles as carriers of thiolated anti-cancer drugs. These dendrimer-encapsulated drugs showed much less cytotoxicity compared with free anti-cancer drugs (figure 4). Jeong et al. [37] also used dendrimer-encapsulated gold nanoparticles for covalently immobilizing a monoclonal electrochemical carcinoembryonic antigen for highly sensitive immunosensing. Dendrimer-encapsulated Pt nanoparticles have also been successfully used as protein mimics and have shown similar catalytic activity to catalase, an enzyme that eliminates excessive reactive oxygen species (ROS) in normal cells [38]. The similarity in size, globular shape and dendritic effect of the generation 9 PAMAM dendrimer used here offer unique advantages to construct artificial enzymes. Both protein cages and dendrimers have also been used as magnetic resonance imaging (MRI) contrast agents with high relaxivity of water protons [39,40].

2.1.2. Protein cage for nanomedicine The most recent development in designing drug delivery systems has been focused on protein-based nanomedicine platforms, which are formed from naturally self-assembled protein subunits of the same protein or a combination of proteins making up a complete system, owing to their biocompatibility and biodegradability coupled with low toxicity [41]. The space within a protein cage can be used for storing drugs, which can then be selectively delivered to affected cells. Because protein cages are the structural shells of viruses when the nucleic acids of viruses have been removed, potential synthetic cargos can be stored in these shells. Furthermore, their uniform cage sizes allow for the loading of relatively uniform amounts of drugs, and also avoid aggregation of the nanoparticles [42,43]. The ferritin/apoferritin protein cage is a naturally derived cage that is stable in physiological conditions and is biocompatible as a drug carrier/delivery system. When the iron atoms are removed from ferritin, apoferritin is formed [44,45]. An important property of ferritin/apoferritin is that its 24 subunits can dissociate at pH 2 and reconstruct into an intact shell structure as the pH of the solution is slowly

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adjusted to neutral [40]. At low pH ( pH 2), ferritin/apoferritin cages disassemble into subunits, allowing the drug to be loaded to assemble into the ferritin/apoferritin cage. When the pH is changed to basic ( pH 8.5), reassembly of the cage takes place. Such a dissociation –reassembly route has been regarded as a promising approach to encapsulate small drugs, biomarkers and even nanoparticles to improve their therapeutic efficacy, stability and biocompatibility [46,47]. Using the enhanced permeability and retention effect (EPR), Maeda et al. [48] showed that the apoferritin drug delivery system accumulated, indeed, at the tumour site. In tumour cells, increased glucose catabolism results in a significant production of lactate and Hþ, thus increasing acidity. The tumour cell, however, maintains an intracellular pH close to normal cells ( pH 7.3), where the acid-load from the generated lactate and Hþ is transported to the extracellular environment [49]. The vascular system is unable to effectively remove the acidity resulting in an acidic tumour extracellular environment. This difference in pH can be used to deliver therapeutic compounds from apoferritin to cancer cells. We were able to encapsulate daunomycin, an anthracycline antibiotic drug that has been used to treat specific types of cancer such as acute myeloid leukaemia and acute lymphocytic leukaemia for drug delivery, loaded in apoferritin [50]. As shown in figure 5, we used apoferritin’s ability to disassemble and reassemble under pH control to load the therapeutic compound—daunomycin. The combination of a modifiable interior and exterior surface and the penetrable hydrophobic and hydrophilic channels through the cage allows the encapsulation of both insoluble and soluble drugs for delivery. Our results showed that encapsulation of the daunomycin within the apoferritin protein cage had little effect upon the intrinsic binding constant, Ki, or the exclusion parameter, n, between daunomycin and DNA derived from fluorescence quenching titration when compared with the free daunomycin model. Fan et al. [51] showed that magnetoferritin nanoparticles could be used to target and visualize tumour tissues without the use of any targeting ligands or contrast agents. Iron oxide nanoparticles were encapsulated inside a recombinant human heavy-chain ferritin (HFn) protein shell, which binds to tumour cells that overexpress transferrin receptor 1 (TfR1). The iron oxide core catalyses the oxidation of peroxidase substrates in the presence of hydrogen peroxide to produce a colour reaction that is used to visualize tumour tissues. They examined 474 clinical specimens from patients with nine types of cancer and verified that these nanoparticles can distinguish cancerous cells from normal cells with a sensitivity of 98% and specificity of 95%. Uchida et al. [52] demonstrated the versatility of using the HFn protein cage as a mineralized cage for in vitro cancercell-specific targeting. The mineralization of the protein cage consisted of incorporating Fe(II) into the interior of the cage as iron oxide (Fe2O3) at a stoichiometric ratio of 3000 Fe per cage. This effectively produces a stable ferromagnetic Fe2O3 nanoparticle without disturbing the cage architecture. In the assembled ferritin cage, the N-terminal of the 24 HFn subunits is exposed on the exterior surface. The ligand peptide RGD4C was genetically modified and attached to the 24 subunits on the exterior surface of the HFn, producing a mutant form of the cage as RGD4C-Fn. C32 cancer cells (human amelanotic melanoma) were used as the cell-targeting model in the study. The RGD4C-Fn mineralized mutant

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PLAA (R = H or Na) + apoferritin subunits + PLAA + daunomycin reassemble overnight incubation







apoferritin–PLAA–daunomycin protein cage CH3





Figure 5. Synthesis of the apoferritin protein cage – daunomycin – poly-L-aspartic acid (APC-DN-PLAA) drug delivery system where the 24 subunits of the apoferritin self-assemble to produce a protein cage containing eight hydrophilic channels [50]. (Online version in colour.)

demonstrated an enhanced specific targeting interaction with the C32 cells when compared with the mineralized HFn formed as a control. The RGD4C-Fn mineralized mutant can act as an imaging agent with cell-specific targeting of cancer cells, and holds potential for use in drug delivery. Such preservation of the architecture of the cage with surface modification through protein mutation offers an approach towards modification of other similar protein cage structures. Recently, Bradshaw et al. [53] showed the dose-dependent, anti-tumour activity of PbS quantum dots (QDs) encapsulated in HSAF (AFt-Pbs) against two human-derived colorectal carcinoma (CRC) cell lines. ROS were generated on in vitro exposure of CRC cells to Aft-PbS, which resulted in the decrease in cell proliferation, and apoptosis. However, the AFt-PbS nanocomposites do not affect the growth and cell cycle of non-tumour human microvessel endothelial HMEC-1 cells. Further, Bradshaw et al.’s in vivo studies showed that the AFt-PbS QDs are well tolerated by mice with no adverse health or behavioural indicators observed throughout the 15 day study. This study shows the potential development of AFt-PbS nanocomposites for simultaneous non-invasive imaging and treatment of malignant tissue. Our group used apoferritin as a template for synthesis of radioisotopes loaded protein cage for potential applications in nuclear medicine [54,55]. Compared with direct loading of radioactive ions such as 177Lu3þ or 90Y3þ to a ligand or chelating agent, the core/shell nanoparticles use apoferritin as a shell to protect and stabilize the radioactive ions. The loading of each nanoparticle is also uniform. The loading efficiency is significantly improved by this approach also suggesting highly effective cancer treatment owing to the higher radiation doses from nanoparticles on cancer cells. Cutrin et al. [56] also recently showed the possibility of using apoferritin

to simultaneously deliver therapeutic and imaging agents loaded into its internal cavity to hepatocytes. Apoferritin was loaded with curcumin, an antioxidant, anti-inflammatory, antineoplastic polyphenolic substance and the MRI contrast agent GdHPDO3A to evaluate the efficiency of drug delivery, and delivered to attenuate thioacetamide-induced hepatitis in mice. The encapsulation of curcumin inside the apoferritin cavity was shown to significantly increase its stability and bioavailability while maintaining its therapeutic anti-inflammatory properties. Lin et al. [57] evaluated ferritin nanocages as candidate nanoplatforms for multi-functional loading. Ferritin nanocages can be either genetically or chemically modified to impart functionalities to their surfaces, and metal cations can be encapsulated in their interiors by association with metal binding sites. Moreover, different types of ferritin nanocages can be disassembled under acidic condition and reassembled at pH of 7.4, providing a facile way to achieve functional hybridization (figure 6). They used combinations of these unique properties to produce a number of multifunctional ferritin nanostructures with precise control of their composition. Then, they studied these nanoparticles, both in vitro and in vivo, to evaluate their potential suitability as multi-modal imaging probes. A good tumour targeting profile was observed, which was attributable to both the EPR effect and biovector-mediated targeting. This, in combination with the generalizability of the functional loading techniques, shows the promise of ferritin particles as powerful nanoplatforms in the area of nanomedicine. Unlike the traditional conjugation methods, such a loading strategy minimizes interference among different docked motifs and enables accurate control over the composition of the final conjugates. The success of this study has implications for

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Figure 6. Schematic of the process of triple-loading. RGD4C and Cy5.5 were introduced onto the surfaces of two sets of ferritins via genetic and chemical means. These two ferritins were then mixed and broken down into subunits at pH 2 and incubated with 64CuCl2 to achieve radiolabelling. The pH was then adjusted back to 7.4 to facilitate the reformation of nanostructures. The reconstituted chimeric ferritin nanocages have both RGD4C and Cy5.5 on their surfaces and 64Cu loaded in their cavities. Adapted from Lin et al. [57]. (Online version in colour.)

ongoing efforts to construct multi-modal imaging probes and nanoparticulate theranostics. Nakajima et al. [58] also synthesized ferritin-like dendrimers, which mimic the mechanism of encapsulation and release of Fe ions in biological ferritins through redox switching driven by the Fe2þ/Fe3þ couple. Thus, it has become possible to create absolutely synthetic ferritin-like systems for enhanced drug delivery.

2.1.3. Protein cage nanoparticles for DNA assay and immunoassay Protein cages can be used as templates for the formation of highly monodispersed nanoparticles for protein assays. In these processes, the protein cage has different functions— (i) it provides a constrained environment providing the proper conditions for the formation of highly monodispersed nanoparticles, (ii) it prevents aggregation of the formed nanoparticles, and (iii) in many cases, it induces a mineralization reaction [59]. An example is the well-defined interior cavity of protein cages such as ferritin, which is used as a template for the synthesis of inorganic nanoparticles [60]. Owing to its unique cavity structure, apoferritin has been used widely as a protein cage to synthesize size-restricted bioinorganic nanocomposites [24,61–63]. Viral cages and bacterial multi-enzyme complexes have also been used for this purpose [64]. These systems have a high charge density at certain regions in their inner cavity, which can act as nucleation sites for mineralization. Using these strategies, monodispersed single crystal nanoparticles can be grown inside capsids and cages. In addition, the protein shell itself can be modified to add more functionalities to the nanoparticles. Several redox and optical markers can be loaded into the cavity of apoferritin by controlling the pH to create optical and electrochemical nanoparticle labels for various bioassay applications. Recently, different marker-loaded apoferritin nanoparticle labels have been developed in our group and used for highly sensitive electrochemical immunoassays of

protein biomarkers and DNA assays [65–67]. We reported a novel approach for electrochemical quantification of singlenucleotide polymorphisms (SNPs) using nanoparticle probes [65]. The principle is based on DNA polymerase I (Klenow fragment)-induced coupling of the nucleotide-modified nanoparticle probe to the mutant sites of duplex DNA under the Watson–Crick base pairing rule. Following liquid hybridization between biotinylated DNA probes, mutant DNA and complementary DNA, the resulting duplex DNA helixes were captured to the surface of magnetic beads through a biotin–avidin affinity reaction and magnetic separation. A cadmium phosphate-loaded apoferritin nanoparticle probe, which is modified with nucleotides and is complementary to the mutant site, is coupled to the mutant sites of the formed duplex DNA in the presence of DNA polymerase. Subsequent electrochemical stripping analysis of the cadmium component of coupled nanoparticle probes provides a means to quantify the concentration of mutant DNA. The method is sensitive enough to detect 21.5 attomol (aM) of mutant DNA, which will enable the quantitative analysis of nucleic acid without polymerase chain reaction pre-amplification. This approach was challenged with constructed samples containing mutant and complementary DNA. The results indicated that it was possible to accurately determine SNPs with frequencies as low as 0.01. The proposed approach has a great potential for realizing an accurate, sensitive, rapid and low-cost method of SNP detection. In a separate study, hexacyanoferrate and fluorescein were chosen as model markers for loading into the cavity of apoferritin to develop protein nanoparticle labels [66]. Briefly, apoferritin was dissociated into subunits at pH 2 and then reconstituted at pH 8.5, thereby trapping the markers in solution within its interior. The numbers of loaded hexacyanoferrate and fluorescein markers per apoferritin were 150 and 65, respectively. An amino-modified DNA probe was conjugated with the marker-loaded apoferritin nanoparticle (MLANP) surface by using the coupling reagent 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride. The number of DNA probes per apoferritin nanoparticle was

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2.2. Biobatteries Biomaterials have been used as electrode materials in rechargeable lithium batteries [19,73]. The nanostructure of


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10 ng ml21 IgG could be detected with this single fluorescence probe. Compared with that of the single fluorescence probe, the sensitivity of the biotin-functionalized fluorescein MLAN label was enhanced 125 times. The significant signal enhancement is attributed to two factors—(i) apoferritin nanovehicle as a carrier to load 65 fluorescence anions, and (ii) streptavidin is used as a bridge to bind two or three biotin-functionalized MLAN labels (one streptavidin has four binding sites to biotin). Application of the MLAN label in the electrochemical immunoassay was also demonstrated with the biotin-functionalized hexacyanoferrate MLAN label in connection with a magnetic bead-based sandwich immunoassay (figure 7b). It involves two immunoreactions between the primary IgG antibody linked to magnetic beads and the biotin-modified secondary antibody in the absence or presence of antigen (IgG). This was followed by introducing streptavidin as a bridge to bind the biotin-functionalized hexacyanoferrate MLAN labels. Jaaskelainen et al. [72] presented a biological method of producing functionalized nanoparticles for effective use as label agents in a bioaffinity assay. The particles are based on the globular protein shell of human ferritin. A single chain Fv fragment (scFv) of an antibody was used as the binding moiety and Eu3þ ions as the label. Conventional chemical conjugation of the particle and antibody fragment was replaced with genetic fusion between the ferritin subunit and scFv genes. The material, for example, the fusion construct was produced in a single bacterial culture as insoluble forms that are easily purified by centrifugation. The subunits were solubilized and self-assembled, and label ions were introduced by changing the pH. Such a method of synthesizing nanoparticles with inherent antigen binding activity is fast, economical and environmentally sustainable, making the system advantageous, particularly in large-scale applications. Recently, we described a new magnetic particle (MP)-based electrochemical immunoassay of human phospho-p5315 using carbon nanospheres (NS) and protein cage nanoparticles (PCNs) for signal amplification [13]. The sandwich-type electrochemical immunoassay with PCN-p5315Ab2 (a) and PCN-p5315Ab2-NS (b) as labels is shown in figure 8. The magnified inset shows the preparation of PCN nanoparticles by a diffusion approach. Briefly, lead ions diffused into the apoferritin cavity (with negative electrostatic potential) through hydrophilic channels and accumulated on the surface of the internal cavity. When the phosphate buffer was slowly introduced into the solution, a Pb3(PO4)2 core is formed within the apoferritin shell. To enhance the detection sensitivity, we used carbon NS as nanocarriers to enable the loading of a large amount of PCN. Greatly enhanced sensitivity was achieved for three reasons—(i) PCN and the p5315 signal antibody (p5315 Ab2) are linked to the carbon NS (PCNp5315Ab2-NS) as a label; (ii) PCN increases the amount of metal ions in the cavity of each apoferritin; and (iii) MPs capture a large amount of primary antibodies. Protein cage templated metallic phosphates, instead of enzymes, as multilabels have the advantage of eliminating the addition of mediator or immunoreagents and, thus, makes the immunoassay system simpler.

calculated by comparing the concentration of apoferritin and DNA probe in DNA probe-modified apoferritin nanoparticle solution. It was observed that about eight DNA probes were attached per hexacyanoferrate-loaded apoferritin nanoparticle. The biofunctionalized apoferritin nanoparticle was thus used as a label for electrochemical DNA detection in connection with a magnetic-bead-based sandwich hybridization assay. This involves a dual hybridization event, with probes linked to the MLANPs and to magnetic beads along with magnetic separation of the target DNA-linked magnetic-bead/apoferritin assembly. This is followed by dissociation of captured hexacyanoferrate MLANPs with 0.1 M HCl/KCl and squarewave voltammetry detection of the released hexacyanoferrate at a disposable carbon screen-printed electrode. The voltammetric peaks are well-defined and proportional to the concentration of DNA targets, with detection limit of 3 ng l21. Protein cages have also been reported as templates to prepare uniform-size metal phosphate nanoparticle labels for highly sensitive electrochemical transduction of antibody – antigen recognition events [67]. The release of metal ions from metal phosphate in an acetate buffer ( pH 4.6) eliminates the harsh conditions in the traditional metallic nanoparticle dissolution (i.e. the strong-acid dissolution of QDs and gold nanoparticles). We reported apoferritin-templated synthesis of cadmium phosphate nanoparticle labels for electrochemical immunoassay of tumour necrosis factor-a (TNF-a) protein biomarker [67]. Well-defined cadmium signals are observed with low concentrations of TNF-a from 0.01 to 10 ng ml21. The response obtained with a TNF-a target concentration of 10 pg ml21 indicates a detection limit of around 2 pg ml21 (77 fM), i.e. 3.9 aM or 2.33  106 TNF-a biomarker molecules in a 50 ml sample. Such low detection is comparable to the values obtained using a common immunological assay, such as the enzyme-linked immunosorbent assay (40 pg ml21) [68], and is higher than that of QD-based electrochemical immunoassays [69]. In addition to single-analyte systems, the template-synthesized metal phosphate nanoparticle labels also offer great promise for the electrical detection of multiple protein biomarkers. It is easy to prepare different metal phosphate– apoferritin nanoparticle labels, whose metal components yield well-resolved, highly sensitive stripping voltammetric signals for corresponding targets. We have demonstrated a versatile bioassay label based on biotin-functionalized MLANs for sensitive protein detection [70]. Sandwich immunoassay was performed with an aminosilanated glass slide (figure 7a). Immunoglobulin (Ig) G was used as a model protein to demonstrate its application. The primary antibody (anti-IgG) was first immobilized on an aminosilanated modified glassy slide, and then the mouse IgG was bound to the antibody, followed by interaction with a biotin-modified secondary antibody. Streptavidin was further incubated on the above-modified slides, and this was followed by adding the biotin-functionalized fluorescein MLAN label. The fluorescence intensity of the antibody-spotted area increased with the increase of IgG concentration ranging from 0.1 to 20 ng ml21. No fluorescence was observed at the spotted area in the absence of IgG. Fluorescence was still observed with 0.06 ng ml21 IgG (0.39 pM). This detection limit is much lower than that of the colorimetric protein assay [71]. Comparable immunoassays were performed with a single fluorescein probe labelled anti-mouse IgG antibody (anti-mouse IgG FITC antibody, Sigma, Ca.F4018) under similar conditions. Fluorescence microscopy images indicate that a minimum of

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secondary antibody


(b) magnetic bead


Figure 7. (a) Protocol of fluorescence microscopy immunoassay based on fluorescein MLAN label. (b) Magnetic beads and electrochemical sandwich immunoassay protocol based on biotin-functionalized hexacyanoferrate MLAN labels [70]. (Online version in colour.) these materials enhances their electrochemical activity, thus improving battery performance. For example, the M13 virus was successfully modified and used as a template to form nanosized amorphous FePO4 particles, which owing to their high specific capacity and safety are attractive cathode materials for rechargeable Li batteries (figure 9) [74,75]. M13 is a well-investigated virus for nanotechnology. It is composed of a circular single-stranded DNA encapsulated by a major coat protein ( p8). Minor coat proteins—p3, p6, p7 and p9 cap the virus end. These major and minor coat proteins provide nucleation sites for functional inorganic materials. For example, the p8 protein of the M13 virus was modified to bind FePO4 cathode material and its p3 protein bound with conducting single-walled carbon nanotubes (SWNTs). The virus-nanoparticle hybrid material shows greater efficiency in battery performance owing to the high specific capacity of FePO4 and the high conductivity of the SWNTs, maintaining a high capacity (approx. 130 mAh g21 at 108C) at high current rates and superior cyclability. Thus, the hybrid cathode materials remain electrochemically stable. Similarly, the p8 protein can also be modified to

contain a Co nucleation site and an Au binding motif to make hybrid virus-Au-Co3O4 cathode materials [19]. Co3O4 has very high specific capacity (approx. 890 mAh g21). The nanostructure of the Co3O4 makes the reaction product, Li2O electrochemically active, which in bulk is inactive. Further, the presence of the Au nanoparticles improves the electrochemical activity owing to the enhanced electronic conduction and catalytic effect of the Au nanoparticles. Nam et al. [19] have fabricated a microbattery using the above hybrid cathode material. The M13 virus was assembled onto a polyelectrolyte (linear poly(ethyleneimine) and poly(acrylicacid) multi-layer film on which the Co3O4 particles were nucleated. This two-dimensional flexible, selfstanding multi-layer film structure used with a Pt current collector could store and release Liþ reversibly and showed highly specific capacity even at high current rates, showing great promise as a virus-based rechargeable Li battery electrode. Using Cu as the current collector, it was shown that the cell could sustain and deliver 94% of its theoretical capacity at a rate of 1.12C and 65% at a rate of 5.19C, thus demonstrating the capability of a high cycling rate.

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primary antibody

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(c) PO43–








Figure 8. A schematic of sandwich immunoassays based on different secondary antibody paths of (a) PCN-p5315Ab2 and (b) the PCN-p5315Ab2-NS conjugate. (c) Preparation of PCN based on the diffusion approach of lead ions and phosphate buffer to form a Pb3(PO4)2 core within the apoferritin shell [13]. (Online version in colour.) (a)

(b) high power lithium ion battery cathode


genes to be engineered a-FePO4 templated virus nanowire



pVIII genetically modified peptides pIII

electrolyte biomolecular recognition and attachment of templated virus to SWNT


Figure 9. A schematic of the multi-functional M13 virus is shown with the proteins genetically engineered in this study. (a) The p8 protein gene ( pVIII) is modified to serve as a template for a-FePO4 growth, and the p3 protein gene ( pIII) is further engineered to have a binding affinity for SWNTs. (b) A schematic diagram for fabricating genetically engineered high-power lithium ion battery cathodes using the above multi-functional viruses. A photograph of the battery used to power a green LED is also shown. Adapted from Lee et al. [74]. (Online version in colour.) Ryu et al. [76] fabricated an electrode based on hybrid nanowires of diphenylalanine peptide and Co3O4 nanoparticles. Such nanowires are generically called peptide tubes, which will be discussed in detail in §3.1. The number of Co3O4 nanoparticles synthesized on the peptide nanowire surface limits the performance of the electrode. In this regard, it has been suggested that removal of the peptide nanowire might improve the performance of the electrode material by leaving behind a nanotubular structure, which offers two surfaces—internal and external of the tube—for Liþ conduction as well as twice the contact with the electrolyte. The nanotubular structure is also mechanically and structurally more stable to the volume changes which occur during Liþ insertion and extraction. Besides rechargeable Li

batteries, biomaterials have also found their applications in solar and fuel cells [77]. Huang et al. [78] assembled a twodimensional array of ferritin on a silicon dioxide surface and then removed the protein shell of ferritin by heat treatment. Thus, the iron oxide cores left behind formed uniform 10 nm nanoparticle arrays resulting in a QD solar cell. Similar to the DENs discussed in §2.1.1, Yong et al. [79] used the Desulfovibrio desulfuricans bacteria as templates for the synthesis of uniform-sized Pd nanoparticles. These nanoparticles, when used as catalysts in proton exchange membrance fuel cells, showed enhanced power output compared with commercial Pd catalysts. Likewise, the tobacco mosaic virus was used as a template to synthesize Pt nanowires, which were used as more efficient catalysts in fuel

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(a) 120


weight (%)

100 80 60


40 Phe–Phe

20 0




Figure 10. The diphenylalanine peptide efficiently self-assembles into discrete, well-ordered nanotubes (b). These nanotubes are stable in aqueous solutions even at temperatures above the boiling point of water and preserve their secondary structure at temperatures up to 908C. Thermogravimetric analysis (TGA) of the peptide nanotubes after dry heat revealed durability at higher temperature (a). It was shown that the thermal stability of diphenylalanine peptide nanotubes is significantly higher than that of a non-assembling dipeptide, dialanine. In addition to thermal stability, the peptide nanotubes were chemically stable in organic solvents such as ethanol, methanol, 2-propanol, acetone and acetonitrile. Adapted from Adler-Abramovich et al. [87]. (Online version in colour.)

cells owing to their high active surface area [79]. Hybrid biobatteries based on arylated CNTs have also been constructed [80]. Single-walled nanotubes (SWNTs) were covalently modified with aromatic groups such as anthracene and anthraquinone, which were then cast onto electrodes further increasing the working surface area of the electrode. These modified electrodes increased the efficiency of direct electron transfer between the enzyme, laccase and the electrode for biocatalytic reduction of oxygen. Despite these obvious advantages of using biomaterials in the fabrication of biobatteries, the high costs associated with them limit their commercial realization [10]. A common fundamental challenge also remains in developing optimum structures for enhanced performance of large-scale commercial devices.

3. Bioinspired nanomaterials as biomimics In the current century, scientists have been inspired by engineering principles in nature and have begun to design materials to specifically clone biological processes to control the design of devices for medical, environmental and energy applications with extreme precision. For example, the water-repellent nature of certain naturally occurring surfaces such as the leaves of the lotus plant and the feet of water-striders have been mimicked by scientists to engineer structured superhydrophobic surfaces with potential applications in glass-coating, microfluidics and others [81]. Biologists, physicists, chemists, mathematicians and computational scientists have congregated to provide a deeper understanding of the mechanisms involved in these processes. Here, we review the applications of nanomaterials in the fast-growing fields of tissue engineering and biomineralization. The synthesis of these materials is inspired by the intrinsic ability of the self-assembly of biological proteins and peptides.

3.1. Biomimetic nanomaterials for tissue engineering and biomineralization The human body’s tissues and organs are composed of nanostructured proteins, and hence nanomaterials become a

favourable choice as scaffolds for tissue regeneration and engineering. Proteins and peptides naturally self-assemble to form solid nanofibrils or hollow NTs, which inspired the synthesis of protein-like tubular structures called peptide NTs that have found applications in tissue engineering [82 –84]. Here, the reader is pointed to excellent reviews by Zhang et al. [85] and Cui et al. [86] on the design of nanostructured biological materials through the self-assembly of peptides and proteins. Dipeptides from the diphenylalanine motif of the Alzheimer’s b-amyloid peptide on dissolving in 1,1,1,3,3,3-hexafluoro-2-propanol and diluted to a final concentration of less than or equal to 2 mg ml21 forms micrometre-long multi-walled NTs with diameters ranging from 80 to 300 nm (figure 10) [87]. These NTs show remarkable chemical, thermal and mechanical strengths. Dry NTs start degrading only above 2008C and show an average point stiffness of 160 N m21 and a high Young’s modulus of approximately 19 –27 GPa [88,89]. This is an order of stiffness higher than biological microtubules which provide a rigid cytoskeleton to the cell and have a Young modulus of approximately 1 GPa. It has been suggested that intermolecular hydrogen bonding and p – p stacking of aromatic side chains afford stability and mechanical strength to these peptide NTs, which can find applications in micro-, nanoelectromechanical systems and other functional devices as well as in tissue engineering. Another advantage of using biological NTs is their biocompatibility when used for biological sensing. For example, peptide NTs deposited on graphite electrodes showed improved electrochemical activity towards the redox reaction of potassium hexacyanoferrate [89]. The above feature in addition to the low cost and good solubility of the peptide NTs also make them commercially viable. Similarly, thiol-modified peptide NTs immobilized on gold electrode surfaces and coated with enzymes showed improved sensitivity and reproducibility for the detection of glucose and ethanol, with short detection times, large current density and high stability [90]. Linear peptides are long peptide surfactants approximately 2–3 nm in length with a hydrophilic head consisting of two-three charged amino acids and a hydrophobic tail of four or more consecutive hydrophobic ones (e.g. AIN D, V6D, G8DD, KV6) [90]. In water at concentrations of

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200 300 temperature (°C)


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hMSCs [101]. Oliveira et al. [102] used a PAMAM dendrimer/ carboxymethyl chitosan nanoparticle system to efficiently deliver dexamethasone into rat bone-marrow stromal cells which were then seeded on starch polycaprolactone scaffolds and implanted to the back of Fischer 344/N rats in the absence of typical osteogenic supplements. New bones were seen to be forming in these rats with significant increased calcium deposition. For in-depth reading, the reader is directed to an excellent recent review by Zhao et al. [103].


4. Summary and future directions

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With the advent of nanotechnology, there has been a tremendous growth in the field of bionanomaterials over the past few years [104]. There is continuous growing interest in the scientific community, inspired by the marvel of nature, in the synthesis of nanomaterials using biological templates as well as materials that mimic biological functions [105]. Very recently, Qi et al. designed an anti-reflective heteronanojunction structure by the hydrothermal growth of ZnO nanorods on silicon micro-pyramids which suppresses light reflection effectively resulting in a simultaneously high photocurrent response and good charge separation for enhanced solar energy conversion [106]. The authors were inspired by the unique configuration of sub-300 nm non-close-packed hexagonal arrays in the compound eyes of moths that effectively capture maximum amount of light while deterring reflection. Based on the same inspiration, Ahn et al. [107] showed earlier that high-index contrast TiO2 nanowires grown in a conventional TiO2 electrode increased the power conversion efficiency of a dye-sensitized solar cell. This increased efficiency was a result of a combination of anti-reflective and diffraction properties of the hierarchical structures. Li et al. were motivated by the distinctive structure of green leaves, which enables them with enhanced light-harvesting efficiency to use them as biotemplates to synthesize morph-TiO2. This conjugated system showed an impressive increase of 103–258% in the absorbance intensities in the visible light range. The photocatalytic activity of morph-TiO2 was also seen to improve [108]. Scientists have also been able to mimic the subcellular complexity of enzymes that function in tandem. Recently, Liu et al. [109] created functional enzyme nanocomplexes encapsulated within thin polymer shells that exhibit catalytic efficiency and enhanced stability when compared with free enzymes. The co-localized enzymes are able to perform complementary functions mimicking biological processes in living organisms. Such continuous interest in the field of bioinspired nanomaterials will stir multidisciplinary research and education, expanding fundamental understanding as well as develop novel materials as prototypes from nature with unique properties for sustainable applications. However, several factors should be taken into close consideration before successful commercial development of bioinspired materials for practical applications, such as the short lifetime of biological substances such as enzymes that can lead to possible degradation of these materials in devices, and cost of manufacturing large-scale devices using biomaterials. While biomimetic structures are interesting and provide new opportunities for designing novel materials with unique properties for several applications, future research in this area should focus on the development of cleaner, more sophisticated yet cost-effective methods for designing them. To this

4–6 mM, these peptides form a network of cationic or anionic open-ended NTs with 30– 50 nm diameters. The walls of these tubes are 4 –5 nm thick and comprise a bilayer of peptides. They pack by hydrogen bonding and are stabilized by hydrophobic effects. Matsumura et al. [91] have shown that biotinylated peptides adopt b-sheet structures and form homogeneous tubes in water with 30 nm thick walls, which can be used as scaffolds for proteins. Nanofibres made from synthetic biodegradable polymers such as polylactic acid, poly(D,L-lactic co-glycolic acid), polyvinylalcohol, polycaprolactone as well as natural materials such as collagen, gelatin and chitosan have been used as scaffolds in tissue engineering, some of which have also been approved by the U.S. Food and Drug Administration [91]. The unique mechanical, electrical and optical properties of carbon-based nanomaterials have inspired their applications in the synthesis of three-dimensional scaffolds for tissue engineering [92]. Their structure is similar to the native extracellular matrix (ECM) and their high electrical conductivity can be used to provide stimulation to artificial scaffolds. For example, graphene, graphene-oxide (GO) and reduced graphene-oxide (rGO) create microenvironments similar to the ECM, which aids in cell adhesion, proliferation and differentiation [92]. Kalbacova et al. [93] showed that human mesenchymal stem cells (hMSCs) showed a spindlelike morphology when grown on graphene, which improved the capacity of differentiation towards osteoblast lineage, and displayed a better adhesion. Owing to the variable surface oxygen content on graphene, it binds with proteins by simultaneous hydrogen-bonding, electrostatic interactions and p 2 p interactions. Furthermore, its highly wrinkled structure on the nanoscale significantly increases osteogenic differentiation. Graphene has also been used as reinforcing materials for hydrogels, which are increasingly being used for tissue engineering owing to their good biocompatibility and biodegradability [94]. The good electrical properties of graphene and CNTs also influence the behaviour of electroactive neural cells. Neuroendocrine PC12 cells have shown neurite outgrowth and extension on rGO [95]. Similarly, multi-walled and single-walled NTs (MWNTs and SWNTs, respectively) increased the frequency of continuous postsynaptic currents and spontaneous action potential frequency in hippocampal neurons, and thus significantly increased network activity [96,97]. The high surface area of the NTs also enhances protein adsorption. The unique mechanical strength of CNTs can be harnessed to improve the mechanical strength of damaged bone tissues. Armentao et al. [98] reported carboxylated and fluorinated SWNTs promoted biomineral formation and the expression of key molecules in the biomineralization process—bone sialoprotein and osteocalcin. Homogeneous composites of surfacefunctionalized MWNTs with HAp crystals improved mechanical strength and MC3T3-E1 proliferation and alkaline phosphatase activity [99]. Mineralized MWNTs synthesized by soaking MWNTs in an SBF solution and resulting in the formation of a uniform hydroxyapatite layer significantly improved compressive strength by adding to calcium phosphate cement [100]. Functionalized carbon nanomaterials also show greater biocompatibility. Three-dimensional nanomaterialbased scaffolds also show an obvious advantage over their two-dimensional counterparts. For example, three-dimensional poly-(lactic acid glycolic acid)/nano-hydroxyapatite support proliferation, osteogenic differentiation and mineralization of

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Funding statement. P.B. acknowledges support from Linus Pauling Distinguished Postdoctoral Fellowship at PNNL. D.D. acknowledges the financial support by the National Natural Science Foundation of China (21275062, 21075047) and the Programme for New Century Excellent Talents in University (NCET-12-0871). Y.L. acknowledges the financial support by the CounterACT Programme, National Institutes of Health Office of the Director (NIH OD) and the National Institute of Neurological Disorders and Stroke (NINDS, grant number U01 NS058161). Pacific Northwest National Laboratory (PNNL) is operated by Battelle for US-DOE under contract no. DE-AC05-76RL01830.














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Bioinspired nanoscale materials for biomedical and energy applications.

The demand for green, affordable and environmentally sustainable materials has encouraged scientists in different fields to draw inspiration from natu...
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