Functional Graphene Nanomaterials Based Architectures

Review pubs.acs.org/CR

Functional Graphene Nanomaterials Based Architectures: Biointeractions, Fabrications, and Emerging Biological Applications Chong Cheng,*,† Shuang Li,‡ Arne Thomas,‡ Nicholas A. Kotov,§ and Rainer Haag† †

Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany Department of Chemistry, Functional Materials, Technische Universität Berlin, Hardenbergstraße 40, 10623 Berlin, Germany § Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States ‡

ABSTRACT: Functional graphene nanomaterials (FGNs) are fast emerging materials with extremely unique physical and chemical properties and physiological ability to interfere and/or interact with bioorganisms; as a result, FGNs present manifold possibilities for diverse biological applications. Beyond their use in drug/gene delivery, phototherapy, and bioimaging, recent studies have revealed that FGNs can significantly promote interfacial biointeractions, in particular, with proteins, mammalian cells/stem cells, and microbials. FGNs can adsorb and concentrate nutrition factors including proteins from physiological media. This accelerates the formation of extracellular matrix, which eventually promotes cell colonization by providing a more beneficial microenvironment for cell adhesion and growth. Furthermore, FGNs can also interact with cocultured cells by physical or chemical stimulation, which significantly mediate their cellular signaling and biological performance. In this review, we elucidate FGNs− bioorganism interactions and summarize recent advancements on designing FGN-based two-dimensional and three-dimensional architectures as multifunctional biological platforms. We have also discussed the representative biological applications regarding these FGN-based bioactive architectures. Furthermore, the future perspectives and emerging challenges will also be highlighted. Due to the lack of comprehensive reviews in this emerging field, this review may catch great interest and inspire many new opportunities across a broad range of disciplines.

CONTENTS 1. Introduction 2. FGNs−Bioorganism Interactions 2.1. Graphene and Its Derivatives: Structures, Chemistry, and Functionalization 2.2. FGNs−Biomolecules Interactions 2.3. FGNs−Mammalian Cell Toxicity and Interactions 2.4. FGNs−Stem Cell Interactions 2.5. FGNs−Microbial Cell and Virus Interactions 3. FGNs-Based 2D-Layered Composites 3.1. Atomic or Multilayer Graphene on 2D Interfaces 3.2. FGNs-Based Biointerfacial Coatings 3.2.1. General Strategies for FGNs-Based Interfacial Coatings 3.2.2. Impact of FGNs-Based Coatings on Interfacial Bioactivities 3.3. Free-Standing FGNs-Based Composite Films 3.3.1. Vacuum Filtration 3.3.2. Templated-Directed Methods 3.3.3. Interfacial Casting-Drying, Assembly, or Gelation 3.3.4. In Situ Growth/Assembly 3.3.5. Free-Standing FGNs Films as Bioactive and Multipurpose Platforms 4. FGNs-Based 3D Architectures © 2017 American Chemical Society

4.1. Self-Assembled FGNs-Based Hydrogels or Aerogels 4.1.1. Hydrothermal/Chemical Reduction 4.1.2. Multi-Noncovalent Assembly 4.2. Covalently Cross-Linked FGNs-Hybridized Hydrogels 4.3. Ice-Templated Growth of 3D Nanochanneled Networks 4.4. Interfacial Assembly of FGNs on 3D Frameworks 4.5. Graphene Coating Layer on 3D Scaffolds via Chemical Vapor Deposition 4.6. 3D Printed FGNs Architectures 4.7. FGNs/Cell Coassembled Biohybrids 4.8. Other Nanostructured FGNs-Based Architectures 5. Emerging Biological Applications of FGNs-Based Architectures 5.1. FGNs for Cellular/Pathogen Detection and Tissue Recording 5.1.1. Cellular Signals and Pathogen detection 5.1.2. Tissue Monitoring and Neural Recording 5.2. Biomedical Implants/Membranes: Surface Modification and Composites

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Received: August 5, 2016 Published: January 11, 2017 1826

DOI: 10.1021/acs.chemrev.6b00520 Chem. Rev. 2017, 117, 1826−1914

Chemical Reviews 5.3. Stem Cell Engineering and Tissues Regeneration 5.3.1. FGNs for Controlling Stem Cell Fate 5.3.2. FGNs for Tissues Regeneration 5.4. Electrode Matrix for MFCs 6. Outlook and Future Directions 6.1. FGNs for Cellular/Pathogen Detection and Tissue Recording 6.2. FGNs for Stem Cell Engineering 6.3. FGNs for Implant Coating and Tissue Regeneration 6.4. FGNs for Electrodes in MFC Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

Review

been devoted to the behavior and toxicology of functionalized FGNs both in vitro and in vivo.30,31 Besides the applications in drug/gene delivery, phototherapy and bioimaging, recent studies have revealed that FGNs and FGNs hybrid architectures can significantly promote interfacial interactions with bioorganisms, such as protein, mammalian cells, and microbials, which makes them a potential platform for multifunctional biological applications. FGNs can increase the adsorption of extracellular biomolecules, especially proteins, thus accelerating the formation of extracellular matrix (ECM). This eventually promotes cell colonization by providing a more beneficial microenvironment for cell adhesion and growth. Furthermore, FGNs and FGNs hybrid architectures can also interact with cocultured cells by physical or chemical stimulation, thus influencing their cellular signaling and biological performances, such as stiffness induced stem cell differentiation, electrical stimulated proliferation, differentiation or topography regulation.32,33 Despite there are already a great number of studies that have been dedicated to the investigation of FGNs-based bioactive architectures, we noted that a comprehensive review in this field is still absent. Therefore we will summarize the recent advancements and present future perspectives for the application of bioactive FGNs and FGNs hybrid architectures in biological areas. In this review, we will first elucidate the interfacial interactions between FGNs and bioorganisms and corresponding mechanisms. Then, we will highlight the state-of-the-art chemical strategies for developing two-dimensional (2D) FGN-based surface coatings and thin films for promoting the interface bioactivities. Thereafter, recent advancements of synthesizing three-dimensional (3D) porous, conductive, and bioactive scaffolds by diverse chemical and physical avenues will be introduced in detail. Finally, we will discuss the representative biological applications regarding these emerging FGN-based 2D and 3D scaffolds, including cellular/pathogen detection, tissue recording, surface coating of implants and membranes, stem cell fate controlling, tissue regeneration, and electrode matrices in microbial fuel cells (MFCs).

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1. INTRODUCTION Graphene, one of the most promising carbon nanomaterials,1 exhibits an atomic layered sheet with sp2-bonded carbon atoms, which can be fabricated by either top-down processes (e.g., mechanical/electrochemical/chemical exfoliation of graphite) or bottom-up methods (e.g., chemical vapor deposition and chemical synthesis).2−4 The family members of functional graphene nanomaterials (FGNs) include single- and multilayer graphene, graphene oxide (GO), chemical/thermal reduced graphene oxide (RGO), graphene oxide quantum dots (GOQDs), graphene quantum dots (GQDs), and corresponding organic/inorganic compounds hybridized nanocomposites.5−7 Each member of FGNs exhibits different physical and chemical properties, such as number of layers, surface chemistry, defect density, composition and purity, and conductivity and mechanical properties, which provides many possibilities for a vast number of applications.8−11 Owing to the unique and diverse physical and chemical properties of FGNs, the FGNs-based composite materials also possess tunable electrical, mechanical, optical, and thermal properties.12 Therefore, FGNs and FGNs-based composite materials have a bright future and present tremendous new opportunities, not only in energy storage,13−16 electronic devices,17 and environmental treatment18−21 but also in diverse biomedical needs, such as bioelectrodes, bioimaging, therapic drug/gene delivery, stem cell, and tissue engineering.22,23 In the past few years, the FGNs and FGNs-based composites have generated great interests for designing functional nanomedicine, nanocarriers, tissue scaffolds, bioelectrodes, antibacterial coating, and microbial supporting materials.24,25 Since the FGNs have an extremely high surface area which is exposed on the surface, they can efficiently adsorb or bioconjugate with molecules and functional polymers and can work as novel nanocarriers for drug/gene delivery in cancer and other related therapeutic treatments.22,26 Utilizing the intrinsic near-infrared (NIR) optical absorbance, the FGNs can be applied photothermally for antitumor treatments.22,27 The FGNs have also shown interesting optical and magnetic properties, which make them a promising nanomedicine for diagnostic imaging and imaging-mediated therapies.28,29 Moreover, several studies have

2. FGNS−BIOORGANISM INTERACTIONS 2.1. Graphene and Its Derivatives: Structures, Chemistry, and Functionalization

In view of fabrication process, two primary methods have been developed for the fabrication of graphene and its derivatives: the top-down or bottom-up method. The top-down fabrication process is analogous to cutting down a tree or slicing a cheese.34 The most representative top-down method is Hummers’ method, which provides a facile protocol for the fabrication of oxidized graphene sheets with good solution process-ability. Up to now, hundreds of modified Hummers’ methods have been developed to obtain oxidized graphene sheets with different nanosizes, sheet-layers, and oxygen contents. The general process of Hummers’ method can be concluded as illustrated in Figure 1A (a), the graphite in a powder, flake or block form will be chemically oxidized and exfoliated into layered structure, with the assistance of ultrasonication, single or multi- layer oxidized graphene (or named GO) can be obtained. This method can also be further modified via using electrochemical exfoliation of graphite through applying external electric field, it has been reported that this approach can scalable fabrication of high-quality graphene (or named low-oxidized GO) with less defects 1827

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Figure 1. (A) Representative top-down method to synthesize oxidized graphene (a, modified Hummers’ method) and graphene (b, CVD prepared graphene coating). Reproduced with permission from ref 39. Copyright 2013, Nature Publishing Group. (B) Representative bottom-up method for the atomically precise synthesis of graphene nanoribbons. (a) The edge-modified 6-zigzag GNR (6-ZGNR) upon polymerization and subsequent cyclization. STM image (b) and constant-height nc-AFM frequency-shift image (c) of edge-modified 6-ZGNR. Reproduced with permission from ref 42. Copyright 2016, Nature Publishing Group. (C) The forms of graphene and its derivatives that have been used for the construction of bioactive architectures: (a) single-layer graphene, (b) multilayer graphene, (c) GO, (d) RGO, (e) GOQD, (f) GQD.

compared to most of the Hummers’ methods.35−37 Chemical vapor deposition (CVD) is another representative top-down method to synthesize graphene, in this method, large graphene sheet with different layers and sizes can be obtained by applying silicon carbide or copper alloy as substrates.38 As shown in Figure 1A (b), by using a stamping method, the CVD prepared graphene sheet can be easily transferred from the growth substrate to the target substrate.39,40 Due to the fine structure and high conductivity, the CVD prepared graphene has always been considered as the primary method for the fabrication of graphene-based electronic devices. Turning to bottom-up construction of graphene, one of the most exciting approaches is demonstrated by the research teams of Mullen and Fasel. They reported that atomically precise graphene nanoribbons (GNRs) with different topologies, widths, and edge periphery can be synthesized by using surface-assisted polymerization and cyclodehydrogenation of specific precursors, Figure 1B.41 Very recently, they report that the similar bottom-up method can be applied to synthesize zigzag graphene nanoribbons (ZGNRs) with yielded atomically precise zigzag edges. 42 These approaches magnificently demonstrate the possibility of using bottom-up chemical synthesis to control the length, width, and edge structure of GNRs.43 From the view of chemical and physical properties, the graphene can be divided into two main classes, the CVD prepared graphene and the oxidized graphene. The CVD prepared single- or multilayer graphene exhibited fine aromatic structures with limited defects, Figure 1C (a and b).44 Since these graphene sheets are difficult to suspend in solutions, it is not favorable to use them as nanomedicine or nanocarriers. However, their highly reactive surface makes them potentially suitable for bioelectrodes, for instance, the detection of

molecules and even bioorganisms. To synthesize FGNs and FGNs-based architectures, good solvent-dispersibility is required in many cases. GO, Figure 1C (c), is the highly oxidized form of graphene which simultaneously exhibits hydrophobic sp2- and sp3-bonded carbon and abundant hydrophilic hydroxyl, epoxide and carboxylic acid groups, especially on the edge and defects of the nanosheet, thus forming a sheet-like amphiphilic colloid.45 With the help of the hydrophilic groups, GO can stably suspend as amphiphilic colloids in aqueous and many polar solvents. Due to the abundant residual sp2-bonded carbon on the GO basal plane, GO is capable of π-π interactions with aromatic molecules. The polar chemical groups, hydroxyl, epoxide, and carboxyl acid, on basal plane enable GO to undergo weak interactions, for instance hydrogen bonding or strong electrostatic interactions and metal ion complexes, which also provide abundant chemically reactive groups for surface anchoring/grafting of polymers or nanoparticles. The amphiphilic sheet-like properties allow GO to interact with lipid membranes and also be used as a surfactant reagent to react with many other molecules and nanomaterials.45 Furthermore, in many cases, GO is fabricated from crystalline graphite with strong oxidation reagents followed by aqueous sonication, with the result that there are many defects on GO sheets. This promotes surface adsorption and anchoring of molecules or proteins, in spite of the fact that GO has decreased mechanical, electrical, and thermal performances compared to graphene.46 RGO, Figure 1C (d), can be obtained by reducing GO with thermal, chemical, and irradiation methods. Compared to graphene and GO, RGO has more balanced physical and chemical properties regarding solvent dispersibility, surface chemical groups, and electrical, optical, mechanical, and thermal performances. GQDs and GOQD are nanometer-sized single1828

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1829

RGD anchored on CD modified RGO thermal reduced RGO

polydopamine reduced RGO nanocomposite and hydrogel dopamine conjugated heparin modified GO and RGO poly(N-isopropylacrylamide)-GO composite hydrogel sodium styrenesulfonate modified GO hydrogels polyaniline modified RGO nanocomposite polypyrrole modified RGO poly(3,4-ethylenedioxythiophene) modified RGO Au, Pt nanoparticles immobilized RGO composites mineralized RGO and polymer-RGO composites

poly-L-lysine

RGD peptide targeted sugar ligand

polydopamine and dopamine conjugated polymer

CaCO3, Ca5(PO4)3(OH) inorganic nanoparticles

Au, Pt nanoparticles

conductive polymers

poly(Nisopropylacrylamide) sulfated polymers

calcium phosphate mineralized chitosan-GO composites poly-L-lysine adsorbed GO and RGO

chitosan

hyaluronic acid

alginate

DNA

DNA adsorbed on graphene/gold nanocomposites alginate mixed GO composite films; alginate-GO fibers by wet spinning hyaluronic acid decorated doxorubicin-GO nanohybrid hyaluronic acid-GO nanocomposite hydrogel chitosan-GO hydrogel

gelatin adsorbed and reduced RGO nanocomposite RGO and GO modified collagen scaffold collagen modified graphene from graphite by sonication DNA adsorbed GO nanocomposites

gelatin

collagen

bovine albumin adsorbed on GO; blood protein adsorbed on RGO

FGNs

proteins

functional compounds

excellent cell adhesion and viability for neural interface and microbial fuel cells improved cell and bacterial adhesion for advanced electrode

in situ growth in situ growth

in situ mineralization

in situ reduction and growth

attachment and growth of bacteria and the extracellular electron transfer of bacteria on the electrode interfaces were enhanced good cell adhesion ability and osteogenic induction

superior blood compatibility including reduced platelet activation, prolonging clotting times, suppressed hemolysis, highly compatible to endothelial and hepatocyte cells. enhanced electric capacity and bacterial adhesion for fuel cell interface

free-radical polymerization in situ growth

ultrahigh tensibility and exhibit rapid, reversible, and repeatable NIR light-responsive properties

red blood cell compatible and high drug loading ratio

in situ polymerization

multiple interactions

multiple interactions

cyclic RGD peptide is capable of selectively targeting for HeLa cells strong multivalent, selective and reversible adhesion on bacterial surface, excellent bactericidal efficacy under near-infrared radiation. excellent cell compatibility and potential in construction of bioadhesive and bioactive interface

beneficial microenvironment for cell adhesion and growth. BMP-2 encapsulated bovine serum albumin and Ag nanoparticles were adsorbed for enhancement of osteoinductivity and antibacterial properties dual functionalities: inhibition of bacterial growth and enhancing the growth of human cells

good cell compatibility and easily processed into 3D composites

pH-responsive tissue scaffold

enzymatically cross-linking electrostatic interactions, hydrogen bonding electrostatic interactions, hydrogen bonding, in situ mineralization electrostatic interactions, hydrogen bonding host−guest assembly host−guest assembly

increased dispersing stability, cell compatibility, and targeted delivery efficiency of nanocarrier

enhanced mechanical strength, better cell adhesion and viability

near-infrared- and pH-responsive cell adhesion interface by DNA modified graphene/gold nanocomposite

87−89

85,86

83,84

81,82

78−80

76,77

75

74

72,73

71

70

69

68

67

66

64,65

63

62

61

targeted inhibition to cancer cell line excellent dispersity and drug and gene loading ability

60

59

57,58

refs

reduce of cell membrane interaction and improve cell compatibility, enhance the stability in physiological fluids, and increase the drug delivery efficiency enhance the cell adhesion and bone regeneration

reduce of cell membrane interaction and improve cell compatibility

interfacial properties and functionalities

hydrogen bonding

π−π stacking, hydrophobic interaction, and hydrogen bonding hydrophobic interaction, and hydrogen bonding hydrophobic interaction, π−π stacking, and hydrogen bonding hydrophobic interaction, and π−π stacking π−π stacking, and hydrogen bonding π−π stacking, and hydrogen bonding hydrogen bonding

surface interactions

Table 1. Representative Biomolecules, Synthetic Polymers, and Nanoparticles Used for Fabrication of FGNs with Tunable Interfacial Properties and Functionalities.

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Table 2. Representative Interactions between FGNs and Proteins and Biopolymersa FGNs graphene GO, RGOpolydopamine

biomolecule types hydrophobic proteins BSA

GO GO

FBS blood protein

GO GO RGO

ovalbumin growth factors RGD-peptide

GO GO, RGO

glucose oxidase horseradish peroxidase and oxalate oxidase horseradish peroxidase DNA plasmid DNA

RGO GO, RGO RGOpolyethylenimine GO, RGOpolydopamine GO, GO-BSA

binding amount and testing method

adsorption amount and applications

refs

no mention of loading amount, AFM

stabilization of graphene

92,116

∼105 mg/g, fluorescence correlation spectroscopy and fluorescence lifetime imaging microscopy or AFM

binding and conformational studies of protein, surface modification, assembly of multiple nanoparticles mitigation of cytotoxicity mitigation of cytotoxicity for A549 cell

72,117,118

1600 mg/g, protein assay kit and AFM bovine fibrinogen (10 mg/mg); immunoglobulin (4 mg/mg); transferrin (4 mg/mg); BSA (4 mg/mg). Fluorescence spectroscopy no mention of loading amount, AFM not mentioned no mention of loading amount, fluorescence staining

57 98

intracellular vaccine protein delivery controlling stem cells growth and differentiation promotion of cell adhesion on live-cell electrodes for real-time detection of nitric oxide nanocarrier for improving enzyme activity nanocarrier for improving enzyme activity and stability

119 120 121

not mentioned

radical scavenger and redox mediator

125

no mention of loading amount, AFM no mention of loading amount, AFM

surface modification gene transfection study

126,127 128,129

heparin

no mention of loading amount, AFM

72,74,130

lipid membrane and red blood cells

GO (4.4 μg/cm2), GO-BSA (0.2 μg/cm2); quantification of adsorbed blood cells mass by quartz crystal microbalance

enhanced anticoagulant activity, colloid stability and cytocompatibility study of red blood cell adhesion and hemolysis on GO film

not mentioned 1.3 and 12 mg/mg, respectively, enzyme activity and AFM

122 123,124

131

Multiple interactions can be existing at the binding sites, such as hydrophobic interaction, hydrogen bonding, π−π stacking, and electrostatic interaction.

a

2.2. FGNs−Biomolecules Interactions

layer-fragments of graphene and GO, Figure 1C (e and f), which are usually obtained by a top-down approach through “cutting” of graphene or GO nanosheets and typically have sizedimensions smaller than 20 nm in diameter.47 The theoretical and experimental property studies indicate that GQD and GOQD show very closely physical and chemical properties as that of graphene and GO. GQD and GOQD exhibit some unique physical properties, for instance the quantum confinement and edge effects induced optical luminescence, which make them interesting candidates for some new applications.7,48 More recently, GQD and GOQD have been chemically modified and used for biological applications in the area of cell imaging and bioelectrodes.49−54 Besides the above oxidized and small-size derivatives of graphene, surface functionalization of the materials of the graphene family by diverse functional molecules or nanomaterials can also result in abundant graphene based derivatives or graphene based nanohybrids, these fabricated FGNs exhibit similar physicochemical properties as graphene or GO in many ways, i.e., the unique and high specific surface area of 2D planar nanosheet structure, high availability of surface functional groups, tunable electrical conductivity and mechanical properties.55,56 Table 1 shows the most typically used biomolecules, synthetic polymers and nanoparticles that have been used to obtain the FGNs with good biocompatibility and versatile biofunctionality. Due to the diverse and exceptional physicochemical and biological properties of FGNs, it is believed that they can show abundant specific interactions with proteins, bacterial, human cells, and even tissues, for instance the FGNs integrated interface can provide a more favorable microenvironment for cell attachment and proliferation. Therefore, it is of great importance to understand these unique interactions with bioorganisms like mammalian cells and microbials when we study the biological applications of FGNs-based architectures.

Due to the high specific surface area, good availability of functional chemical groups, and unique interface properties, the FGNs possess extremely large capacities for biomolecules adsorption in comparison to many other nanomaterials.90 As a result, when exposed in physiological media or tissue environment, FGN surfaces will be immediately covered by various biomolecules, especially by proteins due to their amphiphilic structures (see Table 2).91 With this coating of biomolecules, FGNs exhibit new properties toward the cells and tissue systems, like changes in hydrophilicity, surface charges, topography, immunological reaction, etc.92 These new characteristics significantly influence the interaction and response between FGNs and organisms.93 Therefore, on the one hand, protein adsorption of FGNs can affect the bioactivities of surrounding cells, including viability, adhesion, proliferation, and even differentiation.94 On the other hand, the protein adsorption can also affect the fates and biological responses of these nanomaterials in biological systems.95−97 Protein adsorption on FGNs can be detected and quantified by atomic force microscopy (AFM),57,98 Raman spectroscopy,99 quartz crystal microbalance (QCM),100 surface plasmon resonance (SPR),98 and electrodes.101 The Zhou group has applied AFM, florescence spectroscopy, and SPR to explore the comprehensive protein adsorption on GO and RGO with four serum proteins, Figure 2.98 By applying the molecular dynamic simulations, it is depicted that the protein adsorption of GO is mainly driven by the π−π stacking due to aromatic protein residues; meanwhile, they also suggest that the hydrophobic interactions of protein structure can also promote the adsorption process. GO exhibits higher protein adsorption capacity when compared with other carbon species. Lee et al. reported that graphene adsorbed approximately 8% of serum proteins, while the polydimethylsiloxane (PDMS) only adsorbed less than 1% under the same conditions.102 Depan 1830

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Figure 2. AFM illustrated interactions between bovine serum albumin (BSA), transferrin (Tf), immunoglobulin (Ig), and bovine fibrinogen (BFG). AFM images of bare-GO (first column) and GO-protein complexes after incubation for 5 (A) and 60 min (B). (C) Corresponding CD spectra of the GO−protein complexes. (D) The simulated molecular dynamic snapshots of BFG adsorption on graphene. Reproduced with permission from ref 98. Copyright 2015, American Chemical Society.

the protein-coated GO shows better cell compatibility than the pristine GO or other pristine carbon species, which indicates the serum protein coating on GO may play a useful role for its biomedical applications.98 Mahmoudi et al. have indicated that the plasma protein coated GO nanosheets can adsorb the amyloid beta fibrillation, a factor that causes the neurodegenerative diseases, more efficiently than the bare GO.107 The protein corona on FGNs is able to improve the therapeutic efficiency of cancer treatments by enhancing the cellular uptake efficacy under laser irradiation-induced reactive oxygen species (ROS).57,108 Protein interactions with graphene and FGNs also facilitate the design of advanced and highly sensitive biosensors and therapeutic systems. The targeting species (e.g., peptides, avidin−biotin, antibodies, and aptamers) can be easily anchored onto graphene or FGNs through noncovalent or covalent conjugation.94,109,110 Besides the protein interactions, the graphene, GO, and other FGNs species can also interact with other biomolecules,111,112 such as the DNA, RNA, enzyme, lipid membranes, as shown in Table 2, by a similar manner as protein adsorptions when they are exposed with cells and tissue. After the surface adsorption of different types of functional biomolecules, the FGNs exhibit either better cell compatibility or enhanced biofunctionalities for diverse applications.112−115

et al. have indicated that GO-hybridized chitosan composites adsorb a large amount of proteins that uniformly spread on the material surface with small globules due to the increased hydrophilicity and multi-interactions between the hybrid scaffolds and proteins.103 As for the RGO, Shi et al. report that the ratio of surface oxygen in RGO plays a strong influence on protein adsorption.104 Quantitative measurements indicated that the amount of adsorbed fetal bovine serum (FBS) on moderately reduced RGO was much higher than on nonreduced GO, highly reduced RGO, and glass slides. Thus, the moderately reduced RGO exhibited the best performance on cell attachment, proliferation, and phenotype. More recently, Zhou et al. demonstrated that the blood protein adsorptions onto the GO and RGO were higher than that on the singlewalled carbon nanotubes (CNTs).98 Encouragingly, the functionalization of GO surfaces with protein species will result in less cellular toxicity than nonfunctionalized GO and protein-adsorbed CNTs, which suggests the surface blood protein adsorption may enhance the cell compatibility of FGNs and FGNs hybrid architectures.105,106 For many biological applications, the surface adsorption of graphene or the existence of graphene−protein interactions can be extremely useful. The Zhou group shows that the GO induced protein adsorption is accompanied by substantial changes in protein secondary structure, Figure 2C; however, 1831

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human hepatoma HepG2 blood cells, L929 cell line, EAHY926 cell line mouse embryo fibroblasts 3T3

graphene

1832

male C57BL/6J mice

offspring mice

mice

healthy female balb/c mice

GO

carboxylated GQD

GQD

kunming mice

GO with differing oxidation states

GO

graphene

chitosan-GO

GO

poly(lactic acid) modified GO and graphene GO

A549 adenocarcinoma cells mouse peritoneal macrophages MC3T3-E1 mouse preosteoblast cell line C57BL6 mice

hippocampus cell

FGNs species

graphene

nitrogen doped graphene

cell line or animal model used for toxicity studies

CCK-8 assay, membrane integrity, apoptosis assay, ROS assay lactase dehydrogenaseassay test, protein expression, lysosomal membrane destabilization MTT, cell morphology and mineralization

0, 10, 25, 50, 100, 200 μg/ mL, 24 h 0, 1, 5, 10, 50 μg/mL, 24 h

20 mg/kg; 14 days

directly drank GO solution at 0.5 and 0.05 mg mL−1; 21 days GQD nanoparticles (5 and 10 mg/kg); 22 days

50 μg per mouse (24 h and 7 days) 0.1 mg (low), 0.25 mg (medium), 0.4 mg (high) doses. (1, 7 and 30 days) 0.5 mg and 0.05 mg of GO per mouse, 3 days, 7 days, 14 days, and 1 month

CS-1 wt % GO, CS-3 wt % GO, 14 days

injection, blood chemistry tests and complete blood panel analysis, histological analysis

intravenously administered, blood biochemistry tests, histological analysis

implantation in subcutaneous and intraperitoneal tissue sites, subcutaneous tissue observation, monocytes and macrophage percentages mouth feeding, serum biochemistry data, comparison of isolated organs

pharyngeal aspiration, intrapleural injection, histological examination the lungs and heart intravenous injection, histological examination of lungs, spleen and liver

MTT, platelet adhesion and activation

100 μg/mL, 7 days

1 μg/mL, 48 h

1, 5, 10 μg/mL, 72 h

cytotoxicity assays MTT, lactase dehydrogenase assay, expression of growth-associate protein-43 MTT and protein profile change after exposed with graphene cell adhesion, platelet-adhesion assays, and hemolysis test

100 μg/mL, 7 days

dosage and test time

ref

49

165

147

GO could induce many problems to the filial mice; long-term exposure with GO can cause abnormal development carboxylated GQDs will accumulate in the spleen, liver, kidney, and tumor; no obvious toxicities were observed at different dosage (5 and 10 mg/kg); no severe inflammation symptoms in the spleen, liver, kidney, heart, or lung GQD could be metabolized quickly through kidneys, GO-PEG showed some in vivo toxicity and accumulation in reticuloendothelial system; in contrast, GQD-PEG presented good biocompatibility to the mice, the mice growth, organ appearance and slices, as well as hematology and blood chemistry analyses is normal

151

157

161

178

177

176

175

174

173

172

GO is moderately compatible in vivo in both tissue sites by the inflammatory response, the lower GO oxidation degree results in faster immune cell infiltration, uptake, and clearance

no obvious toxicity signs with low and medium doses, dose dependent lung inflammatory response (high dose), and accumulation in lungs, spleen and liver.

inflammatory reaction and granuloma formation were observed with both types of injections

carbon-based nanomaterials will induce autophagosome accumulation, cause the decrease of autophagic degradation and lysosomal impairment, which indicate caution on their utilization chitosan modified GO network favorably modulated the biological response of osteoblasts

GO will increase oxidative stress; influence of GO on A549 cells is dependent on the GO dose and size

no considerable variation in cell proliferation was observed for the composite film, while GO results in a significant cell toxicity

CNTs severely interfered the intracellular metabolic routes, protein synthesis and cytoskeletal systems; graphene generates moderate influence on protein expression of cells assays indicate that nitrogen doped graphene exhibits lower platelet adhesion and longer blood-clotting time than bare graphene

biocompatible and capable of promoting neurite sprouting and outgrowth

conclusions

Table 3. Summary of the Representative in Vitro and in Vivo Toxicity Studies of the Graphene, GO, and Other FGNs Species.

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Figure 3. (A) Simulation of how graphene sheets enter cell membrane. (a1−d1) Typical interaction states between a lipid bilayer and graphene. (a2−d2) The corresponding thickness fields for the systems of (a1−d1). The color bar shows thickness of the bilayer. Reproduced with permission from ref 134. Copyright 2014, Elsevier. (B) Simulation of GO and lipid bilayer interface when nanosheet lays flat initially at the membrane center; (b) final configurations of 200 ns; (c) side views of water distributions; (d) top views of lipid bilayers with a water pores pointed by black circles. Reproduced with permission from ref 135. Copyright 2016, American Chemical Society. (C) Representative illustrates for BSA-coated graphene induced lipid membrane extraction. (a−c) BSA-coated graphene on lipid membrane. (d−f) Pristine graphene on lipid membrane. (a and b) Initial configuration. (b and e) Early stages of lipid extraction with a 10% coverage of graphene. (e and f) Late stages of lipid extraction with maximum coverage of graphene. BSA is depicted with ribbons. Green color indicates the lipid extracted on the graphene. Reproduced with permission from ref 182. Copyright 2015, Royal Society of Chemistry.

2.3. FGNs−Mammalian Cell Toxicity and Interactions

stays at the water−membrane interface due to the amphiphilic structures. GO is also found responsible for the resulted membrane pore formation and water molecules flowing, which indicates that the shielding of hydrophobic domains of GO by hydrophilic polymers can reduce its toxicity (Figure 3B).135 Another path of cell membrane damage by FGNs is the extraction of phospholipids from the lipid bilayer due to the strong adsorptions between FGNs and lipid molecules.136,137 The direct contact and endocytosis of FGNs will both induce oxidative stress and ROS.138 To figure out the complex processes of GO-induced oxidative stress in living cells, Mokhir and co-workers studied different redox-active groups modified GOs, such as the Mn2+ ions, C-centered radicals, and endoperoxides.139 Their study reveals for the first time that endoperoxide can generate a significant reactive oxygen species by using human cervical cancer cell line as a model system, which indicates that the surface-bound endoperoxide groups

According to the existing literature, as summarized in Table 3, the primary cytotoxic mechanism between FGNs and cells is the direct contact between the cell membrane and FGNs and indirect oxidative stress induced by the contact.31,132 After exposed with live cells, monolayer or few-layer FGNs can cut and penetrate cell membranes during the “edge-to-face” contact,133 thus resulting in directly physical membrane damage. As shown in Figure 3A, Yan et al. have validated that the graphene−lipid bilayer interactions include four typical states: (a) graphene-sandwiched superstructure, (b) graphene adhering to the membrane, (c) graphene lying across the membrane, and (d) hemisphere vesicle structures, which also highly depend on the oxidization degree and size of graphene.134 Chen et al. further demonstrate that graphene can diffuse easily into the cell membrane due to hydrophobic interaction by using simulation method.135 While, GO cannot pass the lipid bilayer within short simulation time period, which 1833

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In vivo toxicity studies have also been carried out, and recent toxicological studies have used the mouse or zebrafish models to evaluate the potential harm that FGNs may cause in human health, as shown in Table 3. Both the graphene and GO exhibit a certain toxicity to the organs of mice and zebrafish, which lead to critical concerns for using these materials as nanocarriers or implantable composites.152 The currently developed pharmacological assessment of small and large animal models can be classified in the following modes: intravenous, intraperitoneal, oral, pulmonary, and intravitreal administration.153 Intravenous administration is a perfect and systematical mode to examine the in vivo side effects of GO or FGNs in such applications as imaging, drug delivery, or photothermal therapy. Singh et al. reported that GO was more effective than RGO toward platelet activation and pulmonary thromboembolism due to the high surface charge density upon oxidation.154 Zhang et al. compared the distribution of GO in mice with other carbon nanomaterials after intravenous injection, and GO showed longer blood circulation time with a 5.3 ± 1.2 h halftime and lower uptake in reticuloendothelial system compared to the other carbon nanomaterials.155 At low dosage, 1 mg/kg, there was no obvious pathological changes in mice organs for 14 days GO treatment. However, at high dosage, 10 mg/kg, significant inflammation cell infiltration, pulmonary edema, and granuloma formation were observed. The intravenously studies of dextran-functionalized GO showed that the dextran-GO could be cleared from mouse liver after 7 days.156 The 125Ilabeled dextran-GO was injected via the tail vein for biodistribution studies, and mouse blood was collected after 4, 24, 72, and 168 h. After 4 h, dextran-GO was found in liver, spleen, stomach, lungs, kidney, and intestine. Later, dextran-GO was mainly found in the liver and spleen. Guo and Cui et al. have reported the GO administered via tail vein injections cause no toxicity to mice for low (0.1 mg) and medium (0.25 mg) doses.157 However, at a high dosages (0.4 mg), 4 out of 9 mice died after 1 week due to the GO accumulation-induced airway blockage. Histology analysis indicated that GO mainly accumulated in liver, kidney, and spleen. Due to the blood brain barrier, no GO accumulation was observed in the brain. These results suggest that GO can become highly toxic at high concentration injections and may lead to irreversible airway damage and chronic pulmonary toxicity. Intraperitoneal administration is another injection method to study the in vivo toxicity of GO or FGNs.158 Kostarelos and coworkers used the highly pure and stable dispersions of GO, up to 50 μg/animal, to study the in vivo pathogenicity by intraperitoneal injection.159 After 1 day, pure GO did not show any influence on the amount of polymorphonuclear leucocyte and protein levels, whereas the control group of CNT induced at least a 2-fold increase in the total number of polymorphonuclear leucocytes. After 7 days, the control group of CNT induced accumulation of giant cells and macrophages with a deposition of collagen on the mesothelial membrane. However, the pure GO did not induce such side effects. Strojny et al. have carried out the intraperitoneal toxicity studies of GO, graphite, and nanodiamonds on female mice with a dosage of 4 mg/kg.160 The study showed that the injected nanoparticles mainly aggregated in the peritoneal cavity close to the injection site. Some smaller aggregates were observed in the liver, but the blood analysis and liver enzyme levels were normal, so no obviously adverse health effects were observed for GO, graphite, or nanodiamonds at 4 or 12 weeks.

are responsible for the GO-induced oxidative stress and cytotoxicity.139 Normally, in live cells, the antioxidant system can metabolize the produced ROS. However, excessive amounts of ROS may cause subsequent cell apoptosis through a number of pathways.140,141 Another important toxicity mechanism is the interference with or damage on DNA or RNA. Although, the unique and strong interactions of FGNs and gene molecules had endowed them great possibility as nanocarriers for gene delivery,142 it should not be ignored that the FGNs may induced potential DNA and RNA damages of normal living cells.143 In some cases, though, the graphene or GO flakes are found to be no obvious impact on cell viability, it may exhibit significant influence on cellular signaling transmission and network functionality.144 Thus, for the future examination of graphene induced toxicity, the complex cellular biofunctionalities should also be carefully studied rather than simple tests on cell viability. In the case of the industrial production of graphene or GO powder, the pulmonary toxicity is one of the major concerns due to the lightweight and respirability nature of graphene, which may cause lung accumulation, damage, and eventually chronic diseases.145 The graphene and GO powder can cause severe and persistent injury in the lungs by inflammatory responses in mice.146 Another risk of using graphene is their carcinogenic and teratogenic potential,147,148 but the available data is not sufficient to allow these nanomaterials to be defined as “potentially carcinogenic to humans” with reasonable certainty. In fact, it is difficult to conclude the general toxicity beheviours for graphene since many parameters need to be taken into consideration when graphene and FGNs are tested for toxicity in vitro and in vivo. Fundamentally, not only the physicochemical and morphological characteristics, but also the application dosages and protocols of each type of materials should be counted and described, which can avoid any bias when describing the toxicity of graphene and FGNs. For example, the inflammatory toxicity of graphene can be closely influenced by their nanosize and surface functionalization. Xia and Liu et al. have demonstrated that GO exhibits lateral-size-dependent proinflammatory effects both in vitro and in vivo.149 They found that large-size GO exhibited higher adsorption ratio on cell membrane due to the stronger binding with toll-like receptors and serious activation of NF-κB pathways. By contrast, smallsize GO results in higher cell-uptake. Therefore, large-size GO induces more macrophage polarization and produced inflammatory cytokines and recruitment of immune cells. Huang and Fan et al. also discovered that ultrasmall GO, less than 50 nm, exhibited lower cytotoxicity but higher cellular uptake ratio than the large GO, which indicated that reducing the size of graphene could achieve better biocompatibility.150 In another recent report, Langer group indicates that GO with different oxidation degrees will elicit different intensities of tissue inflammatory responses.151 Low GO oxidation resulted in a more rapid immune cell infiltration, uptake, and clearance from the injection site following subcutaneous implantation, thus demonstrating less chronic inflammation. GO with higher oxidation would cause increased accumulation of monocytes and an enhanced pro-inflammatory environment. Therefore, it is essentially important to compare the different types of nanomaterials of the graphene family and correlate their different influences on cellular toxicity and physiological process. 1834

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graphene and GO may not be suitable for the prediction of in vivo biocompatibility of the other modified graphene species. The recent findings also suggest that graphene and GO are biodegradable when exposed to various types of peroxidases,166−171 which makes it another positive factor that needs further consideration when assessing the long-term safety of nanomaterials in graphene family. The above-mentioned toxicity studies make FGNs a potential threat to human health when they are exposed in cells and tissues, especially the nanodispersed GO and RGO.49,143,179 After surface functionalization, the physical cell-membrane interaction, oxidative stress, and interaction with DNA and RNA will decrease to a certain degree.74,180,181 Ge and Zhou et al. have used molecular dynamics simulations to validate that BSA adsorption will weaken the lipid−graphene interaction due to the reduced surface area availability. This will also significantly reduce the graphene-induced membrane penetration and damaging of lipid bilayer (Figure 3C).182 However, long-term toxicity and chronic damage on cells and tissues still need to be carefully considered for cell uptakerelated applications with nanodispersed FGNs, i.e., drug and gene delivery, cellular imaging, and other injection therapies. When using FGNs-based composite materials for biological applications (especially the stem cell engineering, implantable scaffold, and MFCs), the strong interactions between FGNs with lipids, DNA, and RNA can be reduced or avoided, because of the FGNs can function as a matrix that supports cell adhesion and growth through “face-to-face” contact.183 In this case, the edge structures of FGNs do not penetrate into the cell membrane with the result that the explosion and disruption of cellular biomolecules in cells will also decrease. Last but not least, there is also less toxicity because of the adsorbed extracellular protein.184,185 As summarized in above section on different in vitro and in vivo toxicity studies of graphene and its derivatives. The available results and investigations validate that this emerging nanomaterial exhibits potential toxicity to different tissues and organs. However, there is strong evidence that the toxicity risks are manipulative by diverse surface functionalization and sizeregulation. And also, the toxicity is highly dependent based on their applications, relatively low toxicities are reported in applications of FGNs-based composites, electrodes, and external usages. Therefore, a general toxicity conclusion of graphene and FGNs should be avoided since the related toxicities associated with them were highly dependent on their characteristics and specific applications. Hence, the long-term evaluations of specific graphene or FGNs-based materials based on their applications should be studied both in vitro and in vivo to further validate their biocompatibility and potential toxicity.

The oral administrations of GO on developing mice offspring have also been done by Fu et al. at doses of 0.5 and 0.05 mg/ mL to maternal mice.147 It was found that a significant decrease in body weight, body length, and tail length of filial mice was observed at doses of 0.5 mg/mL compared to the control groups that received normal water. The pathological examination of heart, lung, spleen, kidney, and liver of filial mice treated with 0.5 mg/mL GO suggested that severe atrophy occurred. This indicates that GO can have significant negative effects on the development of filial mice during the lactation period. Similarly, Chu and Xu et al. investigated how the RGO affected the general locomotor activity, neuromuscular coordination, balance, anxiety, learning, and memory of male mice over a short-term and long-term period using oral administration.148 It was validated that the RGO-treated mice maintained normal body/organ weights and instinctive behaviors compared to the control group. However, their studies show that a short-term decrease in neuromuscular coordination and locomotor activity will result when a high concentration of RGO is exposed to mice via oral administration. Then, it can return to normalcy after a few days, which does not affect learning, memory, anxiety, spatial, and exploratory behavior in mice. It was also observed that the graphene, GO, and FGNs could generate severe pulmonary issues via intrapleural and pharyngeal administration in a mice model, which could eventually lead to frustrated phagocytosis in lungs.161 Duch et al. have also reported on the pulmonary toxicity of different graphene species via intratracheal instillation to male mice at 50 μg/mouse dose.146 It is reported that highly dispersed pluronic copolymer-modified graphene can induce lower fibrotic lung inflammation and persistent lung injury compared to aggregated graphene and GO. The Fan group has systematically studied the in vivo distribution and pulmonary toxicity of GO for up to 3 months by using a mice model.145 It is found that GO can lead to acute lung injury and chronic pulmonary fibrosis, which is highly related to oxidative stress. They also suggest that dexamethasone treatment is effective to relieve the GO resulted symptom. For the intravitreal administration, Liu and co-workers evaluated the ocular toxicity of GO after intravitreal injection in rabbits at doses of 0.1, 0.2, or 0.3 mg per animal.162 They found that GO did not have any effect on the corneas, interior media, posterior media, and the retina compared to the control group. Compared to the controls, GO administration did not result in any significant changes in electroretinography amplitudes at different time periods. Recently, graphene and FGNs have also been proposed to be safe materials for different eye-contacting applications.163,164 However, there is still a lack of comprehensive reports on the in vivo toxicity of polymers modified FGNs, more in vivo studies are needed to conclude their application potentials. Fan and Zhang groups have shown that PEG modified GO still exhibits certain in vivo toxicity, the PEG-GO accumulates in reticuloendothelial system both from dead or surviving mice.49 However, the PEG modified GQD shows much better biocompatibility from the results of mice growth, organ appearance and slices, as well as hematology and blood chemistry analyses, Table 3. Lee et al. also show similar results,165 these findings indicate that the GQD may be a much safer platform than GO for applications in cell-imaging, biosensing, drug/gene delivery, and tissue engineering. It has been validated that the surface modification of graphene and its derivatives can significantly reduce their cytotoxicity impact.29,72,74 Therefore, the established toxicity theory for

2.4. FGNs−Stem Cell Interactions

Since the interaction between stem cells and graphene is more complicated than that for normal cells, we will discuss this type of interaction separately. Besides the toxicity concerns, the literature has revealed that FGNs have a lot of positive influence on the adhesion, growth, and differentiation of stem cells,25 for instance their significant ability to absorb ECM proteins.186 Furthermore, the physicochemical properties and nano-topographies of FGNs films or 3D architectures will significantly improve the formation of focal adhesion points, the large protein complexes connecting stem cells and the ECM, which act as a key role on controlling the cell adhesion and migration.187 Additionally, FGNs can affect the stem cell shape 1835

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Figure 4. ROS-mediated deterioration for the adhesion, viability, and paracrine factor secretion of GO flakes protected MSC in vitro. H2O2 is used as the model of ROS substance. (A) F-actin staining of MSCs and MSC-GO adhered onto TCPS plates after culture in the medium containing no H2O2 (NT)) or 200 μM H2O2. Scale bars: 10 μm. (B) Left: calculated live cells number from A; right: relative live cell numbers after 24 h. (C) GO flakes adhesion on MSCs labeled with red dye. Nucleus (blue). Cell membrane (green). Scale bar: 20 μm. (D) TEM image of GO flakes (arrows) adhered MSC. Scale bar: 20 μm. (E) Schematic illustration of GO flakes protected MSC from H2O2 induced anoikis signaling. (F) Expression of integrin β1 evaluated by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), which indicated that GO protected MSC could inhibit ROS-mediated deterioration. (G and H) Expression of activated intracellular signaling molecules related to MSC anoikis. *p < 0.05 compared to any group; n = 3. Reproduced with permission from ref 197. Copyright 2015, American Chemical Society.

Meanwhile, the other physical properties can also influence stem cell adhesion, growth, and differentiation. The high stiffness of FGNs-based substrates promotes the speed of osteogenic differentiation, and the high electrical conductivity endows signaling stimulation to encourage neural stem cell (NSC) growth and differentiation.191 Besides the above influences, FGNs may also interfere with the biological process during the growth and differentiation of stem cells. FGNs can adsorb not only normal serum proteins but also various growth factors and mediators during stem cell expression and differentiation,192 which make FGNs-based architectures different from traditionally used substrates, like poly(lactic acid) (PLA), polystyrene, and PDMS.193,194

due to the formation of focal adhesion points, thus endowing them with more noticeable filopodia extensions and cellular protrusions.188,189 The electric charge, mechanical stiffness, ripples, wrinkles, and porous structures of FGNs and FGNs hybrid architectures also play important roles in stem cell physiological regulation. Wang and co-workers indicate that the surface charges of FGNs can regulate the neurite outgrowth and branching. The positively charged GO provides a more beneficial environment for neurite outgrowth and branching when compared with zwitterionic, negatively, or neutral charged GO.190 Recent studies have revealed that nanostructured and microrough topographies of FGNs-based architectures can be used for mediating stem cell differentiation. 1836

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Figure 5. (A) Chemical structures of adamantyl-functionalized graphene derivatives (AG4) and heptamannosylated ß-cyclodextrin (ManCD). The schematic illustration of ManCD@AG4 complexes and its bacterial binding ability. (B) TEM images of the ManCD@AG4 hybrid captured bacteria. (C) Confocal images of ManCD@AG4 incubated with E. coli. (D) (a) Schematic image of ManCD@AG4 induced bacterial killing via NIR irradiation. (b) Thermal image of a ManCD@AG4-E. coli sample under NIR irradiation. After 10 min, the temperature increased to 70.9 ± 1.4 °C. (c) Temperature profiles of the ManCD@AG4-bacteria added or control sample. Reproduced with permission from ref 225. Copyright 2015, American Chemical Society.

damaged and some bacterial cytoplasm was even entirely missing.136 This phenomenon should be attributed to the amphiphilic structures of GO, which was similar to the interactions between FGNs and mammalian cells. Another study indicated that GO could generate oxidative stressmediated antibacterial activity to Pseudomonas aeruginosa.203 After reduction, RGO showed decreased inhibition in bacterial viability, but it still induced oxidative stress that affected the bacterial activity. However, a recent study has questioned the antibacterial properties of GO and suggests that the purity of GO may determine its antibacterial activity.204 The study also found that GO neither inhibited nor stimulated the growth of bacteria, for both E. coli and S. aureus, even at concentrations of up to 1 mg/mL after GO was highly purified and thoroughly washed. While, the insufficiently purified GO could act as an antibacterial reagent due to the existence of soluble acidic impurities. These conflicting results encourage additional investigations on the interactions between GO or RGO on microorganisms. When macroscale-sized FGNs hybrid architectures were used, there was no obvious bacterial toxicity since the strong interaction between the bacterial membrane and FGNs sheets was greatly decreased due to the “face to face” contacting manner. Moreover, FGNs have also been used as a delivery vehicle to promote antibacterial ability.76,205−213 The specific properties of FGNs made them ideal candidates for designing antibacterial materials to prevent infections from wound healing or external injuries.212,214−218 On the contrary of antibacterial, FGNs can also be applied as a platform for bacterial adhesion in diverse applications, such as pathogen detection, bioreactors and MFCs.219−224 More recently, Qi, Seeberger, and Haag et al. demonstrate that mannose ligands conjugated FGNs provide a new platform with multivalent adhesion of specific bacteria.225

Furthermore, FGNs may also protect the stem cell from hazardous or toxic molecules.195,196 Poor survival of stem cells after implantation has significantly limited their therapeutic efficacy. One of the reasons for this is primarily due to the ROS generated in the traumatic tissues. ROS can cause the death of implanted stem cells by inhibiting the adhesion of the stem cell to extracellular matrices at the lesion site (i.e., anoikis). Kim et al. have found that GO flakes can be used to protect the implanted mesenchymal stem cells (MSCs) from ROSmediated death by a “face to face” contact manner (Figure 4).197 During the coculture of GO with MSCs, GO adsorbs abundant ECM proteins on its surface. Thus, when MSCs and MSC-GO are subsequently exposed to ROS media in vitro or implanted into the ischemia-damaged and reperfused myocardium, the engraftment of MSC was improved due to GO flakes adhesion on MSCs prior to implantation, which in turn promotes cardiac tissue repair and function restoration. 2.5. FGNs−Microbial Cell and Virus Interactions

Since it has been proven that FGNs can affect the morphologies, metabolism, and viability of microbial cells, FGNs-bacteria interactions have been extensively explored.198,199 The Fan group and many other works have reported that graphene and GO based materials can inhibit bacterial viability.136,198,200,201 The loss of viability may be associated with GO-induced physical damage on bacterial membranes upon direct “edge to face” contact and lipid adsorption, which will result in the release of the intracellular content.136,199,202 Zhou and co-workers have used the TEM to validate a three-staged cell membrane damage from E. coli. At the first stage, the bacteria were tolerant to GO for a short period; then in second stage, the bacterial membranes partially lost their integrity with decreased surface phospholipid density; and then in third stage, the bacterial membranes were severely 1837

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Figure 6. (A) Schematic image of dendritic polyglycerol functionalized TRGO (TRGO-dPG) by “grafting from” method and postsulfation of dPG to synthesize TRGO-dPGS, and corresponding interaction with the virus via a TRGO-dPGS nanosheet. (B) Inhibition of virus infection by TRGOdPG0.8S0.5, heparin and TRGO-dPG0.8 on CPXV BR in Vero E6 cells. (C) Inhibition of orthopoxvirus binding to specific A27 antibodies by different TRGO-dPGS derivatives using inactivated VACV WR tested in an ELISA-based format. The two TRGO-dPG0.8 and TRGO-dPG0.6 precursors served as controls. (n ≥ 3) with ± SD (D) Inhibition of different native orthopoxvirus strains (VACV WR: n = 3, ± SD; VACV IHD-W: n = 2, ± SD; CPXV BR: n = 2, ± SD; MPXV: n = 2, ± SD) to specific A27 antibodies by TRGO-dPG0.6S1.0 was analyzed in an ELISA-based format. Note, CPXV BR (Cowpox Virus Brighton Red), VACV WR (Vaccinia virus, strain Western Reserve), MPXV (Monkeypox Virus), VACV IHD-W (Vaccinia virus, International Health Department-White). Reproduced with permission from ref 244. Copyright 2016, John Wiley and Sons Publisher.

the viability and biocatalytic activity remained stable for at least 15 days, which indicated that the GO−yeast hybrid system was suitable for MFC applications. Viruses present a great threat to both human and animal health worldwide.233 The detection and prevention of viruses are the essential part of infection control.234−237 Since graphene, RGO, GO, and FGNs exhibit physical toxicity associated with the interaction with proteins, the attached proteins always result in changed conformation and denature effects.100,238 The versatile graphene and FGNs nanocomposites may potentially function as novel and promising electrode substrates for the detection and prevention of viruses. The excellent conductivity of CVD-prepared graphene may help to build a virus-sensitive graphene-based electrode. Wang et al. utilize the graphene-Au nanocomposites to electrochemically detect the gene of human immunodeficiency virus (HIV).239 Similarly, silver nanoparticle coated graphene can detect the influenza virus by electrochemical signals.240 GO can also be used to detect the virus gene, Ebola, by applying the fluorescence spectra technique with a detection limit of 1.4 pM virus gene.241 Besides the advantages of potential applications in virus detection, the FGNs can also be used for virus binding and disinfection.242 Wang and Tang groups indicate that GO can efficiently capture viruses and destroy their surface proteins.243 Meanwhile, GO can also extract the viral RNA via using the superficial bioreduction ability of GO in aqueous environment. Recently, as shown in Figure 6, Nitsche and Haag et al. have synthesized a multivalent graphene-based antivirus nanosystem to inhibit the activity of the poxvirus by utilizing the integrated functionalities of flexible graphene surfaces and the multivalent structure, dendritic polyglycerol sulfate (dPGS) mimicking sulfated glycol-structures at the cell surface.244 The synthesized TRGO-dPGS demonstrates efficient disinfection of orthopox-

They assembled the cyclodextrin-based mannose ligands on adamantyl-functionalized thermal reduced GO (TRGO) sheets via host−guest inclusion to fabricate the nanoplatform to capture Escherichia coli (E. coli), as shown in Figure 5.225 Combining the vital recognition role of carbohydrates and the unique 2D large flexible surface area of the TRGO sheets, the addition of multivalent sugar ligands made the resulting carbon material an excellent multivalent scaffold for selectively and reversibly wrapping and agglutinating E. coli. Because of their unusual infrared absorption property, these TRGO derivatives exhibited excellent bacteriostatic properties (>99% elimination) following NIR laser irradiation of the graphene−mannose−E. coli complexes. Furthermore, this study validates the remarkable capacity of functionalized graphene on control microbial behaviors due to its large surface area and flexibility to wrap large-sized microorganism. The integration of multivalent, supramolecular binding on graphene provides a new strategy for protection against bacterial infection as well as a new method for designing selective bacterial adhesion interfaces, e.g., as pathogenic blocking nanomedicine or detecting electrodes.226−229 The interaction between graphene and yeast cells has been explored in addition to bacterial adhesion.230 Maheshwari et al. have shown that depositing FGNs can form an electrically conductive layer on the surface of yeast cell, which eventually leads to electromechanical coupling at the electrode surface.231 The yeast cells revealed decreased cell volume and increased surface roughness when exposure to alcohols environment. The graphene-based electrical signal was then applied to detect the response caused by physiologically stressing. This makes the FGNs-microbial interaction an ideal platform for developing bioelectrical devices or sensors to detect the molecules and study cellular response. GO hydrogels have also been applied to encapsulate Saccharomyces cerevisiae (S. cerevisiae) yeast.232 Both 1838

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Figure 7. (a) Schematic image of the CVD prepared graphene layer on nitinol alloy. (b) Surface SEM morphology of nitinol alloy and graphene layers coated at (c) 950, (d) 1000, and (e) 1050 °C. (f) Immunofluorescence assay to detect the generation of osteocalcin. Actin cytoskeleton, green; osteocalcin positive area, red; nuclei, blue. Reproduced with permission from ref 251. Copyright 2015, American Chemical Society.

not only exhibits excellent mechanical and electrical properties but they also show a chemically reactive surface, which makes them favorable candidates for designing unique 2D architectures in tissue regenerations. Ö zyilmaz et al. have reported that graphene deposited with the CVD method can provide a promising biocompatible scaffold for adhesion and growth of MSCs and accelerate their osteogenic differentiation.188 The coated graphene can also enhance the generation of osteocalcin, a typical protein marker to indicate the osteoblast, and promoted deposition of calcium in MSCs. The rate of graphene induced osteogenic differentiation is similar to that of BMP-2 induced. It is suggested that the graphene layer allows a noncovalent binding of protein nutrition and osteogenic growth factors on its surface via electrostatic interactions, hydrogen bonding, or π-π stacking, thus promoting the adhesion and differentiation of MSCs. Furthermore, it has been found that the surface oxygen contents of FGNs influence the osteogenic differentiation due to the changed interaction between FGNs and proteins or growth factors.104,188 Recently, Di and Liu et al. report that graphene coating on a nitinol shape-memory alloy can also accelerate osteogenic differentiation of MSCs for potential dental and orthopedic applications, Figure 7.251 Meanwhile the obtained graphene multilayers treated at different temperature also affect the adhesion, proliferation, and osteogenic differentiation process. Their results indicate that the CVD coating of a graphene layer can be a highly effective approach for improving the interfacial biological properties of dental and orthopedic implants. Similarly, they further indicate that the directly in situ deposition of large-area graphene film by the CVD method on a germanium (Ge) substrate.252 It is validated that the graphene film-modified Ge alloy can promote the gene expression of osteogenic markers from MSCs, which confirms

virus with an inhibition of VACV IHD-W up to 80% and CPXV BR up to 50%, while free dPGS shows no effect on virus inhibition, which indicates that large sheet-like inhibitors can be more effective on preventing the adhesion and infection of the pathogen. The better inhibition efficiency should be associated with the larger contacting area at graphene interfaces; meanwhile, the unbound sections of graphene sheet will block any further interactions of entrapped virus with other biological interfaces.227 Therefore, it is believed that such 2D sheet-like, multivalent FGNs can be potentially used to capture larger viruses with more complex structures and virulent behavior.245−249

3. FGNS-BASED 2D-LAYERED COMPOSITES 2D-layered coatings or films, which enable cells to adhere, proliferate, and differentiate, are important for the development of bioelectrodes, coating materials for implants, and suitable scaffolds for tissue regeneration. Recent advancements have revealed that FGNs-based 2D substrates promote the adhesion and proliferation of diverse cell lines, such as the endothelial cells, fibroblasts, human osteoblasts, hepatic cells, stem cells, and bacteria.250 It has been found that endothelial cells can fully spread on FGNs-based multilayer coating, while lower cell adhesion and growth ratio are obtained on a pristine polymer substrate.77 Human osteoblasts also adhere well to the FGNsbased substrates with a confluent monolayer of normal fibroblast-like morphology, whereas they exhibit separate round-shaped cells on silica surfaces.188 3.1. Atomic or Multilayer Graphene on 2D Interfaces

Atomic or multilayer thickness of graphene on 2D interfaces are mainly fabricated by CVD methods on catalytic metal substrates (Ni, Cu).2,3 The CVD prepared graphene sheet 1839

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Figure 8. (A) (a) Schematic image of a graphene-based FET electrode. (b) Optical microscopy image with eight transistors in the electrode. (c) Transistor current vs electrolytic gate voltage for eight different devices and corresponding transconductance vs gate voltage (d). Reproduced with permission from ref 259. Copyright 2011, John Wiley and Sons Publisher. (B) (a) TEM image of hRGO. (b) Schematic picture of the modified hRGO-based FET device for selective detection of E. coli due to the covalently functionalized antimicrobial peptides. (c) Comparison of the mean normalized responses of four functionalized carbon nanomaterials to E. coli at a concentration of 107 cfu/mL. pSWNTs: pristine single-walled CNTs; oSWNTs: oxidized single-walled CNTs. Reproduced with permission from ref 265. Copyright 2014, American Chemical Society.

their good cell compatibility. Meanwhile, the graphene layer coated surface also shows better antibacterial activities. The proposed method may provide novel insights to functionalize the Ge-based medical implants or electrodes to meet clinical needs better. Besides the influences on MSCs, Hong and coworkers have discovered that the CVD-prepared graphene multilayer can also significantly enhance neuronal differentiation of human neural stem cells (hNSCs).191 The graphene layer serves as an extraordinary biofunctional platform during the long-term differentiation process of hNSCs, and it can promote hNSCs to differentiate more toward neuronal cells than the glial cells. Interestingly, it was also proven that the graphene layer revealed excellent electrical coupling with adhered neurons for electrical stimulation. Due to the high special surface area, good electrical conductivity, facile surface modification, and strong interaction between the graphene and cells, it is expected that this bioactive platform can be further applied for various intrinsic applications in bioelectrodes,253−255 for instance, detecting cancer cells as well as pathogens, which have been examined using the CNTbased electrodes for cell capture and signal detection.256,257 Qu et al. have reported using a graphene-based electrochemical aptasensor to detect cancer cells.258 By taking advantage of AS1411 (clinical trial II aptamer), high specific binding affinity to the overexpressed nucleolin on the surface of cancer cells, the fabricated aptasensor can effectively differentiate cancer cells from normal cells. The detection limit of this sensor can be as low as one to a thousand cells. With the assistance of DNA-hybridization-technique, this proposed protocol of graphene-based electrochemical aptasensor can be regenerated and reused for detecting cancer cells. Since graphene exhibits high capability and sensitivity to generate strong coupling with cell membranes, the graphenebased field-effect transistors (FETs) can also be applied for detecting cancer cells.259,260 The Garrido group has reported their use of graphene solution-gated FETs for detecting electrical activity of the electrogenic cell (Figure 8A).255,259

The arrays on FETs are obtained from CVD-fabricated large area graphene films on copper foil. Then, the action potentials of cardiomyocyte-like cells are detected by the underlying graphene based transistors, thus it is possible to record and analysis of the cellular signals of any adhered cells. This nanotechnology enables electrodes to detect minor changes of individual cells, which is a novel and complementary way to diagnose disease, such as cancer cells. How to detect early stage cancer cells from the abundant normal cells still needs to be addressed, whereby an accurate probing of these cancer cells is critically important for achieving such sensitive electrodes.261 Pathogen detection is another hot research area for atomic or multilayer graphene-based electrodes.262,263 During the last century, the pathogenic contamination and resistant infections have arisen as enormous attention in both the clinical and food industry fields, but there has been a lack of highly sensitive, cheap, and portable methods to detect them. As earlier as 2008, Mohanty et al. found that the graphene-based electrochemical device was able to detect bacteria due to its conductive, flexible, and adhesive nature.264 Later, Star and co-workers discovered that the antimicrobial peptides functionalized holey RGO (hRGO) could act as a selective and highly sensitive platform for bacterial detection, Figure 8B.265 The fabricated hRGObased FET devices are able to selectively detect bacteria due to the immobilized antimicrobial peptides, which can recognize target pathogens by interacting with surface components of microbial cells. This study indicates that both the good electronic conductivity and specific FGNs-bacteria interactions are important for designing pathogen detection electrodes. By switching the anchoring functional molecules, it is possible to achieve a specifically targeted or more broad pathogen detection.266 3.2. FGNs-Based Biointerfacial Coatings

3.2.1. General Strategies for FGNs-Based Interfacial Coatings. Coating FGNs onto interfaces may endow these materials with better physiochemical and biological properties, 1840

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especially the strong bioactivity of interfacially coated FGNs. Meanwhile, most FGNs are flexible, especially GO, RGO, and polymers grafted GO/RGO, and can adapt to any dimensionally solid substrate.267 Besides the CVD growth and deposition of the graphene layer, solution-based interfacial coating of FGNs is more universal and cost-effective. Direct drop casting is one of the simplest methods for preparing FGNs-based thin films on the substrates. Spin coating is another kind of convenient solution-based method for producing interfacial thin film coatings.268 Typically, a dispersion containing FGNs is dropped onto the substrate. A certain thickness of coating film can be obtained after that by controlling the rotation speed and time.269 Similar to spin coating, spray coating is another highly efficient method for coating the surface with FGNs layer. Via the assistance of an air spray gun, the dispersion containing FGNs can be quickly and uniformly sprayed onto the substrates, which allows large-scale coating of the biointerface.270 However, accurate spray techniques and modified substrates are required to control the thickness and surface roughness. Dip coating is another favorable technique for interfacial coating, which can be simply achieved by dipping, wet layer formation, and solvent evaporation.271 To achieve large-area fabrication of uniform RGO films on flexible substrates, rod coating is found to be more efficient than the above-mentioned methods.272 The electrophoretic deposition technique is also an efficient and industrially available approach for achieving a uniform and highly conductive FGNs-based thin film coating on the substrates.273,274 The electrophoretic techniques are greatly advantageous for surface coating, because the coating thickness can be easily and accurately controlled from a few atomic layers to micrometers, even millimeters.275−277 Nevertheless, this method is mainly limited to the functionalization of electrically conductive substrates, such as metal frameworks, carbon matrix, and indium tin oxide glass (ITO). Therefore, many nonconductive substrates cannot be applied for the electrophoretic coating. Although the above-mentioned techniques are highly efficient for obtaining FGNs-based thin films, the number of coated FGNs layers on the substrates cannot be precisely controlled with these techniques.278 The interface self-assembly of FGNs is a highly controllable method that can be classified into two main methods: the Langmuir−Blodgett (LB) assembly and electrostatic interaction based layer-by-layer (LbL) assembly. LB assembly is used to prepare various thicknesses of coating layer ranging from single-layer coating to an ultrathin film, Figure 9A−C.278−280 Furthermore, LB assembly also allows one to get a pure GO and RGO layer by LbL manner. LbL assembly of a FGN coating via electrostatic interaction is also possible to precisely control coating thickness due to the gradual growth of the films with increased bilayer numbers, Figure 9D.281−283 The EI-LbL assembly can also be applied to construct many other FGNsbased nanostructures, for instance, microcapsules.284 Unlike the LB assembly, it is almost not possible to get pure a GO, RGO, or graphene coating with an EI-LbL assembly because the FGNs have to be modified to endow them with positive/ negative charges.282 3.2.2. Impact of FGNs-Based Coatings on Interfacial Bioactivities. As discussed in section 3.1, the pure graphene multilayer deposited by the CVD method can provide a promising biocompatible 2D interface for adhesion, proliferation, and differentiation of MSCs and NSCs.188,191 Different from pure graphene, FGNs may exhibit specific interactions

Figure 9. (A) Schematic illustration of two fundamental interacting geometries between two single layers: edge-to-edge and face-to-face. (B) Schematic image of the total potential energy versus separation profiles, edge-to-edge (dashed red line, strongly repelling colloids), face-to-face (solid blue line, kinetically stable colloids forming reversible flocculation), and face-to-face (dotted green line, unstable colloid forming coagulation). (C) SEM images of the LbL assembly of GO double layers: (a) close-packed single-layer GO, double layers with a dilute top layer (b) and a high-density top layer (c). Reproduced with permission from ref 278. Copyright 2009, American Chemical Society. (D) Schematic procedure of the LbL assembled FGNs-based electrochemically active nanostructures on electrodes. MWNT: multiwall carbon nanotube, MG: methylene green, and PDDA: poly (diallydimethylammonium chloride). Reproduced with permission from ref 282. Copyright 2011, American Chemical Society.

with stem cells. Loh et al. have demonstrated that the fluorinated graphene prepared by the CVD method can promote differentiation of MSCs toward neuronal lineages and it has a neuro-inductive effect on adhered cell via spontaneous polarization, which influences the cell morphology and elongates the cytoskeletal and nuclear of MSCs.285 Choi et al. discovered that micropatterns of adhered fibroblast and hippocampal neurons can be fabricated by surface-initiated ATRP and soft lithography method on the CVD-prepared single-layered graphene substrate.286 Wallace’s group reports that the CVD-fabricated few-layered graphene can act as a biocompatible and flexible electrode to stimulate the growth of neurons by transferring the graphene onto the PLA or poly(lactic-co-glycolic acid) (PLGA) film.287 Furthermore, the coated graphene-layer is conductive enough to support the electrical stimulation to PC-12 cells, thus promoting their neural-phenotype’s differentiation.288 Besides the CVD-based graphene hybrid film, the solutionbased GO and RGO multilayer coating was also applied for cell adhesion. Wu and co-workers report that a simple drop cast of GO on glass can result in a few-layered GO. Compared to the strongly reduced GO, the moderately reduced GO has the best cell adhesion, proliferation, and phenotype.104 They suggested that the enhanced cell adhesion and proliferation should be 1841

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Figure 10. (A) FGNs-based patterned thin film guides the differentiation and axonal alignment of NSC by using SiO2 nanoparticle with coated GO to align the axons extending of NSCs, and the differentiation into neurons (a and b). Reproduced with permission from ref 301. Copyright 2013, John Wiley and Sons Publisher. (B) RGO-PEDOT-based microelectrodes for on-chip manipulation of hMSCs. (a−d) Osteocalcin expression after culturing hMSCs on RGO-PEDOT-based microelectrode arrays of different sizes with immunofluorescence staining. (e) Enlarged immunofluorescence image of cultured hMSCs on the surface of RGO-PEDOT-100. Scale bar: 100 μm. (f) Schematic illustration of the RGOPEDOT devices integrated with bioelectronic features. Reproduced with permission from ref 83. Copyright 2013, John Wiley and Sons Publisher.

adipocytes since the insulin is denatured via π-π adsorption. In contrast, GO does not interfere with the adipogenesis since insulin is adsorbed by electrostatic binding with no denaturation, and the high insulin affinity of GO can further enhance adipogenic differentiation. The similar findings had also been reported by using the GO-polypeptide thermogel to induce the differentiation of MSC.290 Wang and co-workers have applied the LbL assembled method to coat the poly(sodium 4-styrenesulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) modified GO on substrate surface,291 the GO hybridized polyelectrolyte multilayer (PEM) exhibits better cell spreading area compared to the pure PEM films, which indicates that fibroblasts cells have a higher affinity to the LbL-assembled GO nanocomposites. In the meantime, Cheng and Zhao et al. have demonstrated that the polymeric substrates reveal better adhesive ability to both endothelial and hepatocyte cells after a coating of heparin-mimetic RGObased nanolayer compared to the pristine interface.77 The heparin-mimetic RGO coating can simultaneously improve the hemocompatibility by suppressing the platelet adhesion and complement activation, which is crucially important for many blood-contacting applications. Loh et al. find that the functionalized GO can be instantaneously cross-linked at the air−water interface by the

attributed to the enhanced adsorption of ECM proteins in the moderately reduced GO with noncovalent interactions. Zhang and Chen et al. have used the spin-coating method to examine the adhesion ability of neuroendocrine PC-12 cells, oligodendroglia cells, and osteoblasts on the RGO and CNT layer. It was found that RGO was more favorable for these cell types than the CNT network. Hu et al. applied the combined drop casting and covalent anchoring method to explore how the GO and RGO layers influence the proliferation of induced pluripotent stem cells (iPSCs). RGO exhibits favorable activity to maintain the undifferentiation of iPSCs, while GO promotes the differentiation.289 Both the RGO and GO surfaces can promote iPSCs differentiate into ectodermal and mesodermal lineages without significant disparity, but RGO inhibits the endodermal lineage formation of iPSCs, whereas GO can enhance the endodermal differentiation.289 The different performances of GO and graphene coatings have also been compared for stem cell adhesion and differentiation. Loh et al. indicate that both graphene and GO have strong adsorbing abilities that allow them to serve as preconcentration platforms for the osteogenic inducers, therefore, graphene and GO films can promote the differentiation of MSCs toward an osteogenic lineage.102 However, the graphene surface suppresses the MSCs differentiation to 1842

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Figure 11. (A) Fabrication of crumpled graphene film on the PDMS substrates. (a) Graphene film is anchored onto the biaxially prestretched PDMS, which is then (b) uniaxially and (c) biaxially relaxed. (d) The initially graphene film, (e) uniaxially relaxed parallel ridges graphene film, and (f) biaxially relaxed crumpled patterns. Reproduced with permission from ref 309. Copyright 2014, Nature Publishing Group. (B) (a) AFM image of multilayer GO-based film after release from 1.5% strain. (b) AFM height profile from (a). (c) SEM image of wrinkled GO layer with 50% prestrain. Fibroblast culture on wrinkled GO layer (d) and flat GO layer (e). Reproduced with permission from ref 311. Copyright 2016, Elsevier.

dip-coating method, whereby the coated film forms a highly wrinkled film. Meanwhile, the highly wrinkled GO film can induce osteogenic differentiation without adding any chemical inducers, it is believed that the highly wrinkled structure plays a driving force toward osteogenic differentiation.292 Akhavan reports that ginsenoside functionalized RGO exhibits higher NSC adhesion and differentiation ability than the hydrazinereduced RGO, which indicates that the antioxidant reagent can enhance stem cell viability.293,294 To design a stimuli responsive cell attaching/detaching system, the polydopamine functionalized RGO anchored with Au nanorods serves as a substrate, and the double-stranded DNA acts as a switchable linker for NIR- and pH-responsive dual control on the catch-and-release of cells, which shows high potential for the sensitive and specific cell or pathogenic attachment or detection.63 The nanoscale topography of scaffold surfaces can also present a unique extracellular microenvironment that influences the behaviors of cell or stem cell, such as cell shape, adhesion, growth, and differentiation.187,295−299 Liu and co-workers develop an easy approach to fabricate patterned GO film structures via vacuum-assisted deposition. The patterned GO substrates serve as a bioactive platform to concentrate polyethylenimine (PEI)/pDNA complexes and gradually release them for selective gene delivery, thus selectively influencing the cell activities.300 Lee et al prepared an array of graphene−nanoparticle hybrid structures to guide the

differentiation and alignment of hNSCs (Figure 10A).301 Positively charged silica nanoparticles are first coated on glass substrates using a centrifugation process, and then the negatively charged GO is deposited on the nanostructures surface. It has been demonstrated that the hybrid film can not only promote the stem cell differentiation but also guide the axonal alignment on the hybrid films. Photolithography has also been applied to construct huge FGNs hybrid pattern structures that influence the adhesion of stem cells by the Chen group, Figure 10B.83 The designed pattern structures are composed of dexamethasone loaded RGO-poly(3,4-ethylenedioxythiophene) (PEDOT) microarray-electrode on ITO glass. In the devices, the RGO acts as a bioactive platform to accelerate the cell attachment, alignment, and osteogenic differentiation of human MSCs (hMSCs). The poly(L-lysine-graft-ethylene glycol) modified RGO-PEDOT electrodes can also function as electroactive drug-releasing electrodes.83 Therefore, by modulating biophysical cues (e.g., elasticity and porosity, micropatterns, and nanopatterns of the substrates), it is possible to control the stem cell fate by using the emerged FGNs-based films as a versatile approach.302,303 Elastic and stretchable hybrids or hydrogels are extremely useful in constructing biointegrated electronics, soft tissue scaffolds, soft robotics, and biomedical devices.304−306 The Zhao group has been reported to reversibly construct a patterned graphene film with crumpling and unfolding 1843

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Figure 12. (A) (a) RGO can self-assembled into the oriented conductive hydrogel film with a “face-to-face” manner. Reproduced with permission from ref 316. Copyright 2011, John Wiley and Sons Publisher. The photoimage (b) and cross-section SEM image (c and d), scale bar: 10 μm. Reproduced with permission from ref 326. Copyright 2013, Science. (B) (a) the vacuum-assisted chitosan-RGO film with artificial nacre structure prepared by HI (hydriodic acid) reduction. A digital photograph (b) and a cross-section SEM image (c) of chitosan-RGO film. Reproduced with permission from ref 318. Copyright 2015, American Chemical Society. (C) Schematic image of the fabrication of 3D macroporous graphene-based films, the chemically modified graphene (CMG) film, and in situ growth of MnO2 (a). SEM cross-section images of CMG composite film (b and c). Reproduced with permission from ref 330. Copyright 2012, American Chemical Society.

cell death. Altogether, FGNs-coated substrates can significantly support the adhesion, growth, and differentiation of different types of mammalian stem cells, including MSCs, NSCs, and iPSCs, and the stem cell behaviors can be further altered after specific surface modification.

properties on a prestretched substrate. The fabricated patterned graphene films are conductive, superhydrophobic, and transparent, which can even be used as artificial-muscle actuators and supercapacitors.307−309 These facilely developed large-scale, crumpled graphene or GO layers-based pattern structures are also found to be promising for guiding cell aligned growth, Figure 11.309−311 Since the hierarchical and high-aspect-ratio pattern structures are fabricated by using the wrinkling and localized ridge instabilities of graphene or GO-based coating films on prestrained elastomer substrates, mechanically stretching the elastomer substrate can easily adjust the pattern structures, thereby mediating the wettability, optical transmittance, cell adhesion and cell alignment on the substrates. Utilizing the electrospinning method to fabricate nanofibrous matrix as micropatterned substrates could be another facile and low-cost approach for the construction of FGNs-coated patterned scaffolds. Forsythe and co-workers have deposited graphene-heparin/poly-L-lysine (PLL) PEM multilayers onto electrospinning nanofibers scaffold by the LbL method to enhance neuron attachment.312 The LbL coating allows a uniform coating of the graphene/polyelectrolyte onto nanofiber matrices. Meanwhile, the graphene-PEM coating supports both the neuronal adhesion and neurite outgrowth with no obvious

3.3. Free-Standing FGNs-Based Composite Films

The free-standing FGNs hybrid film and paper have drawn much attention due to their flexibility, lightweight, and good conductivity and shown great potential in a number of areas as flexible supercapacitors, robust membranes, and bioactive architectures.79,313,314 Recently, many solution-based processing protocols have been proposed for fabricating free-standing FGNs hybrid films including vacuum filtration, template directed methods, interfacial casting-drying, assembly or gelation, and in situ growth/assembly, which will be discussed in detail in the following sections. 3.3.1. Vacuum Filtration. Vacuum filtration is a highly efficient method for preparing free-standing, paper-like FGNs hybrid films.315 The thickness can be easily controlled, and the obtained films usually exhibit multilayer structures due to the spontaneous face-to-face assembly manner at the solution and filtration membrane interface.316 The Young’s moduli of FGNsbased films usually range from 23 to 42 GPa,315,317 which is 1844

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porous film.332 GO can wrap on the silica spheres surface by mixing the GO solution and hydrophobic functionalized silicaspheres in neutral aqueous solution, and then the nanoporous foams can be obtained by removing the silica in the composite film with HF. 3.3.3. Interfacial Casting-Drying, Assembly, or Gelation. Compared with vacuum filtration and templated methods, interfacial casting-drying, assembly, or gelation methods are easier. Using the casting-drying method, Shi group has prepared nacre-like composite films via the interfacial casting of silk fibroin (SF)-GO hydrogels.333 The fabricated composite film with 15 wt.% of SF exhibits a tensile strength of 221 ± 16 MPa, a failure strain of 1.8 ± 0.4%, and a modulus of 17.2 ± 1.9 GPa, which partially exceed those parameters from natural nacre. The authors suggest that the film’s high mechanical properties could be ascribed to the integrated benefits of high GO content (85 wt.%), strong hydrogen bonding interaction, and compact layered structure between GO nanosheets and SF polymer chains.333 With a similar gelation and interfacial casting method, many other synthetic polymers-GO-based films can be prepared.334 Recently, Liao et al. reveal that PVA functionalized GO nanocomposites are easy to disperse in aqueous solution and can be assembled into a nacre-like thin film structure by using the evaporation-induced assembly, Figure 13A−D.335 The resulting films with their nacre-like, bricks-and-mortar, chemically reduced PVA/GO (R-PVA/GO) microstructures achieve excellent mechanical property and electrical conductivity after postreduction treatment. Interestingly, the composite film has excellent cell compatibility and the endothelial cells show good adhesion and proliferation on the composite film, which is even higher than the common tissue culture polystyrene (TCPS). More recently, with the assistance of a similar process of evaporation-induced assembly, Cheng et al. fabricated the strongly integrated artificial nacre-like GO free-standing film via dopamine cross-linking, Figure 13E. The tensile strength and toughness of the composite film can reach 1.5 and 2 times higher than the corresponding parameters of natural nacre.336 Similar, interfacial evaporation-induced assembly of RGO and double-walled CNT (DWCNT) can also result in strong and tough ternary nacre-like nanocomposites with a tensile strength and toughness 374.1 ± 22.8 MPa and 9.2 ± 0.8 MJ/m3, respectively, which is 2.6 and 3.3 times higher than that of a pure RGO film, respectively, Figure 13F.337 It is expected that these types of synthesized GO or RGO based artificial nacre-like films integrated with strong mechanical properties and biocompatibility will have great potential for diverse applications in artificial muscle, flexible sensors, and bone tissue engineering.338−347 With the assistance of an interfacial assembly method, Cheng et al. have produced flexible and a free-standing GO thin film at the liquid−air interface, Figure 14A. The resulting thickness and size of the macroscopic films are controllable and adjustable, which is assembled by LbL stacking of GO sheets.348 Interfacial gelation is another facile, time-saving, and straightforward way to construct macroscale hydrogels or films. Kim and co-workers combine the interfacial self-gelation procedure to construct macroscale porous RGO-based hydrogel films by simply immersing the arbitrary Zn plate into aqueous GO solution (Figure 14B).349 Notably, this interfacial gelation process allows for high controlability on the formation of hydrogel films. The freeze-dried aerogel films reveal that RGO sheets have a well-interconnected macroscopic morphol-

comparable to that of concrete. The tensile strengths of FGNsbased films range from 15 to 526 MPa,317−319 which is comparable to cast iron.319 The conductivity of thermally treated RGO can reach to 351 S m−1.320 Interestingly, for GObased thin film, water molecules can readily penetrate into GO interlayer during filtration due to the hydrophilic property and oxygenated functional groups of the GO sheets,315 which can afterward be applied for water separation from the organic solution.321 Further cross-linking of FGNs layers may greatly improve the mechanical properties of FGNs films, in terms of using covalent cross-linking322 or divalent cations (Mg2+ or Ca2+) to cross-link the carboxylic acid groups and hydroxyl groups.323,324 Meanwhile, Li and co-workers have indicated that water molecules can act as an effective “spacer” during filtration or thermal treatment to prevent the RGO sheets from restacking.325 Furthermore, exchanging water with a miscible mixture solvent of nonvolatile liquid electrolytes and volatile (water) can produce a flexible RGO-based hydrogel film after removing the volatile liquid by vacuum evaporation (Figure 12A, a and b).316,326 SEM images (Figure 12A, c and d) show that the fabricated film reveals a highly uniform face-to-face separated multilayered microstructure with a continuous ion network and high energy storage densities. It has been demonstrated that the polymer components can improve the flexibility and functionalities of FGNs hybrid film. Shi et al. have reported using poly(vinyl alcohol) (PVA) and chitosan to functionalize GO or RGO in order to make robust and flexible composite films.327,328 The obtained composite films are highly flexible and therefore can be shaped into diverse structures or bent into large angles as desired. Similarly, RGO/polyaniline (PANI)-based nanowire composite films have also been prepared by vacuum-assisted filtration for the fabrication of flexible electrodes.78 Inspired by the natural nacre, Cheng et al. have used a vacuum-assisted method to fabricate the GOchitosan based artificial nacre with almost the same ratios of inorganic and organic components in the nacre. This GOchitosan mimetic artificial nacre successfully integrates strong mechanical properties with 4 times the tensile strength and 10 times the toughness higher than that of natural nacre, Figure 12B.318 Similarly, Yue and Guo et al. indicated that the binaryhybridized building blocks of sodium alginate and GO could also be applied to design the FGNs-based nacre-like paper.329 Systematic mechanical evaluations in different environments (dry/wet) also exhibit similar results as the other nacre-like composite paper with ideal integration of high strength and toughness. 3.3.2. Templated-Directed Methods. The templatedirected method was thought to be a highly efficient and controllable way to fabricate a porous thin film with tunable pore-size distributions. In many reports, polystyrene (PS) and silica colloidal particles are the most commonly used sacrificial templates. Choi and co-workers mixed PS with a GO solution to filtrate GO thin film. After removal of PS particles by organic solvent, a GO-based foam with highly uniform and 3D porous structures was obtained (Figure 12C).330 The PS nanoparticles can also be applied as templates to prepare porous carbon architectures by Zhang et al. via impregnating the mixed solution of sulfonated PS particles, poly (vinyl pyrrolidone) and GO onto nickel foam. After freeze-drying, the film was treated by calcination in N2 atmosphere to remove the PS and PVP, thus obtaining a heteroatom-doped 3D carbon network.331 Notably, the Zhao group has demonstrated that silica spheres can also function as a hard template to fabricate FGNs-based 1845

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good mechanic properties.355 Although the LbL assembly can significantly improve the mechanical strength by prohibiting the aggregation of graphene nanosheets, this strategy is usually time-consuming, which is suitable for multilayer construction but costly for fabricating free-standing, FGNs hybrid film. In summary, the FGNs-based films made from in situ growth or assembly methods exhibit interconnected structures that inhibit the graphene nanosheets from agglomeration and/or restacking, therefore, ensuring good electrical conductivity and mechanical strength for many exciting applications, such as robust and flexible sensors, MFC electrodes, and tissue scaffolds. 3.3.5. Free-Standing FGNs Films as Bioactive and Multipurpose Platforms. FGNs hybrid films can be fabricated by filtrating biocompatible molecule-functionalized RGO suspensions, such as chitosan, PANI, cellulose, cellulose nanocrystal and bacterial cellulose, which have shown high conductivity and good biocompatibility.328,356−361 The Li group has built a biomimetic and free-standing RGO-based sensor with covalently anchored RGD-peptide on pyrenebutyric acid modified RGO.121 The resulting well-packed layered RGO biofilm sensor owns excellent human cell adhesion properties on the sensor surface that facilitates the real-time NO (an important cellular signal yet short-lived molecule) detection. The RGO-film-based sensor exhibits excellent electrochemical stability even after 45 bending/relaxing tests and the current responses maintained unchanged after 15 cycling tests. The sensor also has good sensitivity and high selectivity against the interfering molecules in tissue systems. Huang et al. have demonstrated that the assembled sandwiching RGO@TiO2 structure with deposited Au nanoparticles onto the RGO shell can also serve as a renewable microsensor to detect nitric oxide release from adhered cells.362 These pioneer works demonstrate that FGNs-based films or hydrogel films can be applied for real-time quantitative test of living cell released NO.363,364 Zou et al. utilized a cellulose ester filter membrane as a support to obtain a filtrated self-supporting RGO hydrogel film via direct-flow vacuum filtration.365 The RGO hydrogel film has a higher mechanical strength and flexibility and can be applied to stimulate osteogenic differentiation of human adiposederived stem cells (hADSCs). Interestingly, the RGO hydrogel film alone can accelerate the adhesion and osteogenic differentiation of hADSCs without any other inducers, which is better than that of conventional RGO or carbon fiber films. However, the overall osteogenic induction capacity of hADSCs is not as high as that of the osteogenically induced medium. Most recently, the Li and Zou groups demonstrated that the filtration-prepared multilayered RGO hydrogel (MGH) membranes can act as promising scaffolds for guiding bone regeneration. In particular, the MGH can significantly promote the osseous space and accelerate early osteogenesis, as shown in Figure 15A.366 It is validated that the MGH speeds up the protein adsorption, cell adhesion, and apatite deposition, which eventually allow favorable bone tissue adhesions and fast bone regeneration. Furthermore, the MGH membranes exhibit excellent mechanical strength, flexibility, and selective permeability. Khademhosseini et al. finds that thermally retreated RGO also shows high cell adhesion and spreading of C2C12 myoblasts compared to glass surface.367 Jin and co-workers have fabricated RGO/chitosan films by the solution casting method. By adding a low ratio of RGO in a chitosan matrix (0.1−0.3 wt.%), the elastic modulus increased over ∼200% and

Figure 13. (A) Schematic image to fabricate R-PVA/GO composite films. (B) SEM views of the GO and PVA/GO films. (C) Digital images of PVA/GO and R-PVA/GO composite films. (D) Microscope and fluorescence images of endothelial cells grown on bare TCPS and R-PVA/GO coated TCPS surfaces for 48 h. Scale bars: 50 μm. Reproduced with permission from ref 335. Copyright 2012, John Wiley and Sons Publisher. (E) Illustration image to prepare mussel inspired artificial nacre-like film by using dopamine as cross-linker. Reproduced with permission from ref 336. Copyright 2014, American Chemical Society. (F) Schematic image to prepare ternary GODWCNT hybrid-layered nacre-like film via evaporation induced selfassembly. PCDO: 10,12-pentacosadiyn-1-ol, HI: hydriodic acid. Reproduced with permission from ref 337. Copyright 2015, American Chemical Society.

ogy with a large pore sizes distribution from nanometers to micrometers. 3.3.4. In Situ Growth/Assembly. Nam et al. have reported that large-area RGO free-standing film can be fabricated by in situ electrophoretic deposition, and the obtained flexible film shows a high conductivity, 5.51 × 105 S/m, after thermal annealing.277 In situ growth of polymers on FGNs composite films is another effective way for forming polymer hybrid films with uniform distributions of polymers on FGNs-based substrates.350,351 For instance, the Yu group fabricates a flexible RGO-PANI composite film by the in situ growth of PANI gray metallic luster on a pure RGO substrate, Figure 14C.350 The RGO-PANI film has the properties of low weight (0.2 g cm−3), good flexibility, and good electrical conductivity (15 Ω sq−1). Meanwhile, the film size and shape can be freely exchanged when different Teflon substrates are used. Therefore they may be good candidates for neural scaffolds, bioelectrodes, or electrodes for MFCs. The in situ LbL assembly can also be applied for constructing FGNs-based free-standing thin film.352,353 The negatively charged CNTs can be assembled with positively charged GO to form layered films.354 Yu group has found that the LbL assembly of GO and layered double hydroxide nanoplatelets can generate a strong, colorful, and fire-retardant micrometerthick hybrid film with uniform nacre-like layered structures and 1846

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Figure 14. (A) (a) Photo images illustrate the self-assembly process of GO film. (b) The self-assembled GO film at the liquid−air interface. (c) The photoimage of an as-prepared GO film (15 mm × 30 mm). (d) The as-prepared large-area GO film. (e) SEM image of the film exhibits LbL structures. (f) Schematic illustration of the proposed liquid−air interface self-assembly. Reproduced with permission from ref 348. Copyright 2009, John Wiley and Sons Publisher. (B) Interfacial gelation of RGO film on the Zn metal substrate. (a) Schematic image of RGO film gelation procedure. (b) Photoimage of the freeze-dried RGO-based aerogel films. Reproduced with permission from ref 349. Copyright 2014, John Wiley and Sons Publisher. (C) Fabrication of RGO-PANI free-standing films. (a) Photograph of the flexible RGO-PANI paper. (b) Photograph of the flexible RGO-PANI film by electrochemical deposition of PANI on RGO film. (c) SEM images of the RGO-PANI film. (d) Photograph of RGO-PANI composite films with different electropolymerization times. (e) Schematic image for fabrication of RGO-PANI paper. Reproduced with permission from ref 350. Copyright 2013, Royal Society of Chemistry.

The Cui group has explored to use the GO/PEDOT composite film for improving the differentiation of NSC toward the neuronal lineage.373,374 Later on, they further functionalize GO surface with neural active biomolecules, such as the interferon-γ and platelet-derived growth factor, which are able to selectively promote the NSC differentiate into neuron or oligodendrocyte. The composite film generates more neurons when interferon-γ is anchored, while it produces more oligodendrocytes when platelet-derived growth factor is immobilized. This study validates that GO/PEDOT composite film can be applied for different specific cell-scaffolding applications due its potential for mediating the behaviors of NSC, thus improving the therapeutic potential of NSC. FGNsconductive polymer-based thin films can also be applied for implantable bioelectronic devices.375−378 Liu and co-workers have applied GO to dope into PEDOT by electrochemical deposition to enhance the performances of neural and microelectrodes interfaces as shown in Figure 15B,C.81 The GO-PEDOT composite film exhibits not only an enlarged surface area but also higher charge storage capacity than the bare GO or PEDOT film. Furthermore, the repeated usage test and cell adhesion and proliferation examination indicate the excellent stability and biocompatibility of the electrode-tissue interface, which opens a new way to construct tissue

the cell adhesion of L929 cell on the RGO/chitosan composite films was also enhanced compared to the bare chitosan film.368 These significant advancements of FGNs hybrid architectures suggest that they may find potential applications in tissue regeneration, bioelectronics, and biorobotics.361,369,370 The GO-modified polymeric films have also been found to be promising biomaterials for tissue engineering as they are both cell compatible and nontoxic. The GO modified SF composite films combined with fibroin had excellent activities in the mesenchymal phenotype, viability, adhesion, and proliferation rate of the human dental stem cells, which indicated that the fibroin/GO based and biodegradable constructs could be therapeutically useful for regenerative dentistry.371 The Yu group has applied the interfacial castingdrying method to obtain a bioinspired ultrastrong, highly biocompatible and bioactive GO-modified konjac-derived glucomannan (KGM) hybrid film.372 They validate that the obtained KGM-GO composite films have obviously higher mechanical strength than the bare KGM film due to the strong hydrogen-bonding interactions between GO and KGM. Combined with excellent adhesion ability of muscular cells, this indicates that they have a promising future in the fields of tissue engineering and food packaging. 1847

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Figure 15. (A) (a) Schematic image for using MGH membrane to treat the rat calvarial defects. (b) The suggested healing mechanism of the rat calvarial defect. Micromorphometric bone parameters of (c) bone volume fraction and (d) bone mineral density. The in vitro bioactivities of the tested MGH on (e) protein adsorption and (f) cell adhesion. (g and h) The fluorochrome analysis of newly formed bone between the membrane side (M) and dura side (D) in the defects. Reproduced with permission from ref 366. Copyright 2016, John Wiley and Sons Publisher. (B) Schematic chemical structure of PEDOT/GO composite film. SEM images of cells adhered on PEDOT/GO surface. SEM image of PC-12 cells (a and c) and NIH/3T3 cells (b and d) on PEDOT/GO, respectively. (C) CLSM image of PC-12 cells (a) and NIH/3T3 cells (b) proliferation on PEDOT/GO films, respectively. PC-12 cell viability (c) and NIH/3T3 cell viability (d) on bare gold (black), cell plate (red), and PEDOT/GO (blue). Reproduced with permission from ref 81. Copyright 2014, Elsevier.

engineering and implantable electrophysiological devices.81 FGNs can also be applied to enhance the cell adhesion ability of engineering plastics, the GO-blended, ultrahigh molecular weight polyethylene composites exhibit enhanced adhesion and growth of the MC3T3-E1 osteoblasts. This makes the composite films attractive candidates for designing human artificial joints.379 A GO-blended silicone elastomer has also been reported, which has better mechanical strength as well as cell attachment and proliferation with promoted osteoinductive signaling of the surface adherent cells. Therefore it can be applied to construct bioactive and compatible implants, for instance in joint reconstruction.380 Lee et al. have indicated that the RGO-coated nanofibrous film can provide instructive physical cues for selectively differentiating NSCs into mature oligodendrocytes that require no differentiation inducer in the culture medium.381 These hybrid scaffolds, which combine the unique RGO properties

and morphological nanofibrous features, can be a beneficial cell adhesion platform and function as a powerful method to develop clinical therapies for nerve-related injuries and diseases. In the meantime, Dai and Zhang have also reported that GO can be doped into PLGA nanofiber membrane via the electrospinning technique.382 They indicate that the doping of GO can improve the hydrophilic performance, and the adsorption of ECM proteins and differentiation inducers compare the bare nanofiber membranes so that accelerating the adhesion, growth, and osteogenic differentiation of hMSCs. Graphene-inorganic composite films are also interesting for many applications. The Chen group has used the solutioncasting method to prepare a gelatin−GO composite film, which can be applied for mineralization of calcium phosphate nanocrystals on the composite.383 GO serves both as a mechanical strong reinforcement filler and an activator in the gelatin matrix. The RGO hybridized calcium silicate composites 1848

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Figure 16. (A) (a) Photographs of GO solution before and after hydrothermal treatment at 180 °C for 12 h. (b) Photographs of hydrothermal reduced RGO hydrogel with robust mechanical properties. (c−e) SEM images at different magnifications. (f) The I−V curve of the self-assembled hydrogel at RT. Reproduced with permission from ref 397. Copyright 2010, American Chemical Society. (B) (a) Scheme illustration to prepare GO/ DNA self-assembled hydrogels. (b) Effects of acidic, basic, NaCl, buffer, and tetrahydrofuran (THF) on the stability of GO/DNA hydrogels. (c and d) SEM images of GO/DNA. (e) Self-healing process after being cut into small blocks. Reproduced with permission from ref 427. Copyright 2010, American Chemical Society.

have also been prepared by hydrothermal treatment and followed by hot-isostatic pressure.384 After blending of RGO to chitosan, the elastic modulus increased by ∼52%, hardness by ∼40%, and the fracture toughness by ∼123%. The bone-like apatite can form on chitosan/RGO composites in simulated body fluid (SBF). Meanwhile, the human osteoblast cells show good adhesion on the composite films and exhibit better cellular proliferation and alkaline phosphatase activity compared to the pure chitosan ceramics. Notably, several groups have indicated that the AgNPs incorporated RGO multilayered film exhibits selectively adhesion properties, the mammal cells can survive well on the composite films, while the bacteria show poor adhesion and survival ratio on the hybrid films.385−388 Therefore these composite films have promising potential for wound healing materials and food packaging.

design of biofunctional scaffolds is therefore an important goal for tissue regeneration.392,393 FGNs, such as graphene, GO, RGO, and organically/inorganically functionalized graphene, have been proven to enhance the adhesion and growth of mammalian cells (including osteoblasts, fibroblasts, endothelial cells, and stem cells) and microbial cells.394−396 Thus, it is important to explore how the FGNs-based 3D scaffolds influence the adhesion and growth of cells. Recently, 3D scaffolds consisting of FGNs have been successfully synthesized by different methods, such as hydrothermal/chemical reduction and multinoncovalentally induced assembly, covalently crosslinked FGNs-based hydrogels, ice-templated growth of 3D nanochanneled networks, interfacial assembly of FGNs, and chemical vapor deposition on 3D frameworks. These proposed methods and corresponding emerging biological applications will be discussed in detail in the following sections.

4. FGNS-BASED 3D ARCHITECTURES Recent studies indicate that synthetic 3D architectures can create microenvironments similar to ECM, which thus enhances cell adhesion, growth, and differentiation due to the physiological relevance of the ECM structure.389−391 The

4.1. Self-Assembled FGNs-Based Hydrogels or Aerogels

4.1.1. Hydrothermal/Chemical Reduction. GO sheets are able to be dispersed well in aqueous solution to produce a stable colloidal solution due to the amphiphilic nature and electrostatic repulsion between nanosheets. Therefore, lyophi1849

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chains can adsorb and assemble with GO nanosheets via hydrogen bonding interactions and π-π stacking, which results in gelation after mixing an aqueous dispersion of GO and double-stranded DNA (dsDNA) after additional heating to 90 °C, the GO-DNA hydrogel formed, Figure 16B.427 The prepared GO/DNA composite hydrogels own excellent adsorption ability to different molecules and show an interesting self-healing ability. Following this method, the GO/hemoglobin, GO/BSA, and GO/chitosan supramolecular hydrogels were also obtained by mixing the aqueous blends of these components with violent shaking or sonication for a few seconds.428,429 Various synthetic polymers can also function as binders to assemble with GO nanosheets and form hybrid hydrogels. Ruan et al. have reported a PVA/GO hybridized hydrogel upon the self-gelation of PVA solution with GO nanosheets.430 It was found that an extremely high-watercontent GO/PVA hydrogels, 95−98 wt %, could be obtained.430 A small addition of GO also significantly reinforces the mechanical strength and elongation of GO/PVA hydrogels. To maintain the intact graphene network, Chen and Fu et al. have used the PVA to dope the RGO hydrogel framework to form a second polymer network;431 the obtained RGO/PVA double-network not only exhibits largely improved mechanical property but also well-preserved conductivity, which provides another efficient protocol for constructing strong and conductive FGNs-based composite hydrogel.

lized GO dispersions are the simplest way to obtain the GObased aerogel, which typically produces a 3D porous and interconnected GO network. Although further thermal or chemical treatment of freeze-dried GO can result in RGO aerogel, freeze-dried GO has very limited mechanical strength. Shi et al. found that submission of a homogeneous GO solution to a Teflon-tube under hydrothermal treatment could obtain a robust RGO hydrogel. 397 The resulting 3D architecture exhibits a macroporous cellular-type morphology, the 3D RGO-framework is formed by physical cross-linking with partial overlapping or coalescing of RGO nanosheets (Figure 16A). Interestingly, a few tens of milligrams of RGO hydrogels are mechanically strong enough to hold weights of several hundreds of grams. Apart from the excellent mechanical properties, these RGO aerogels exhibit a pretty decent electrical conductivity (10−3 S cm−1). The obtained RGO-immobilized hydrogel matrix provides a cell compatible architectures for proliferation of the human osteosarcoma.398 In the meantime, hydrothermal treatments have also been widely taken to prepare the functional and hydrogel-like 3D RGO composite using different organic or inorganic compounds as additional reducing reagents. For instance, the hydrothermal treatments of GO dispersion with divalent ions (Ca2+, Ni2+, Co2+, or Fe2+) can result in metal oxide-loaded hydrogel.399,400 Chemical reducing agents can also induce the formation of FGNs hybrid hydrogel either combined or not with hydrothermal treatments. Within this context, hydrazine,401 NaBH4, and HI402 have been widely used as reducing agents. More recently, L-ascorbic acid,403 dopamine,404,405 Vitamin C,406 and hydroquinone407 also exhibited the capability to chemically reduce GO with the assistance of heating for a few hours. After simple freeze-drying, the resulting aerogels demonstrated intriguing and desirable features (high porosity, large specific surface area, and reactive interface). Reducing reagents can be applied not only to induce gelation but also to further functionalize the surface or strengthen preformed structures, for instance, the polydopamine or dopamine conjugated polymers,408−412 which both serve as reductants and surface functionalization agents to cross-link and modify the RGO networks for versatile environmental and biological applications.72−74,413,414 4.1.2. Multi-Noncovalent Assembly. GO has been regarded as an amphiphilic supramolecular colloid. In colloidal chemistry of nanoparticles, it is well-known that gelation or aggregation can be induced by mediating the repulsion forces between colloidal nanoparticles.415 This principle can also be applied to form hydrogels from the aqueous dispersion of GO as well, whereby foreign reagents act as noncovalent binders (DNA, polymers, and metal ions) to cross-link GO nanosheets and then congregate into GO-hybridized hydrogels.416 The following dehydration of the hydrogel by freeze-drying or supercritical drying techniques can lead to highly porous aerogel scaffolds.416−420 Xie et al. find that the GO-amaranth extract-Au nanoparticles coassembled hydrogels can be applied for capturing tumor cells, thus preventing them from migrating to normal tissue.421 Electrostatic interactions, π-π stacking, hydrogen bonding, and van der Waals force are the main driving forces for the construction of these composite hydrogels. Herein, various biopolymers have been applied to induce the gelation of GObased hydrogels due to the abundant hydroxyl and amino groups, which are able to interact or cross-link the GO nanosheets.422−426 Shi et al. have validated that DNA polymer

4.2. Covalently Cross-Linked FGNs-Hybridized Hydrogels

Diverse functional polymers with amino groups, such as PEI and chitosan, can cross-link the GO dispersion, not only because of the electrostatic interaction, but also the reaction between the amino groups and the epoxy groups on the GO sheet that form cross-linked structures.432 Fu et al. have proposed to use aqueous dispersible 2,2′-(ethylenedioxy)diethanethiol to a cross-linked GO skeleton, which is then in situ incorporated into a PVA matrix. This resulted in novel interpenetrated hydrogels with super mechanical and chondrocyte cell-adhesion properties.433 These composite hydrogels are strong, tough, and nicely supportive of chondrocyte adhesion and growth, which make the functionalized GO/ PVA composite hydrogels promising candidates for loadbearing biotissue substitution. A series of GO/conducting polymer based hybrid hydrogels, including GO/PEDOT, GO/ PANI, and GO/polypyrrole (PPy) hydrogels have been constructed via in situ polymerization,79,434,435 Most recently, Park et al. have developed in situ cross-linkable tough and elastomeric composite hydrogels by enzyme-cross-linking of various types of FGNs (different oxidation degrees) and 4-arm poly(propylene oxide) (PPO)-poly(ethylene oxide) (PEO)tyramine (Tet-TA) with the addition of horseradish peroxidase, Figure 17.436 The blending of GO into Tet-TA hydrogels dramatically enhances the mechanical property. In addition, after immobilization of the RGD peptide, the osteoblastic cell line, MC3T3-E1, can successfully adhere onto the scaffolds. It was proposed that the obtained tough, elastomeric, and bioactive Tet-TA/GO composite hydrogels will have great potential as in situ-formed tissue implants or injectable longterm drug delivery systems. Besides introducing polymers directly to cross-link the GO solution, in situ polymerization of vinyl groups containing monomers with GO nanosheets may also be highly suitable for the formation of GO hybridized hydrogels.425,437−440 For instance, Yu et al. has mixed the N-isopropylacrylamide with a 1850

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of cancer cells from integrated functionalities of the bioadhesive ligand of RGD and NIR-stimulus, which thus has a better capture-release control over cancer cells than the other conventional hydrogel-based cell depots, Figure 18.444 In the study, GO served as both cell compatible and NIR-responsive nanocomponents to stimulate the “on−off” switch for dynamically controlling cancer cell capture-release. The NIR light can allow spatial and temporal control of cells by a noncontact way; it also circumvents the problems of UV light, such as the poor tissue penetration and detrimental irradiation effects. This work offers a novel way to design and construct a NIR-triggered reversible substrates for specific cell-collection, isolation, analysis or delivery in diverse disease treatments. More recently, Li group has used the NIPAM and N,N′methylene bisacrylamide to develop polymeric hydrogels that incorporate thermal responsive polymer into graphene-based aerogel to construct ultralight and superelastic binary networks, which will eventually combine excellent stimuli responsiveness, electrically conductivity, and mechanical strength for diverse applications.445 Besides the single covalently cross-linked network, addition of metal ions may result in double cross-linked networks in the FGNs-based hydrogel. Yu et al. have proposed an intertwined, double network mechanism to prepare double network GO/ poly (acryloyl-6-aminocaproic acid) composite hydrogels. The double cross-linked networks are triggered by applying the GO nanosheets and calcium ions as cross-linkers.446 Following the same protocol, they also achieved highly elastic and superstretchable GO hybridized polyacrylamide hydrogels.447 Xie and co-workers have prepared self-healable, supertough GOPAA composite hydrogels by adding Fe3+ as an ion crosslinker.448 When stretching the hydrogel, the ionic interactions between the -COOH group will dynamically break and then reform again to dissipate energy; the cross-linked GO can maintain the hydrogel morphology by serving as stress transfer centers to deliver the force to surrounding matrix. Surprisingly, the GO-PAA hydrogels exhibit remarkable stretchability, elongation at break = 2980% and good toughness, tensile strength = 777 kPa. These as-prepared hydrogels all reveal superior mechanical and self-healing properties due to the double cross-linked networks, which are highly demanded for designing advanced artificial skin and injectable implants. Besides the robust and elastic mechanical properties, the in situ polymerization of vinyl monomers may also introduce multifunctional and biocompatible hydrogels. Cheng and Zhao et al. have synthesized heparin-mimetic hydrogels via an onepot in situ polymerization, Figure 19.449 In the heparin-mimetic hydrogel, GO is covalently doped into the networks of heparinmimetic matrix due to the cross-linking between the initiated macromolecular radicals and sp2 bonds of GO. Consequently, the GO bonded heparin-mimetic hydrogels show well interconnected porous structures, reinforced mechanical strength and elastic properties, thus they can withstand cyclic compressions under an extreme amount of stress. Furthermore, GO doped hydrogels can significantly improve endothelial cell viability and adhesion by enhancing the production of actin filaments and ECM. Due the integrated high drug loading ratio and good hemocompatibility, the constructed GO bonded heparin-mimetic hydrogels are promising candidates for various biomedical applications, particularly in tissue regeneration and implantable hydrogel for drug/gene delivery.450,451 Wang et al. also establish that the one-pot in situ polymerization prepared Ag/graphene hydrogel can be applied for treatments in wound

Figure 17. (A) Schematic and (B) photo images of HRP-catalyzed cross-linked Tet-TA/GO composite hydrogels. (C) Live/dead staining of MC3T3-E1 cells after cocultured with Tet-TA and Tet-TA/GO hydrogels. Scale bars: 200 μm. Reproduced with permission from ref 436. Copyright 2015, Royal Society of Chemistry.

GO solution with N,N′-methylenebisacrylamide as cross-linker, and then in situ polymerized the solution upon γ-irradiation in a N2 atmosphere to fabricate a poly (N-isopropylacrylamide) (PNIPAM)/GO composite hydrogel.441 The GO integrated PNIPAM composite hydrogel shows excellent photothermal capabilities, whereby the phase-transition of the PNIPAM/GO composite hydrogel can be remotely stimulated with laser irradiation, which may be a useful concept to design smart microfluidic devices or advanced scaffolds with stimulated drug delivery properties. Similarly, Sun et al. have reported on designing of GO interpenetrated PNIPAM-co-poly (acrylic acid) (PAA) hydrogel networks. With the covalently bonding cross-linking, the mechanically enhanced composite hydrogels reveal pH and temperature dual sensitivities.442 Tong and coworkers revealed that incorporation of hectorite clay in GOPNIPAM hydrogel could significantly enhance the mechanical strength of the in situ polymerized hydrogels, since the hectorite clays served as both cross-linkers and reinforcing agents.443 Benefiting from the thermal sensitive property of PNIPAM, the Qu group has designed GO-hybridized macroporous hydrogels to efficiently capture and on-demand release 1851

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Figure 18. (A) Photograph of lyophilized hydrogel. (B) SEM image of the composite hydrogel; scale bar: 100 μm. (C) NIR laser induced temperature changes. (D) Schematic image of the cell capture and cell release stimulated by NIR laser. (E) The cell numbers in the cell culture media before (left) and after (right) immersing with hydrogel. (F) The fluorescence image of released cells from hydrogel: left, with RGD, right, without RGD. (G) The steps to conduct the NIR-triggered cell release. (H) The fluorescence image of released cells from composite hydrogel with proper RGD (a) or excessive RGD (b). Scale bars: 100 μm. The released cell ratios at different irradiation times and laser power. Reproduced with permission from ref 444. Copyright 2013, John Wiley and Sons Publisher.

healing.452 These prepared hydrogels show strong antibacterial abilities, while excellent biocompatibility to mammal cells. Meanwhile, the in vivo animal experiments have indicated that the composite hydrogel is capable to promote the healing rate of wounds on rat skins, and histological studies have revealed that composite hydrogels helps successfully reconstruct intact and thickened epidermis after skin-healing experiments from impaired wounds for 15 days. Grafting the vinyl groups onto the backbone of polymers is another efficient way to achieve covalent cross-linking with GO nanosheets. Khademhosseini group has applied a methacrylate group-anchored polymer as a covalent cross-linker to form GObonded hydrogels via radical copolymerization.453 The encapsulation of fibroblast cells indicates that the composite hydrogels can significantly promote the viability and proliferation of the loaded cells. Recently, they developed an injectable and cell compatible hydrogel with high gene delivery efficiency for myocardial therapy.454 The PEI-modified GO complexed with vascular endothelial growth factor-165 (VEGF) gene, DNA(VEGF), were integrated into a soft hydrogel consisting of methacrylated gelatin (GelMA) to achieve an implantable and controlled gene therapy. Meanwhile, the fGO(VEGF)/GelMA hydrogel shows excellent mitotic activities on endothelial cells and reduction in the scar areas of infarcted hearts with a

remarkably enhanced cardiac performance in echocardiography.454 4.3. Ice-Templated Growth of 3D Nanochanneled Networks

The ice-templated method is a versatile technique to fabricate the nanochanneled and interconnected porous aerogels and scaffolds. During the freeze-drying process, the bottom of the solution is frozen first, and then the resulting phase-separation of materials and ice crystals forms a vertical porous structure upon subsequent freeze-drying. Therefore, the ice-templated method can be recognized as a self-assembly process that is driven by a dynamic ice−water interface, the ice crystals serve as removable templates for the formation of pore structure and thus change the growth of ice crystals, which can control the pore size. Therefore, the ice-templated freeze-casting has been used as effective processing method to construct a wide variety of oriented porous materials, such as silicon nitride, hydroxyapatite (HA), polymeric materials, and ceramic slurry, biomaterials.455−458 These vertically porous architectures have been significantly investigated as multifunctional and soft composites for application in catalytic area, energy storage, sensors, tissue engineering, and actuators.456,459−462 FGNs-based, ice-templated 3D nanostructures usually integrate with vertically porous microstructures and also have high conductivity, which is favorable for a broad range of 1852

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Figure 19. (A) Schematic image to prepare the GO doped heparin-mimetic hydrogels. Hydrogel with no GO is coded as HH-M1, low GO ratio is coded as HHG5-M1, and high GO ratio is coded as HHG25-M1. (B) Photo images present the morphology changes of the HHG25-M1 during compression tests. (C) Cross-section SEM images of HH-M1 (a), HHG5-M1 (b), and HHG25-M1 (c) (scale bars: 50 μm). (D) Confocal images for cell adhesion on HH-M1 (a), HHG5-M1 (b), and HHG25-M1 (c) (scale bars: 25 μm). Reproduced with permission from ref 449. Copyright 2015, Royal Society of Chemistry.

applications.463,464 Qiu et al. have applied the freeze-casting method to prepare the RGO-hybridized aerogels with cellular microstructure as shown in Figure 20A.465 The RGO-based aerogels exhibit a cork-like hierarchical porous structure and have many unique advantages, such as the facile synthesis, ultralight, superelasticity, high energy absorption efficiency, and good electrical conductivity. This unique RGO-based cellular material can also provide enough space to include foreign components to construct multifunctional composite materials. In another system, a bare GO suspension is used to prepare GO-based 3D foams to adsorb the SO2 gas and then convert it to SO3. The 3D structures of GO-based foams not only function as container for SO2 gas but also serve as catalyst to transfer the SO2 into SO3 with the assistance of O2 .466 Furthermore, besides the above-mentioned GO-hybridized architectures, ice-templated freeze casting has also been applied to polymer-functionalized FGNs. For instance, Mann et al. have utilized the polystyrene sulfonate to stabilize the RGO suspension sheets to produce 3D sponge-like composites with highly oriented macropores.467 Recently, the Bergström group has produced superinsulating, fire-retardant, and strongly anisotropic foams with the ice-templated freeze-casting method, which consists of GO, cellulose nanofibers, and sepiolite nanorods, Figure 20B.468 The ultralight foams exhibit

remarkable combustion-resistance with an extremely high thermal conductivity (15 mW m−1 K−1). The foams can remain more than half of their initial strength during a 85% relative humidity at 30 °C, thus indicating that the icetemplated, freeze-casting method is a promising protocol for fabricating oriented porous 3D foams with excellent mechanical properties using GO, RGO, or other nanoscale compounds.468−471 Recently, the ice-templated 3D porous RGO scaffolds have been applied as implantable ECM in injured rat spinal cord by Serrano et al.183 Interestingly, these structures performed excellently with local spinal tissue and in the major organs (i.e., liver, kidney, lung, and spleen), especially regarding the mechanical matching with neural tissues. The 3D RGO composites own good neural cell compatibility and versatile ability to induce biological guidance or topographical influences. No obvious neural and systematic toxic responses have been observed. Meanwhile, the 3D RGO scaffolds exhibit soft features that can inhibit the generation of macrophages and neural scares at the interface. The proposed designs will encourage further investigation of ice-templated FGNs hybrid architectures as a promising and efficient platform for the injury treatment of the spinal cord. Meanwhile, there is still a need to 1853

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Figure 20. (A) (a−c) SEM images of top view (a and b) and side view (c) of graphene monolith. (d) Schematic image to prepare the graphenebased cork-like monolith. Reproduced with permission from ref 465. Copyright 2012, Nature Publishing Group. (B) (a) Schematic illustration of the growth of anisotropic ice crystals in composite hydrogel by freeze-casting process. (b) Photograph of the nanocomposite foam. (c) Cross-section SEM image of freeze-casting produced foam. (d) 3D illustrated reconstruction of the tubular pore structure derived from X-ray micro tomography. (e) X-ray micro tomography image in the nanocomposite foam. Reproduced with permission from ref 468. Copyright 2014, Nature Publishing Group.

method can provide enough specific surface for bacterial diffusion and colonization, thus enhancing the bacteria affinity, density and extracellular electron transfer, which provide a 78times improvement of the maximum powder density as compared to the control group. The ice-templated freezecasting method may push forward the MFC technology closer to practical applications.

explore the influences of the oriented porous structure on the growth and differentiation of NSC and neurons. Bacterial colonization is another potentially important application area for ice-templated FGNs hybrid architectures due to the matching characteristics for anode electrodes in MFCs.472,473 Yan and co-workers have used the ice template to develop flexible and macroporous 3D RGO-based sponge.474 The porous structures of this 3D RGO architectures can be easily controlled by changing the formation rate of ice crystals and they are able to recover from a 50% deformation. The RGO-based sponges have been applied to construct MFCs electrodes, the macroporous structure of sponge can allow the bacteria to diffuse more easily and propagated inside the materials. Therefore, the RGO-based oriented porous sponge exhibits very high power density, 427.0 W/m3, which is higher than that of the carbon felt based anode. Li and co-workers have shown that the ice-templated freeze-casting method can be used to construct chitosan/vacuum-stripped graphene architectures, which exhibit a hierarchical porous structure consists of oriented, layered and branched meso/micropores, Figure 21.475 The vertical macropores and hierarchically porous architecture induced by the ice-templated freeze-casting

4.4. Interfacial Assembly of FGNs on 3D Frameworks

FGNs hybrid 3D architectures have also been prepared by simply impregnating preformed 3D architectures with FGNs solutions. Typically, soaking the porous foam in an aqueous GO suspension, then drying and reduction with hydrazine/HI results in a 3D RGO-coated framework with excellent electrically conductivity and a large available surface area. Recently, Cui group has coated FGNs multilayer onto a polyurethane network to act as 3D anode materials in MFCs, Figure 22.476 To coat the sponges with FGNs multilayer, graphene nanopowder was first dispersed in water by robust sonication, and then the polyurethane 3D sponges were immersed into the dispersion with graphene nanosheets. It was found that the coating of conductive graphene sheets could maintain the morphology of sponge without blocking its open 1854

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pores, as illustrated by the SEM image in Figure 22. The microbial adhesion was observed after 50 days operation, whereby the microorganisms that were interconnected by microbial nanowires had covered the networks and the microbial biofilms that were wrapped around the sponge branches had not clogged the macroscale pores, Figure 22A (c−f). The power generation profiles show that the modified anodes have high power and current density, Figure 22B. It was concluded that the MFC performance of the graphene modified electrode could compete with that of CNT modified electrodes, and it was much higher than that of the commercial electrode based on carbon cloth. Furthermore, the overall price of the composite electrode will be ∼$2000 per m3, which is at least 1 order of magnitude lower than many of the previous reported CNT-modified sponge electrode477,478 and commercial MFC electrodes.479 Interfacial coating of a FGN layer can also be applied for biomedical applications. Chen et al. have proposed a high yield, cancer-cell-capture filter based on an interfacial 3D assembly of GO layer on Ni foams, Figure 23.480 It was demonstrated that the obtained filter-like foam can selectively capture cancer cells, MCF-7 cells, from blood stream due to the strong topographic interactions between the 3D nanostructured matrixes and extracellular features of cancer cells. The adding of specific antiEpCAM/cell adhesion molecules can further enhance the selectively biological recognition of cancer cells. It is conceivable that the filter-like sponge can supply a facile and low-cost alternative for detecting the circulating tumor cell (CTC) during clinical screening. Meanwhile, Tai and coworkers have utilized the melamine-based sponges to create a RGO-based 3D sponge with superhydrophobic properties through a dip coating method.481 The hydrophobic RGO nanosheets can be controllably anchored on the sponge matrix to mediate the wetting ability from superhydrophilic, 0°, to superhydrophobic, 162°. Therefore, the constructed super-

Figure 21. (A) Schematic image to construct the 3D chitosan/ vacuum-stripped graphene and RGO from the ice segregation induced self-assembly. The inserted MFC performance indicates the power density can reach to 1530 mW/m2. (B) SEM images for composites after incubation with bacteria (blue arrows): chitosan/vacuumstripped graphene-50 (a, b) and chitosan/RGO-50 (c, d). Reproduced with permission from ref 475. Copyright 2012, American Chemical Society.

Figure 22. (A) (a) Schematic image for the bare sponge (a) and the graphene coated sponge (b). (c−f) SEM images of the bacterial colonized graphene-based sponge anode after 50 days. (B) (a) Power generation profiles and (b) Linear staircase voltammetry curves. Reproduced with permission from ref 476. Copyright 2012, Royal Society of Chemistry. 1855

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Figure 23. (A) Schematic synthesis procedures and (B) photograph and SEM images of the RGO/ZnO foam. (C) Schematic synthesis of biotinylated epithelial-cell adhesion-molecule antibody (anti-EpCAM) grafted RGO/ZnO foam; (D) cell capture number on different substrates; and (E) SEM image of MCF7 cell being captured on RGO/ZnO/anti-EpCAM foam. (F) Schematic picture of the captured CTC cells from blood sample. Cell capture number with (G) different capture times and (H) different foam thicknesses. Reproduced with permission from ref 480. Copyright 2014, John Wiley and Sons Publisher.

graphene on nickel surface.487,488 They also found that superhydrophobic graphene foams can also be prepared by coating Teflon onto a CVD-prepared graphene foam.489 The composite foams have an extremely water-repellent nature and potentially can be applied in different areas from antifouling and anticorrosion to self-cleaning coatings. In addition to these pioneering works for synthesizing 3D graphene-coated networks with large surface areas, good conductivity, and unique porosity (99.5 ± 0.2%) and pore size (100−300 μm), the proposed CVD-fabricated 3D graphene foams may also have potential application in the biomedical field. Recently, Cheng et al. have used CVDfabricated 3D graphene foam as a neural scaffold to support the adhesion and differentiation of NSC and provide a conductive microenvironments for electrical stimulation of NSC, Figure 24B,C.490 In general, X-ray photoelectron spectroscopy (XPS) has demonstrated the efficient laminin adsorption on graphene, which is vitally important for the NSC adhesion and formation of ECM on the scaffold. It was validated that 3D graphene foam not only supported better growth of NSC but also maintained the NSC cells in a more active proliferation state compared to the 2D graphene coating layer. Furthermore, the 3D graphene foam can promote the differentiation of NSC toward neurons more efficiently. Therefore, it has been proven that CVDprepared 3D graphene foam can serve as an ideal platform to support the growth and differentiation of NSCs, which

hydrophilic RGO-coated sponge can selectively absorb a wide range of oils and organic solvents with excellent recyclability and high absorption capacities (165 times compared to the weight of the sponge). Based on earlier studies,482−484 the proposed changing of surface wetting ability can be used as a highly efficient protocol for controlling cell adhesion on these composites. 4.5. Graphene Coating Layer on 3D Scaffolds via Chemical Vapor Deposition

The FGNs hybrid 3D hydrogel scaffolds can be easily fabricated by the hydrothermal/chemical induced reduction, noncovalent assembly, covalent cross-linking, ice-templated growth, or interfacial assembly method, but sometimes hydrogels prepared from these methods exhibit poor electrical conductivity and low structural stability due to the high contact resistance at the intersheet junctions and severe structural defects during gelation process. Cheng and co-workers used the CVD method to deposit highly conductive graphene multilayer on 3D templated nickel foam with CH4 as the carbon source at 1000 °C under ambient pressure, Figure 24A.485 These graphene frameworks have the beneficial 3D features of an inherent and interconnected macroporous structure. The CVD-prepared graphene sponge has been utilized to serve as a gas-sensing electrode due to its high sensitivity on NH3 and NO2 .486 Meanwhile, Cheng et al. has found that wrinkled graphene coatings can be generated by using the thermal expansion of 1856

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Figure 24. (A) Representative method of CVD growth of 3D graphene layer on the nickel foam. Reproduced with permission from ref 485. Copyright 2011, Nature Publishing Group. (B) (a) SEM image and (b) magnified SEM image for 3D graphene layer grown on Ni foams. (c) Typical Raman spectrum of 3D graphene foam. (d) High-resolution C1s and (e) N1s XPS of 3D graphene foam with pre- and postlaminin treatment. (C) NSC adhesion and proliferation on 3D graphene foam (a and b). (c) Cell viability assay of NSCs on 3D graphene foam and statistic live cell ratio on 2D graphene films and 3D graphene foam. Fluorescence images of (d) NSCs and (e and f) differentiated NSCs under different conditions proliferated on 3D graphene foam. Reproduced with permission from ref 490. Copyright 2013, Nature Publishing Group.

graphene scaffolds suggest that their physical characteristics may have an important role in the enhanced differentiation. In conclusion, it is suggested that both chemical and physical properties of graphene act synergistically while ruling osteoblastic differentiation of stem cells.494 The excellent electrical conductivity, large and continuous porous structures, and good bioactive properties of the 3D graphene architectures obtained by CVD method make them also good candidates as anode electrodes in MFCs.495,496 Song and Chen et al. have fabricated PANI-modified, 3D graphene foams for anode materials in MFCs, Figure 25B.219 The composite anode was fabricated by deposition of PANI on the interface of graphene coated 3D foam via CVD method. The 3D graphene/PANI composite sponge shows high bacterial loading capability since the sponge provides large surface area and high bioactivity to produce the bacterial biofilms in 3D manner. Meanwhile, due to the large surface area to accept electrons and highly conductive pathways of graphene-based 3D network, the electron transfer at its interface is also significantly enhanced. Furthermore, because of the CVDprepared 3D foam and continuous and largely smooth graphene layer in the scaffold, the lipid membrane of bacteria will not be disrupted due to the face-to-face contact, the sharp nanoscale features of FGNs induced cell membrane penetration will be limited, and cytotoxicity from the uptake of nanomaterials will also be suppressed. Therefore, it is expected that the 3D graphene/PANI composite scaffolds will be promising electrode materials for fabricating large-scale MFCs, whose

indicates that this scaffold owns potential applications in neural tissue engineering and neural prostheses. It is also worth noticing that the 3D graphene foam not only promotes NSC growth and differentiation, it also encourages adhesion and growth of many other types of cells. In another study, Sung and co-workers have validated that the graphene coated 3D foam can act as a biocompatible substrate to accelerate the osteogenic differentiation of hMSC, Figure 25A.491 They employed 3D graphene foams as culture substrates to maintain the viability and osteogenic differentiation of hMSC. hMSCs on 3D graphene foam showed long protrusions extended from defined cell bodies (black arrows); the length is up to 100 μm (yellow arrowheads). Therefore, we may conclude that CVD-fabricated 3D graphene foams can be potentially developed into novel, conductive, and robust scaffolds for regenerative medicine. Graphene layer and FGNs hybrid calcium phosphate compounds have been applied for osteogenic differentiation of stem cells.492,493 However, the cellular mechanisms involved in this process remain unclear. Rosa et al. have applied 3D graphene foam and 2D graphene substrate to investigate key factors on both the genomic and protein levels that are involved in the osteogenic differentiation.494 It has been found that 2D and 3D graphene scaffolds induce differentiation of stem cells into mature osteoblasts at higher levels than the glass or PS substrates. Bone-related genes and proteins were upregulated on graphene regardless of the use of osteogenic medium. The high gene expressions of MHY10 and MHY10-V2 on 2D and 3D 1857

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Figure 25. (A) Construction of 3D graphene foam from nickel foam. SEM images of 3D foams (a) before and (b, c) after removal of nickel. (d-f) hMSCs cultured on 3D graphene foam. Reproduced with permission from ref 491. Copyright 2013, Royal Society of Chemistry. (B) SEM images of graphene/PANI (a−c) anodes with bacteria after 60 h with Shewanella oneidensis (S. oneidensis) MR-1 cell suspension. (d) Power generation and (e) polarization curves (inset I−V relation) of the MFCs. Reproduced with permission from ref 219. Copyright 2012, American Chemical Society.

and a small amount of polylactide-co-glycolide, as a building block to construct arbitrarily shaped scaffolds, Figure 26.498 This obtained FGNs-based architectures exhibit the highest electrical conductivity compared to any other 3D printed carbon-based scaffolds to date. Meanwhile, the composite 3D printed scaffolds also show flexible mechanical property, high stem cell compatibility and neurogenic activity, and surgically friendly. In vivo studies also suggest that the 3D printed graphene is biocompatible since there is no evidence of graphene flakes observed in the liver, kidney, or spleen. However, these methods always require some additional composites to adjust the viscosity of graphene based ink for achieving a self-supporting 3D structure. Constructing pure GO or RGO 3D architectures with boundary free and controlled microstructure are still difficult to process by 3D printing. To overcome this bottleneck, most recently, Zhou and Lin et al. developed a new 3D printing method by ejecting the waterdispersed GO ink on ice support, followed with freezing-drying and thermal reduction, the designed 3D graphene aerogels were lightweight (90%, within a few minutes. The observed antibacterial activity can be retained even when the FGNs multilayer is placed underneath pork tissue (3 mm thick), which indicates the FGNs multilayer can adsorb the near-infrared solar light. The proposed RGO-based multilayer with near-infrared sensitive antibacterial activity may provide a novel surface coating strategy to achieve highly efficient surface disinfection of biomedical implants and many 1872

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Figure 38. (A) Schematic image of using the LbL cell seeding and deposition method to synthesize the PLL-GO based multilayer tissue. (B) (a) Cross-sectional confocal images of the (top) control group and (bottom) 3-layer tissue constructs. (b) Hematoxylin and eosin stain images of 3-layer 3T3 fibroblasts. (c) Schematic cross-section image of a 2-layer construct. (C) (a) Schematic image (left) and 3D reconstructed confocal images (right) of 2-layer cardiomyocytes and endothelial cells, (i) without any ECM layers, (ii) with pristine PLL, (iii) with PLL-coated GOs, and (iv) 3layer cardiomyocytes and endothelial cells with PLL-coated GOs. (b) Photograph of the peeled cellular construct and the confocal images of the 2layer cardiomyocyte construct. (c) Optical images of the 2-layer cardiac actuator. (d) Substitution of the actuator in (c) under electrical stimulation. Reproduced with permission from ref 657. Copyright 2014, John Wiley and Sons Publisher.

pristine graphene coating, due to its strong hydrophobic surface, Parra et al. indicate that there is no obviously bacterial inhibition ability to the graphene coated copper surface.646 Meanwhile, the graphene coating could successfully protect metal surfaces from corrosion in biological and medical applications. While, the study of Villalobos et al. has revealed that the graphene coatings show no bactericidal ability, but when bacteria are in contact with bare graphene-coated surfaces, they may exhibit certain reduction of the adhesive ability due to the reduced expression genes related to adhesion.647 For the FGNs, Tang et al. suggested that GO could act against the viability of dental pathogens, such as the Streptococcus mutans, Porphyromonas gingivalis, and Fusobacterium nucleatum.648 In another study, Wang et al. validated that the composite of zinc oxide (ZnO) and GO (ZnO/GO) exhibited excellent antibacterial activities to E. coli without obvious toxicity to the other mammal cell lines.649 The ZnO

nanocomposites have been proven to function as efficient coating materials to modify the Ti substrate via the cathodic electrophoretic deposition process.639,640 Compared to pure HA coating, the addition of GO or graphene into HA coatings can decrease the potential of surface cracks with increased adhesion strength and resistance to body fluid induced corrosion. Moreover, the GO/HA or graphene/HA coating both exhibit much higher cell adhesion and viability compared to the HA uncoated and coated Ti substrates. The above studies suggest that coating FGNs on implants or substrates can significantly improve the interfacial properties of biomaterials and thus enhance their performance in clinical treatments and tissues regeneration.641 Except for the enhanced cell adhesion ability, using graphene or FGNs multilayers to inhibit the interface bacterial growth and attachment is another hot research area due to the strong interactions between bacteria and FGNs.617,642−645 For the 1873

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PLL-GO, it is even possible to fabricate hybrid cardiac constructs with spontaneous beating behavior as shown in Figure 38C (b-d).

nanoparticles have long been used as biocompatible and high efficient antibacterial reagents.650 The synergistic bactericidal activity of ZnO and GO may lead to the better growth inhibition to bacterial cells. In the composite system, GO can maintain the stability of ZnO and serve as the nanocarrier to store the dissolved zinc ions. The Ag-GO composites modified polyamide membranes and its bacterial inhibition ability have also been studied by Rahaman et al.651 To apply the photothermal ability of graphene, Ling et al. have proposed to use the RGO-Fe2O3 nanocomposite as photothermal reagent for fast killing of bacteria under NIR irradiation.652 Integration of antibacterial peptide or protein with FGNs is another promising strategy to achieve surface bacterial inhibition. The Zhang group has immobilized lysozyme-GO (RGO) on a polyethersulfone ultrafiltration membrane due to its excellent antibacterial performance and nontoxicity.653 The hybrid membranes exhibited a much better bacterial inhibition performance against E. coli than the pristine membrane. Besides the applications in efficient surface modification of implants or medical devices, FGNs-coated nanostructures have also proven to be promising candidates for mimicking certain structures and can function as native ECM materials for artificial tissues. By applying the technology of electrospinning, Kim et al. successfully prepared the chemically bonded GOpolyurethane composite fibers.654 Doping of 1 wt % GO can significantly enhance the mechanical properties and hydrophilicity of a polyurethane matrix. Meanwhile, the assynthesized fibrous polyurethane composite membrane can be coated on the surface of a stent, notably, no crack or delaminate was observed upon repeated cyclic stress. Similarly, Parameswaran et al. have used the GO to reinforce poly(carbonate urethane) electrospun membranes.655 The static mechanical properties indicated a tensile strength increase 55%, toughness increase 127% for the 1.5 wt. % GO doping. The in vitro cytotoxicity and hemolysis tests displayed the membranes with excellent biocompatibility. Besides GO, GQDs is also promising additive to improve the properties of nanofibrous membranes, and Su and Wei et al. have reported a facile technique to fabricate a GQD blended nanofibrous PVA membrane.410 This membrane was utilized to achieve dualpurpose fluorescent and electrochemical biosensors to simultaneously detect hydrogen peroxide and glucose. Mixing biopolymers with FGNs can provide a more biodegradable membrane scaffold for diverse applications. Wang et al. utilize the silk fibroin to prepare GO-based hybrid film by simply casting.656 The presence of GO in the silk fibroin matrix increased the silk II content due to the intermolecular forces between GO and silk fibroin molecular chains, which contributed to enhanced mechanical properties and thermal stability. The composite films, with 0.5 wt % GO doping, could support better cell adhesion and proliferation than the pristine silk fibroin film. Recently, the Khademhosseini group has proposed that the bioactivity of FGNs can be used to fabricate cell-hybridized multilayer construct through the LbL selfassembly of positively charged PLL-GO and negatively charged cells, Figure 38.657 The PLL-GO structures were able to act as cell adhesive platform that significantly facilitated the production of layered FGNs-cell hybrid constructs with strong interlayer connectivity. Interestingly, this approach enables controlled growth of FGNs-cell multilayer constructs with tunable thickness and high cell viability, which is extremely useful for constructing dense and tightly connected cardiac tissues. By coculturing the cardiac cells and other cell lines with

5.3. Stem Cell Engineering and Tissues Regeneration

FGNs are important candidates for the construction of synthetic scaffolds in both stem cell engineering and tissue regeneration. In the design of ideal FGNs-based artificial scaffolds, one must be able to mimic the properties of native ECM in terms of chemical and physical properties. FGNs show outstanding mechanical properties that strengthen the scaffolds. Their high affinity for proteins and many other biomolecules promotes adhesion of human cells and bacteria and their high electronic conductivity provides electrical stimulation to the adhered cells. Therefore, researchers have developed various functionalized FGNs to obtain high cell compatibility and adhesive moieties.250 In this section, we will shortly summarize the current advantages in using FGNs-based architectures for stem cell engineering, as shown in Table 6, and highlight the recent progress in the fabrication of FGNs-based architectures for stem cell based therapy. It should be noted that the cell culture media or scaffold compositions are important when analyzing all the cell culture results from the following studies. In most of the cases, the growth factors are additionally added or immobilized in FGNs-based architectures to achieve stem cell differentiation, but there are also some cases where growth factor is not needed for stem cell differentiation. These factors should be taken into account to assess the future impacts of certain FGNs-based architectures. 5.3.1. FGNs for Controlling Stem Cell Fate. FGNs-based coating films can function as implantable and multifunctional platforms for stem cell adhesion, growth, and selective differentiation.290,303,667−669 Park et al. have found that GO can stimulate myogenic differentiation by promoting the formation of multinucleate myotube and enhancing the generation of differentiation-specific genes.670 Lee et al. have reported that graphene can serve as a preconcentration nanoplatform to adsorb the osteogenic inducers via noncovalent interaction ability, which accelerates the formation of osteogenic lineage of MSCs.102 Similarly, Nayyak et al. show that the graphene-coated substrates, including the glass, Si wafer, polyethylene terephthalate, and PDMS, are remarkable bioactive and cell compatible platforms to accelerate the growth and targeted osteogenic differentiation of hMSCs.188 In another report, Chen et al. report that graphene and GO-based film coated platforms can promote the growth and spontaneous differentiation of iPSCs into the ectodermal and mesodermal lineages.289 However, the graphene-based surface inhibits the endodermal differentiation of iPSCs, while GO-coated film enhance the differentiation of iPSCs toward the endodermal lineage. And very recently, the GQD has been found can promote the self-renewal and osteogenic differentiation of MSCs.671 Combined with many recent reports, it is believed that the surface physical and chemical characteristics of graphene and GO can govern the differentiation activity of stem cells, including ESCs, iPSCs, MSC, and embryoid body.668,672−677 One of the most promising applications of FGNs is for NSC engineering due to their high electrical conductivity.376,678 Park et al. have demonstrated that the hNSCs can adhere and grow well on graphene multilayers.191 Cocultured hNSCs on graphene-coated surfaces are able to differentiate into neurons by simply transforming the normal media to growth factors 1874

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hBMSCs

hBMSCs

RGO-cell biocomposites

fibronectin adsorbed RGO-cell spheroid

rBMSCs

3D graphene foams

hMSCs

hMSCs

3D graphene foams

3D printable RGO inks

rNSCs

hMSCs

rBMSCs

3D graphene foam from CVD coating

CNT and RGO blended poly-L-lactic acid (PLLA) nanofibrous scaffolds GO-CaP nanocomposites

rBMSCs

self-supporting RGO hydrogel films GO/PLL composite films

rBMSCs

hMSCs

2D RGO-chitosan film

hBMSCs

2D RGO and GO films

DMEM, with 10% fetal bone serum. RGO samples are incubated with 100 nM dexamethasone, 50 μg/mL ascorbic acid-2-phosphate, 10 ng/mL of transforming growth factor-beta 3 (TGF-β3), 100 μg/mL sodium pyruvate, 40 μg/mL proline, 1% insulin, transferrin and sodium selenite overnight DMEM, with 10% fetal bone serum

DMEM, with 10% fetal bone serum, no neurogenic factors is added during neurogenic differentiation of hMSC

DMEM with 10% FBS and 0−5.96 g/L HEPES buffer. Myogenesis was induced by DMEM-H, 10% FBS, 5% horse serum, 50 μmol/L hydrocortisone, 0.1 μmol/L dexamethasone

growth medium (Thermo Scientific HyClone AdvanceSTEM MSC expansion kit) and osteogenic differentiation medium (Thermo Scientific HyClone AdvanceSTEM MSC osteogenic differentiation kit) DMEM-F12 with 2% B27 supplement (Life Technologies), EGF (20 ng/mL) and FGF-2 (20 ng/mL); differentiation of NSCs was induced by with medium containing DMEM-F12, 2% B27, retinoic acid (RA, 1 μM) and FBS DMEM with 10% heat-inactivated FBS

DMEM with 10% heat-inactivated FBS, 2% BSA, 2 mM l-glutamine, 10 ng/mL EGF, and 10 ng/mL bFGF. EGF and bFGF are removed to initiate the differentiation ReNCell VM media from Millipore, culture dish coating with laminin (20 μg/ml) and poly-L-lysine (10 μg/ ml) coated culture dishes. bFGF-2, 20 ng/ml, and EGF, 20 mg/ml, are supplied. EGF and bFGF are removed to initiate the differentiation DMEM with 10% FBS, 2 mM L-glutamine, and 10 ng/mL bFGF-2. Osteogenesis of hMSCs was induced by adding 10−4 mM dexamethasone, 10 mM β-glycerophosphate, and 0.1 mM ascorbic acid DMEM with 10% FBS; osteogenic differentiation is initiated with 10 mM β-glycerophosphate, 10−8 M dexamethasone, and 0.2 mM ascorbate DMEM with 10% FBS; osteogenic differentiation is initiated with 100 nM dexamethsone, 50 μM ascorbic acid, and 10 mM glycerol 2-phosphate DMEM with 10% FBS; osteogenic differentiation is initiated with 50 mg/ml L-ascorbic acid, 10 mM glycerophosphate and 100 nM dexamethasone low-glucose DMEM medium supplied with 10% FBS; osteogenic differentiation is initiated with dexamethasone (10−8 M), β-glycerol phosphate (10 mM), and ascorbic acid (0.2 mM) culture medium (Cyagen) supplemented with 10% FBS; osteogenic differentiation is initiated with 0.05 mmol/L vitamin C, 10 mmol/L b-sodium glycerophosphate, and 1 × 10−8 mol/L dexamethasone

hNSCs

hMSCs

Geltrex in mTeSR1 media (Stem Cell Technologies)

hESCs

2D RGO nanogrids

DMEM with 10 vol. % FBS, and BMP-2 slow releasing from graphene surface

hMSCs

hNSCs

α-MEM medium, with heat inactivated 10% FBS

hMSCs

hBMSCs

2D RGO-nanoparticle coating films

2D single-layer graphene produced by CVD 2D GO-coated Ti substrate 2D CNT−graphene hybrid layer synthesized by CVD 2D RGO and GO films

DMEM with 10% FBS; 30 μM of retinoic acid is added for neural differentiation

hNSCs

culture medium

high glucose Dulbecco’s Modified Eagle Medium (DMEM) without sodium pyruvate, supplied with 15% FBS, 0.1 mM nonessential amino acid, 0.1 mM 2-mercaptoethanol and 1000 U/mL mouse leukemia inhibitory factory DMEM with growth factors (bFGF and EGF); graphene surface coating with laminin

cell lines

iPSCs

FGNs-based architectures

2D GO layer on glass substrate from dip coating 2D graphene layer on a glass substrate 2D fluorinated graphene layer from CVD coating

Table 6. Summary of FGNs-Based 2D and 3D Architectures for Controlling Stem Cell Fate highlights and new findings of the study

ref

660

RGO nanogrids show fast osteogenic differentiation of the hMSCs

RGO flakes cocultured within the MSC spheroids, which promote the generation of angiogenic growth factors and Cx43 in hybrid spheroids

3D graphene-based foams enhance the adhesion and viability of hMSCs, and accelerate the osteogenic differentiation 3D graphene-based foams exhibit good biocompatibility and can enhance the growth and proliferation of rBMSCs. And also, the rBMSCs loaded 3D scaffold obviously facilitate the wound closure based on the rat model 3D printing scaffold supports the adhesion, viability, growth, and neurogenic differentiation of hMSC with remarkable enhanced expression of glial and neuronal genes RGO-cell biocomposites can preconcentrate growth factors for chondrogenic differentiation

GO-CaP nanocomposites can significantly facilitate the osteogenesis of hMSCs and also promote more calcium deposition 3D graphene-based foam promotes the rNSCs differentiation toward neurons

192

507

498

666

491

490

665

664

663

662

661

102

301

2D-patterned structures can enhance the adhesion, axonal alignment, and neuronal differentiation of hNSC

RGO and GO are effective preconcentration platforms to enhance the growth and differentiation of stem cell nanotopographic cues of the film promote adhesion, growth, and differentiation of hMSCs hydrogel film can induce the osteogenic differentiation without adding of any chemical inducer GO/PLL constructs not only promote the growth of MSCs, but also increase the speed of osteogenic differentiation RGO shows more significant influence on accelerating the osteogenic differentiation of BMSCs and in vivo osteogenesis than the CNT blended scaffolds

293

659

658

189

285

191

289

RGO film induces more neuronal differentiation of hNSCs than the GO film

fluorinated graphene exhibits neuro-inductive effect via spontaneous cell polarization, therefore significantly improving the cell adhesion, growth, and neuro-induction of MSCs graphene coating made from CVD is promising for bone reconstruction by directing the MSC differentiation into osteoblast lineage GO modified substrates can adsorb a large amount of BMP-2, thus significantly enhancing the osteogenic differentiation of hMSCs CNT-graphene layered hybrid can enhance the adhesion of hESCs and maintaining their viability

graphene induces more hNSCs’ neuronal differentiation than toward glial cells

GO modified substrates allow attachment, proliferation and differentiation of iPSCs

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Figure 39. Schematic image to depict the controlled differentiation of adipose-derived stem cells on different graphene hybrid-pattern arrays. Fluorescence images show the F-actin-stained hADMSCs. Scale bar: 100 μm. Reproduced with permission from ref 302. Copyright 2015, American Chemical Society.

differentiation of NSCs. In a recent study, fluorinated graphene was utilized to promote the adhesion and growth of MSCs, which also exhibited a neuro-inductive influence due to the spontaneous cell polarization.285 By applying the ink-jet printing method, it is validated that fluorinated graphene shows enhanced neurogenesis via channel-confined cellular elongation without adding of any chemical factor. Not only can graphene be used as a chemical cue to retain the stem cell phenotype, but it can also be fabricated into nanopatterns for a noninvasive regulation of stem cells’ growth and targeted differentiation.302,683,684 The Lee group has cultured hNSCs on a graphene-nanoparticle film with patterned structures that shows a unique behavior with enhanced adhesion, axonal alignment, and neuronal differentiation of hNSC.301 They have also fabricated the GO structures with combinatorial patterns to significantly regulate the specific differentiation of human adipose-derived MSCs (hADMSCs), Figure 39.302 Notably, the GO film-based line-pattern is highly powerful for regulating the stem cells with elongated morphology, thus leading to higher osteogenic differentiation. Meanwhile, it has been demonstrated that the generated GO grid-patterns can convert mesodermal stem cells to ectodermal neurons with high differentiation ratio (30%) due to the GO grid-patterns mimicking neuronal networks of native tissues. Besides the substrate coating, FGNs-based 2D film and 3D foam structures may be more efficient in promoting NSCs adhesion, growth, and differentiation.27,601,680 Cheng and coworkers have shown that the 2D graphene-based film can promote well on the proliferation of neural circuits and accelerate the electrical signaling in the neural network.601 Meanwhile, the 3D graphene-coated foams can also encourage NSC proliferation and differentiation toward neuronal lineages with high electrical stimulation, which is even better than the 2D film on stimulating the neuronal differentiation of NSCs.27 Furthermore, the GO-hybridized polymeric hydrogels may

absent media.679 After three weeks of differentiation, many detached hNSCs are observed from the glass surface; while, it is observed that the graphene modified surface was fully colonized by the differentiated neuron with well extended neurite. They suggest that graphene-coating layer provides more beneficial microenvironments for the hNSC adhesion, differentiation, and neurite outgrowths than conventional substrates. They also have indicated that graphene has better electrical coupling with the NSCs during the differentiation or electrical stimulation. Recent studies have indicated that both the CVD prepared and wet synthesized FGNs can be applied for electrical stimulation to the growth of NSC. Cheng et al. had found that NSCs were able to differentiate into a neuron network on 2D graphene layers. The graphene layer was used to further electrically stimulate the neuron networks.601 They concluded that more neuron cells and corresponding spontaneous postsynaptic action potentials were generated on the graphene layer than on the TCPS. Akhavan et al. have also achieved similar results by using electrical stimulation currents to facilitate the differentiation of NSCs into neural cells on a 3D GO foam.680 They indicated that the electrical stimulation could promote the growth speed of the NSCs and boost their differentiation to neuronal cells (rather than glia cells). Meanwhile, by the same group, they have also indicated that both the pulsed laser and flash photo can be applied to stimulate the differentiation of NSCs on a graphene or FGNsbased multilayer.294,681 In a recent study, Sung get al. indicate that graphene-based substrates can promote the efficacy of neuronal differentiation in hMSCs at low frequency electromagnetic fields.682 They clearly proved that the induced neurogenesis was caused by tuning the gene expression, and enhanced cell adhesion with activated focal adhesion kinase and intracellular influx. Besides electrical stimulation, the functional groups on FGNs can play a chemical cue to influence the growth and 1876

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Figure 40. (A) Schematic illustration to prepare the PCL/FGNs composites for orthopedic use. (B) SEM image and energy dispersive spectrometer of mineral deposited composites. (C) Calculated mineralization ratio induced by hMSCs on different substrates. The *, ◆, ○, ●,⊕, ⌀, Φ, θ, and ⊗ indicate the statistically significant difference (p < 0.05) compared to neat PCL, PCL/GO_1, PCL/GO_3, PCL/GO_5, PCL/RGO_1, PCL/ RGO_3, PCL/RGO_5, PCL/AGO_1, and PCL/AGO_3, respectively. (D) Antibacterial activity of the PCL and PCL/FGNs composites. The *, ◆, and ● indicate the statistically significant difference (p < 0.05) compared to neat PCL, PCL/GO_5 and, PCL/RGO_5, respectively. (E) SEM images of biofilm formation on the surfaces of bare PCL, PCL/GO_5, PCL/RGO_5, and PCL/AGO_5. Reproduced with permission from ref 694. Copyright 2015, American Chemical Society.

provide a suitable and conductive scaffold for neural tissue regeneration.685 Lee et al. have indicated that graphenemodified 3D nanofibrous scaffolds are able to selectively guide the neuronal differentiation of NSCs toward oligodendrocytes, which are the myelinating cells of the central nervous system. Moreover, this process is facilitated without adding any chemical differentiation inducers into the cell cocultured media, which underlines the potential of this biomaterial approach for neural tissue regeneration.381 Hersam and Shah groups have designed a 3D printed, FGNs-based architecture, which not only supports the adhesion, viability, and growth of hMSC, but also achieves neurogenic differentiation and function with remarkably enhanced expression of glial and neuronal genes in simple DMEM culture medium without neurogenic factors.498

The missing in vivo studies from current reports, however, would have provided useful insight to the neural tissue toxicity of FGNs-based architectures and their potential in repairing neural functionalities at the lesion site. Another recently reported interesting results from electrical stimulation of neural differentiation had been achieved by Li, Liu, and Wang et al.;686,687 they found that the RGO hybridized PEDOT or collagen hybrids could be used for electrical stimulation systems for promoting the differentiation of MSC into neural cells without adding any chemical or biological factors. Due to their strong stiffness, strength, and modulus, FGNsbased composites are potential candidates for bone reconstruction, which is a major and global health problem. FGNsconstructed scaffolds for biocompatible platforms to enhance 1877

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Figure 41. (A) Schematic image to prepare GO-collagen scaffolds. (B) Immunocytochemical staining on bare collagen and GO-collagen scaffolds. Scale bars: 100 μm. (C) Relative ratio of PCNA (proliferating cell nuclear antigen)-positive cells to the total cell number. (D) The proposed signaling pathway of cellular mechanosensing on stiff substrates. (E) Western blot analysis and quantification in hMSCs. (F) Immunocytochemical images of F-actin (green) in hMSCs after 3 days. Scale bars: 50 μm. (G) Expression of ALP (alkaline phosphatase) and OP (osteopontin) genes by Y27632, a coiled-coil-containing protein kinase inhibitor, as evaluated by quantitative real-time reverse transcriptase polymerase chain reaction analysis. Reproduced with permission from ref 699. Copyright 2015, Elsevier.

compatibility and osteoinductivity, which demonstrates the potential of FGNs hybrids in bone regenerative medicine.662,693 More recently, the PCL-FGNs composites with GO, RGO, or amine-functionalized GO (AGO) have been examined for orthopedic applications, Figure 40.694 Besides markedly increased storage modulus, the in vitro studies of cell attachment and proliferation reveal that both the AGO and GO can significantly increase the growth of hMSC, while simultaneously induce bacterial cell death. The AGO composites exhibit the best inhibition on biofilm formation due to their positive charged amine groups, which may increase the GO-membrane interactions. The large surface area and highly active surface of FGNs endow them with the ability to act as efficient delivery vehicles to bind and solubilize biomolecules. The conductive matrix can be used for long-term cell culturing with electrically controlled differentiation of stem cell.83 Meanwhile, since the osteogenic differentiation needs several weeks, sustained release of proteins, like BMP-2, can accelerate this process. Titanium substrates with GO-coated layers have been explored for loading and sustained release of BMP-2 to increase osteogenic

stem cell viability, attachment, migration, and differentiation will greatly promote the development of bone stem cell therapy.671,674,688−692 Compared with several traditional materials, like PLLA, polycaprolactone (PCL), PLA, and other bioactive inorganic materials, FGNs can mechanically, chemically, and physically better match the properties and characteristics of native bones. In the meantime, FGNs-based composites have shown better adhesion properties for the bone stem cells that are being widely used in bone research.302 Li and Zou et al. find that a graphene-based self-supporting hydrogel film (GSHF) can be utilized to investigate the intrinsic properties and potential applications of graphene-based bone scaffolds.662 This free-standing film has proved to have excellent cell adhesion, spreading, and growth rate to rat bone marrow stromal stem cells (rBMSCs). It is particular interesting that the GSHF film alone, without additional inducer, is capable to induce the osteogenic differentiation of rBMSCs both in vitro and in vivo. After implanting the GSHF film into the rat subcutaneous position, there is limited formation of fibrous capsule, low in vivo tissue response, and generation of new blood vessel. Therefore, the GSHF film exhibits good cell 1878

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Figure 42. (A) Schematic image describing the enhanced chondrogenic differentiation of hASCs-GO hybrid. (B) SEM images of P+TGF-β, P-GO +TGF-β, and P-GO-TGF-β (white arrows indicated GO on the hybrid pellet surface). (C) Distribution of DiI-labeled GO sheets (red) in the hybrid pellet. Scale bar: 100 μm. (D) TEM images of GO sheets (arrows) interacted with cells in the hybrid pellet. Scale bar: 0.5 μm. (E) (a) Western blot analysis for type II collagen. RT-PCR (b) and real time-PCR (c and d) chondrogenic markers. Reproduced with permission from ref 120. Copyright 2014, John Wiley and Sons Publisher.

differentiation in vitro and in vivo.695 Microcomputed tomography and histological analysis have proven that there is more extensive bone formation than in unmodified substrate. Free-standing RGO films with controllable nanofiber patterns and adsorbed fibronectin protein have also been fabricated to enhance stem cell adhesion and proliferation via the synergistic effects of the reactive protein and the patterned roughness.696 Additionally, GO-modified nanofiber scaffolds with PCL or PLGA have also been prepared using electrospinning for MSCs-based bone regeneration.382,697 The RGO modified nanofibrous scaffolds were proved to be more efficient in promotion of MSC cell anchorage and proliferation compared to that of free-standing RGO film without the nanoscale fibrous structure.698 Since collagen has been widely applied for osteogenic regeneration, Kim and co-workers have demonstrated that covalent anchoring of GO nanosheets to 3D collagen-based scaffolds not only enhances the mechanical strength (3-fold of increased stiffness) but also promotes osteogenic differentiation with no obvious toxicity, Figure 41.699 By using hMSCs as model bone stem cells, it is found that the obtained better osteogenic differentiation on the GO doped scaffolds is more likely induced from the mechanosensing of MSCs. The cell adhesion involved molecules will be either up-regulated or activated upon contacting with a stiff interface. It is expected that the constructed 3D GO doped collagen-based scaffolds will enable a beneficial platform for bone-related stem cell culture and regeneration treatments.700

For chondrogenic generation, Agarwal’s group has used the dip-coating method to coat poly (lactic acid-poly epsiloncaprolactone) (PLC) copolymer on a CVD-prepared graphene 3D scaffold for stem cell engineering. The obtained PLCgraphene hybrid foam demonstrated excellent compatibility and chondrogenesis.701 More recently, Kim’s group has proposed to use the growth factor and other extracellular protein adsorption properties of GO for the chondrogenic differentiation as shown in Figure 42.120 They utilize GO to adsorb a cell-adhesion protein, fibronectin, and a chondrogenic factor, TGF-β3, and then incorporate them with human adipose-derived stem cells (hASCs) to form GO hybridized cellular-pellets. The hASC-GO-based pellets is demonstrated to enhance the hASCs survival and promote their chondrogenic differentiation with enhanced formation of cell-fibronectin interaction and more effectively in delivery of TGF-β3. Therefore, this approach presents new insights to provide a more biofunctional and biohybrid system in stem cell based regenerative treatment. Inorganic-based nanocomposites have also been developed to enhance the osteoinductive effect on hMSCs.702,703 Bi et al. have reported that the GO-CaP nanocomposites significantly facilitated the osteogenesis of hMSCs with improved deposition of calcium, which enables their promising future in bone regeneration.665 Xiao and co-workers demonstrated that GOblended β-tricalcium phosphate (β-TCP) bioceramics had better osteogenic capacity of human bone marrow stromal 1879

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DMEM R1640 medium not mention DMEM

mouse skeletal myoblasts C2C12 NIH-3T3 fibroblasts L929 fibroblasts cells, MC3T3-E1 osteoblast cells osteoblast cells HUVECs endothelia cells

NIH-3T3 cells, in vivo mouse skin tests

2D GO and RGO layer on glass 2D RGO-CNT coating 2D GO-chitosan films, patterns

1880

carrageenan-RGO/HA composites octacalcuim phosphate mineralized GO/ chitosan scaffolds GO-peptide nanofibers/HA nanocomposites LbL assembly of GO-fibrinogen nanofibers HA scaffold

3D GO grafting with methacrylated gelatin (GO-GelMA) hydrogel 3D GO-modified poly(propylenecarbonate) foam via supercritical drying 3D GO/Ag blended PAA-NIPAM hydrogel GO, RGO, RGO-HA composites

GO and Ag modified PLGA-chitosan electrospun fiber RGO-blended chitosan-PVA electrospun fiber GO-based heparin-mimetic hydrogels

2D tea polyphenol-RGO/chitosan film 2D polydopamine-GO-based nanocomposites and ultrastrong film 2D GO-incorporated collagen-fibrin composite film RGO-PCL composites

adult mouse brain

TRGO nanosheets

wound dressing

wound dressing osteoblast engineering

in vivo tests R1640 medium DMEM R1640 medium DMEM

HUVECs endothelia cells

fibroblasts and cardiac cells

L929 fibroblasts

S. aureas, L929 fibroblasts, in vivo mouse skin test MC3T3-E1 osteoblast cells

refs

722

versatile tissue regeneration biointerfacial coating materials for tissue regeneration and drug delivery

not mention

87

638 69

bone regeneration and implantation bone regeneration

637,720,721

452

719

454,717,718

76,449

716

214

714,715

713

712 72,336

670 710 68,368,711

297

288,709

172

DMEM, and basal media from Sigma high-glucose DMEM α-MEM (HyClone, USA), BMP-2 release from scaffolds not mention

implantable and hemocompatible hydrogels for drug/protein delivery and tissue regeneration GelMA-based hydrogels show high application potentials in many fields of tissue regeneration, including the cartilage, bone, and vascular and cardiac tissues versatile tissues scaffolds

antimicrobial coating materials

versatile tissue scaffolds

wound dressing

TPG/CS composite promoted the proliferation and differentiation of osteoblasts ultrastrong artificial skin

Luria−Bertani broth

MC3T3-E1 osteoblast cells bone marrow stromal cells and in vivo mouse bone test L-929 fibroblasts cells and MC3T3-E1 osteoblast cells L-929 fibroblasts cells

applications

no influence on the neurogenesis, survival ratios of neuronal and astrocyte are also not influenced skeletal tissue regeneration surface coating materials stiff and conducting substrates for bone tissue regeneration

neural regenerative scaffolds

neural regenerative scaffolds

fibroblast (L-929), neural (PC-12), and muscle (C2C12) cell lines Gram-negative (E. coli and P. aeruginosa) and Gram-positive (S. aureus) bacteria mouse and rabbit in vivo skin tests

DMEM DMEM DMEM

PC-12 neural cells

2D RGO based composite film coating

DMEM with Ham’s F-12 nutrient mixture DMEM, Electrical or NGF stimulation in vivo rat brain injection

culture medium

mouse hippocampal cells

cell types or in vivo tests

2D graphene layer on TCPS

FGNs-based architectures

Table 7. Representative Applications of FGNs-Based Architectures for Tissue Regeneration.

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Figure 43. (A) (a) Schematic diagram of using the mPEG−RGO film for electrical stimulation of PC-12. (b) Electrical stimulation of PC-12 cells on mPEG−RGO and RGO substrates. Reproduced with permission from ref 288. Copyright 2015, Royal Society of Chemistry. (B) The experimental steps of (a) preparation of RGOSH/PMAASH multilayers NGF loaded particles and (b) preparation of RGOSH/PMAASH array on ITO surface for electrical stimulation of neural cells. (c) Confocal microscopy image that shows the resulting PC-12 cells after electrical stimulation with extended neurite outgrowth. (red = microcapsules; green = β-III-tubulin/Alexa Fluor 488, cytoskeleton; blue = DAPI, nuclei.) (d) The neurite length of PC-12 cells on NGF-encapsulating RGOSH/PMAASH by electrical stimulation after 2, 4, and 7 days. (n = 5; *P < 0.05) (E + : electrical stimulation; E − : no electrical stimulation.) Reproduced with permission from ref 709. Copyright 2015, John Wiley and Sons Publisher.

cells (hBMSCs) than pure β-TCP both in vitro and in vivo.704 These scaffolds significantly enhanced the growth, activity of alkaline phosphatase, and osteogenic gene expression compared to the bare β-TCP. The RGO hybridized HA composites also showed enhanced osteogenic differentiation for hMSCs.493 The tests of alkaline phosphatase activity and mineralization of calcium and phosphate indicate that the RGO-HA nanocomposites can synergistically enhance the osteogenic differentiation of hMSCs with no obvious toxicity. Therefore, FGNs hybrid inorganic nanocomposites show high potential to serve as bone related scaffolds due to their high osteoinductive bioactivity and potent effect on inducing mineralization.493,705 5.3.2. FGNs for Tissues Regeneration. Tissue regeneration is an interdisciplinary research topic that aims to provide biocompatible and bioactive substitutes to retain, restore, or enhance the biofunctionalities of a dysfunctional tissue or whole organs.706 Besides the earlier developed conventional or natural biomaterials, the FGNs-based architectures have been intensively investigated for diverse tissue regenerative applications.707,708 Since the stem cell based tissue regeneration has been separately discussed in section 5.3.1, here we will summarize the nonstem cell-based therapy and the applications of FGNs-based architectures in tissue regeneration; some representative examples are listed in Table 7. Until now, many different approaches have been proposed for the construction of 2D FGNs hybrid architectures. Graphene coating on substrates via the CVD method has been validated to be an effective inducer to mediate cell behavior without adding cell nutrition factors.723−725 Choi et al. discover that micropatterns fabricated by surface-initiated

ATRP and soft lithography on CVD-prepared single-layered graphene can be applied for controlling the adhesion of fibroblast and hippocampal neurons.286 More recently, Delacour et al. have reported a detailed protocol on the effect of single layer graphene for the development of primary hippocampal neurons in vitro.726 They proved that neurons grown on PLL modified graphene-coating layers exhibited larger sizes and highly developed dendritic architectures with long and branched neurites. Meanwhile, they revealed that the uncoated pristine single-layer graphene provided similar performance in terms of neural cell adhesion and neurite outgrowth when compared to the PLL coated glass substrate. This study indicated that neurons showed remarkable adhesion ability to graphene, unlike other active substrates used at the cell-biointerface, neurons could directly attach to the singlelayer graphene with high detection sensitivity and improved electrical stimulation, which offered unique advantage for achieving a very strong electrical coupling to study the neural regeneration and treatment of chronic neuronal interfacing.726 Biopolymers, such as gelatin, cellulose, and chitosan, have been applied to construct FGNs hybrid thin-films via solventevaporation or casting-drying methods.68 After adding GO into the biopolymers, the mechanical, thermal stability and electrical conductivity can all be significantly improved.379 For instance, the GO-incorporated collagen-fibrin composite film (GOCF) has been utilized for the wound injury treatment.713 The biochemical, histopathological, and hematological investigations on rats demonstrate that the GOCF film-treated wound skin heal faster than the control and bare collagen-fibrin. Thus it is 1881

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Figure 44. (A) SEM morphology (a-c), electrical (d), and mechanical (e) properties of the G-NFs. (B) The growth of motor neuron cells on different substrates. (a) neuritogenesis (left, green: dendrite marker protein of the microtubule-associated protein-2 (Map) for neurites, red: the neuronal marker protein of III β-tubulin (Tuj) for filopodia; and right: cell maturation, red: neuraxon marker protein of tau expression). (b) The average number of neurites and (c) the average branches of neurites. Data are mean ± SD, n = 4, *p < 0.05, **p < 0.01. Reproduced with permission from ref 736. Copyright 2015, John Wiley and Sons Publisher.

transparent, flexible, and biocompatible poly(ethylene terephthalate) and graphene-based electrode to conduct noncontact stimulation of human neural cells, the electrode allows optical testing of the morphological changes of neurons before and after electrical stimulation.602 Their results showed that at least 4.5 mV/mm electric field was needed for the noncontact stimulation to promote cell coupling of neurons, whereas high electric field stimulation (450 mV/mm) facilitated neuron decoupling. Recently, Wallace et al. have reported that the CVD-fabricated few-layered graphene can be transferred onto a series of biocompatible polymer films, PLA or PLGA, to function as a flexible and cell compatible neural interface to stimulate the growth of neural cell.287 Results showed that the PC-12 cells on graphene coated surfaces showed similar cellsubstrate interactions as that of noncoated polymer films. However, after applying the electrical stimulation by the graphene-based thin film, the differentiation of neural cells was enhanced, which gave clear evidence that graphene-biopolymer composites could provide sufficient charge to influence neural cells in electrically driven nerve-repair applications. Besides the CVD prepared graphene layer, the RGO have also been developed for the electrical stimulation of neural cells. The Liu group has shown that the synthesized methoxy poly(ethylene glycol) (mPEG) grafted RGO can be potential conductive substrates for electrically stimulation of neural cells

expected that the GOCF film shows high potential to act as scaffold materials for wound dressing in the future. One of the most promising applications for graphene and FGNs-based 2D coating/thin films are in neural tissue regeneration due to their high electrical conductivity and bioactivity.678,727−731 Since the neural cells are electroactive, and the electrical conductivity of graphene and FGNs can be easily changed to adapt to the required conductivity of neural interfaces. Furthermore, the chemical and mechanical characteristics of graphene and FGNs can also provide great benefits for long-term neural implants.732,733 Meng has studied to apply the electrical stimulation for in situ modification of PC-12 cells behavior by using graphene-based substrate under different stimulation period, intensity, frequency, electrical pulse and interval change.734 It has been proven that the optimized stimulation condition is at the intensity of 100 mV/mm with the most significant enhancement on PC-12 cell differentiation, neurite extension and growth. Meanwhile, comparing the constant (100 mV/mm) and the programmed stimulation (100 mV/mm) at 1 and 10 Hz, the programmed stimulation results in longer neuritis length, and also the corresponding positive enhancement to PC-12 behavior by programmed stimulation can be significant maintained at long periods (48 h). Graphenebased coating on electrode can also be used for the noncontact stimulation to neurons. Heo et al. have constructed a 1882

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Figure 45. (A) Schematic image of proposed processes to construct the hydrogel and subsequent heart injection of fGO/DNAVEGF/GelMA (GG′). Scale bar: 1 μm. (B) The viscosity of GO/GelMA hydrogels at different shear rates. (C) Proliferation of HUVECs from GG′ transfected H9c2 cardiomyocytes. (D) The representative photomicrographs of each group. Scale bar: 100 μm. Reproduced with permission from ref 454. Copyright 2014, American Chemical Society.

due to its high performances in charge injection, Figure 43A.288 It was suggested that the covalent functionalization of mPEG on RGO could not only benefit the dispersion of RGO in solution, but also enable better double-layer charging capacitance. The tests of calcium imaging on stimulated PC12 cells indicted a predominant increase in cell percentage on mPEG-RGO films due to the higher charge injection capacity compared to pure RGO films, which might provide a much safer and efficient solution for neural prostheses applications. However, more critical and control experiments are needed since only PEG (with a certain antifouling ability) has been anchored, more different polymer species (such as the chitosan, heparin, and PLL) are required to compare the performances on charge injection and neural adhesion. Similarly, Khademhosseini group has demonstrated that the ultrathin RGO films show higher cell adhesion and spreading of C2C12 myoblasts compared to the results of GO films and glass slides.367 More importantly, the increased generation of myogenic proteins and genes demonstrate that a significantly enhanced myoblast cell differentiation can be achieved by electrical stimulation via the RGO film. All these studies validated that RGO-based composite materials are potential candidates to construct electroactive cell-based tissue interfaces, bioelectrodes, and biorobotics.

In addition to these in situ neural stimulation studies, using more-multifunctional, chronic, long-term stimulation via FGNsbased films to enhance nerve growth or differentiation has been demonstrated. Chen et al. have achieved a multiparametric study to enhance the neurite length in PC-12 cells; the ITO substrate can provide electrical stimulation and RGO-poly(methacrylic acid) (PMAA) coated mesoporous silica is able to release NGF, as illustrated in Figure 43B.709 The results suggested that the RGOSH/PMAASH with microscale-morphology could not only serve as bioactive platform to enhance the growth of PC-12 cells but also stimulate the release of NGF and accelerate the PC-12 differentiation under the electrical stimulation, which eventually led to obviously increase both in the cell percentage, neurite number and length. Therefore, these multifunctional RGOSH/PMAASH microcapsules may show potential applications as 3D patterned substrates in neural regeneration and for prosthetic devices. To achieve fully 3D scaffolds with FGNs coating, Lee group has demonstrated that GO coated nanofibers can be a potential scaffold to control neural cell behaviors without adding any differentiation inducers in the culture media since these nanofiber structures have provided an ideal topography in inducing nerve conduits, guiding neurite outgrowth and enhancing axonal regeneration.381 Similar to this strategy, Gao group has coated GO sheets on aligned PLLA nanofiber, 1883

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Figure 46. (A) Schematic image of rat heart with acute myocardial infarction (AMI). (B and C) Determination of the scar area by morphometric analysis. GG′ (fGO/DNAVEGF/GelMA), GG (GelMA with free pDNAVEGF), G (only GelMA), and control (nontreated). (D) Echocardiographic assessment of cardiac function. Reproduced with permission from ref 454. Copyright 2014, American Chemical Society.

significantly enhance the adhesion and growth of fibroblast and endothelial cells.743 Earlier studies have proposed that the synthetic hydrogels that exhibit viscoelastic and transport properties with highly hydrated frameworks are structurally and biologically similar to the local ECM of many different human tissues,744−747 while their weak mechanical properties and insufficient cell interactions have limited their wide range of applications in tissue regeneration. Since the FGNs have good mechanical strength and electrical conductivity and are facile to anchor with diverse polymers and nanomaterials, it may be suitable to serve as a building block for construction of hydrogels for tissue regeneration. The RGO-based hydrogel prepared by the hydrothermal method had excellent adhesion and growth of MG63 cells for 7 days because of the 3D ECM mimicking microenvironment.398 Meanwhile, incorporation of GO into polymeric matrices not only significantly enhance tensile strength and compressive strength but also improve cell adhesion and compatibility.748 Biopolymers (e.g., collagen, DNA, chitosan, and heparin) have been intensively used for fabrication of FGNs hybrid architectures for tissue regeneration due to their excellent cell compatibility and biological degradability. The covalently conjugated GO-chitosan hydrogel can significantly improve cell adhesion, growth, differentiation, and deposition of calcium phosphate by coculturing with mouse preosteoblast cells, MC3T3-E1.711 Furthermore, conductive hydrogels with diverse shapes and structures, tunable swelling properties, excellent cell adhesion, and proliferation activity have been created from graphene-hybridized chitosanlactic acid scaffolds.68 In a recent study, the Khademhosseini group has used the GelMA and GO to construct the GO doped gelatin scaffolds for diverse biomedical applications.718 By incorporating GO, the gelatin hydrogels exhibit improved mechanical strength and electrical conductivity with no obvious cytotoxicity. The GO

which can significantly promote the proliferation of Schwann cell and rat PC-12 cells along the nanofibers, and the differentiation and neurite growth of PC-12 cells are significantly promoted with the addition of nerve growth factor (NGF).735 Most recently, Feng et al. has demonstrated that the RGO sheets coated nanofibers scaffolds (G-NFs) exhibit great potential as soft and flexible neural implants due to their soft physical characteristic, recoverable electrical conductivity, and excellent cell compatibility as shown in Figure 44.736 The GNFs scaffolds show unprecedented acceleration of the primary motor neurons due to the long-term electrical stimulation period. Compared to the conventional used chemical cues, the proposed G-NFs-based electrical stimulation allow more controllable parameters and possibility when dealing with neurologic diseases. In addition, the G-NFs may not only benefit for the applications in neuroscience but also provide methods to extend the excellent properties of FGNs from 2D surface to 3D dimension by assembly of GO, RGO, or other FGNs coating onto nanofibrous architectures.375 Besides the neural tissue regeneration, the FGNs hybrid architectures are also of great interest for regeneration studies of a wide range of human tissues and organs.737−740 Since the structural similarity to ECM components of cardiomyocyte, the FGNs-containing nanofiber scaffolds have been developed for repair of cardiac tissue.697,741 RGO-based chitosan-PVA nanofibrous scaffolds have been applied for wound healing studies in mice and rabbits by Lu et al.716 GO-blended PLA could also be fabricated into nanofibrous scaffolds via the electrospinning technique.742 It was found that adding GO not only improved the mechanical properties but also the adhesive nature of PLA scaffolds toward NIH 3T3 cells. GO had also been incorporated into thermoplastic polyurethane to prepare the nanofibrous membrane as small diameter vascular grafts. It was observed that the GO-hybridized scaffolds could 1884

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Figure 47. (A) MC3T3-E1 cell-induced HA mineralization on the GO-Car substrate. (B) (a) SEM image of GO-Car after mineralization for 14 days, (b) and (c) show the magnified SEM images of (a). (C) MC3T3-E1 cells cultured on glass (a), GO (b), and GO-Car (c) for 14 days. Confocal images of MC3T3-E1 cells cultured on glass (d), GO (e), and GO-Car (f) for 7 days. Reproduced with permission from ref 638. Copyright 2014, American Chemical Society.

and poly (ethylene glycol) methyl ether-ε-caprolactone to form the hydrogel scaffold. Compared to the GO absent group, by using the systematic studies of tissue repair, micro computed tomography and histology observation of rabbit cartilage, it was suggested that the GO doped hydrogel scaffold owned better cellular morphology of chondrocyte, continuous subchondral bone, and thicker newly formed cartilage, which thus confirmed their potential for articular cartilage tissue regeneration. FGNs-based inorganic composite scaffolds also present promising applications in tissue regeneration, especially in hard tissue repair and regeneration.739,750−753 The combination of an interpenetrated organic matrix with calcium phosphate minerals has drawn many interests in hard tissue regeneration.87 In recent years, FGNs-based inorganic composites, i.e., HA and calcium carbonate (CaCO3), have emerged as promising candidates for bone tissue regeneration due to their excellent mechanical properties and cytocompatibility. Park et al. have reported the biomimetic mineralization of CO2 into CaCO3 in the presence of GO nanosheets. After chemical

doped gelatin hydrogels can also be constructed into scaffolds with different shapes (channels, star, and spheres) as hybrid multilayered architectures by using the microfabrication techniques. In another study, they developed an GO and DNAVEGF integrated gelatin hydrogel as injectable and biocompatible ECM mimetic platform for myocardial therapy as shown in Figure 45.454 Then, the therapeutic performance of the composite hydrogels in the peri-infarct regions was studied by using the acute myocardial infarction from rat model. It is validated that the infarcted heart exhibits enhanced density of myocardial capillary and reduced area of scar tissues after treatment with the composite hydrogel as shown in Figure 46A. Furthermore, the GO-DNAVEGF modified gelatin hydrogel treated group showed a better cardiac performance in echocardiography than other control groups after 14 days postinjection as shown in Figure 46B−D.454 Qian et al. revealed that GO-hybridized hydrogels could also be used for articular cartilage tissue regeneration.749 To achieve this, a GO solution was copolymerized with the methacrylated chondroitin sulfate 1885

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Figure 48. (A) General principle of a classic dual chamber MFC. (B) The schematic image shows that the FGNs-based anodes increase the extracellular electron transfer by providing a more conductive and bacteria-adhesive interface.

hybridized, 3D macroporous biofilm. The RGO-based biofilm allows the fast and bidirectional electron transfer from bacteria to the electrodes,508 which can generate much higher outward and inward current than the naturally formed biofilms. RGO, crumpled RGO, and RGO aerogel have also shown promising potential in enhancing the MFC electrical power density when used to modified or construct the anode substrates.772,773 However, as discussed in section 5.2, the GO and RGO exhibit certain bacterial toxicity due to strong interactions between GO and bacterial membrane, especially at the initial contact stage. To clearly illustrate the bacterial inhibition potential of RGO on anodic exoelectrogen, Hu et al. have compared the growth of S. oneidensis MR-1 biofilms on RGOmodified anodes and bare graphite anodes.774 The confocal image and CV results demonstrated that RGO exhibited an obvious bacterial inhibition effect for the initial growth of bacterial biofilm. After 5 h of inoculation, compared to bare graphite anode, the RGO-modified anode exhibited approximately 70% lower electrochemical activity. However, after 18 h colonization, the bacteria on the RGO-modified anodes exhibited a significantly enhanced viability compared to that of the bare graphite, and the electrochemical activity also increased to the same level as that of bare graphite anode. This study revealed that the dual effect of RGO, the initial strong cell membrane interaction may inhibit the bacterial activity, while, after the interfacial protein adsorption, the RGO surface becomes favorable to bacterial attachment and extracellular electron transfer. Therefore, to enhance the initial bacterial attachment, it is believed that introduction of a shielding polymer coating will moderate the strong membrane interactions between bacteria and the FGNs interface. Beyond the minimized toxicity, another potential benefit for polymers decoration is the increased surface hydrophilicity, which can enhance the bacterial adhesion and boost extracellular electron transfer at the interface.775 Zhu and Zhang et al. indicate that the positively charged ionic liquid polymer can be used to functionalized RGO nanosheets and achieve higher biocurrent generation and power output than the bare carbon paper.776 Meanwhile, the PPy or PANI functionalized RGO composites,777−780 PANI networks decorated graphene nanoribbons and PEDOT deposited graphene films by electropolymerization all achieve better MFC performances due to the synergistic effect compared to the nonmodified anodes.80,84,781 In addition, a macroporous and monolithic PANI-hybridized 3D anode has been demonstrated to create a porous structure.219 This anode

reduction of GO, the RGO-CaCO3 scaffold shows increased formation of HA in SBF solution and excellent adhesion and viability of osteoblast cells.88 Besides CaCO3 or HA, strontium can also promote the development of bone tissue, and strontium-decorated RGO (RGO-Sr) hybrid nanoparticles have been applied to incorporate in poly(epsilon-caprolactone) (PECL) scaffold by Chatterjee et al.89 The resulting PECL/ RGO-Sr 3D scaffolds exhibited much better performance in osteoblast proliferation and differentiation compared to the bare PECL and PECL/RGO scaffolds. The sustained release of strontium ions from the hybrid scaffolds is responsible for the increased biological activity and bone cell adhesion and growth. In another study, GO is mixed with poly(methyl methacrylate) (PMMA) and HA to reinforce the bone cement.754 FGN/ mineral hybrid materials can also be fabricated by depositing RGO layers on the gold/HA composite films.755 The obtained RGO/HA composites can synergistically enhance the osteogenesis of MC3T3-E1 preosteoblasts.756 Compared with bare GO, the biopolymer-functionalized GO can perform better in osteogenesis. It has been found that mussel-inspired functionalization of RGO can also induce formation of HA. Inspired by the adhesive mussel foot proteins, dopamine,757 can chemically reduce and form a coating on GO.72 The catecholamine moieties can act as Ca2+ ions binders,758 which lead to the formation of HA on GO surface during the incubation in SBF. Carrageenan-functionalized GO (GO-Car) composite films have been prepared and serve as a platform for bone cell induced HA mineralization, Figure 47.638 It is observed that the GO-Car substrate facilitates the nucleation of HA. Meanwhile, the adhesion and differentiation of MC3T3-E1 cells on GO-Car surface are more efficient than GO or glass. Combined with some other recent studies, it is concluded that the biopolymers-GO composites can act as more effective and promising scaffolds for bone regeneration.738,740,759−762 5.4. Electrode Matrix for MFCs

3D FGNs-based composites with high specific surface areas and electrical conductivity for bacterial colonization have emerged as novel electrode materials in MFC, Figure 48A.763−770 In general, the FGNs-based composites can significantly promote the interfacial microbial colonization and accelerate the formation of extracellular biofilm, which eventually promotes the electrical power density by providing a conductive microenvironment for extracellular electron transfer, Figure 48A.473,771 The Song group reported that they assembled GO and S. oneidensis MR-1 to form an electroactive, RGO 1886

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Figure 49. (A) (a) Construction of 3D macroporous MWCNTs and Fe3O4 decorated graphene foams as MFC anode. (b) SEM image of S. oneidensis MR-1 cells adhered foams. (c) Polarization and power-density curves with different anodes. Reproduced with permission from ref 771. Copyright 2016, American Chemical Society. (B) (a) Schematic image for the synthetic procedures of 3D graphene frameworks. (b) SEM images of the bacterial colonized anode for both exterior and inside areas. Reproduced with permission from ref 767. Copyright 2016, Royal Society of Chemistry. (C) (a) Designing miniaturized MFC with 3D graphene-based macroporous anode. (b) SEM image and (c) Raman spectra of the 3D anode. (d) A comparison of the power density of the 3D anode with different power sources and converters, including thermoelectricity (TE), piezoelectricity (PE), indoor photovoltaics (indoor PV), outdoor photovoltaics (outdoor PV), nickel−cadmium (Ni−Cd) batteries, lead-acid batteries, lithium manganese dioxide batteries and lithium ion batteries. Reproduced with permission from ref 793. Copyright 2016, Royal Society of Chemistry.

toward S. oneidensis MR-1 on the 3D FGNs foams, and the modified anodes exhibit much higher bacterial loading capability than the bare graphene foam. Though, some other inorganic nanoparticles decorated FGNs composites have also shown promising MFC efficiency, such as the TiO2 and SnO2,782,783 their application potential is still unclear since these nanocomponents also exhibit excellent antibacterial activity as reported in many publications.784,785 Graphite, carbon paper, and carbon cloth are generally used for current collectors in MFC;786−790 however, their 2D features have limited the fabrication of high-performance FGNs-based electrodes for use in microbial energy harvesting. Though, FGNs-based 3D monolith or foam can significantly enhance MFC performance, the large-scale applications of these currently developed 3D MFC materials are limited by their complex and high-cost process during scale-up fabrication. Recently, Tong et al. have proposed a scalable and effective electrochemical exfoliation approach to construct monolithic 3D graphene frameworks for high-performance MFC anodes with much improved electrocatalytic activity and macroporous networks for mass transfer, as shown in Figure 49B.767 Li and co-workers have also reported that RGO can be deposited on Ni foam as an 3D graphene frameworks based anode for MFC, which can produce substantially higher power density than many other currently designed carbon-based electrodes (e.g.,

outperformed the planar carbon-based electrode due to its 3D contacting with bacterial biofilm, which can accelerate the electron transfer with highly conductive pathways. Besides the conductive polymers, Zhang and Zhu et al. have proposed that gold nanoparticles decorated FGNs can further enhance the electricity generation in MFCs, which can directly influence bacterial attachment and extracellular electron transfer between bacterial and the electrode.85 Very recently, the Tang and Liu et al. have designed a 3D RGO aerogel decorated with Pt nanoparticles as an efficient and freestanding anode composites for MFCs.86 The 3D graphene/Pt−based anode shows a continuous 3D macroporous structure for bacterial colonization and efficient electrolyte transport. The 3D graphene/Pt−based MFC produces a remarkable power density as high as 1460 mW/m2, which is 5.3 times higher than that of the carbon cloth (273 mW/m2). Moreover, to demonstrate its potential in a real application, the 3D graphene/Pt-based MFC has been successfully applied in driving timer for the first time, this report may provide new avenue toward the real application of MFCs. For designing the inorganic nanoparticles decorated foam, Zhu et al. have created a MWCNTs and Fe3O4 nanospheres modified 3D FGNs foams with open porous structures as anodes for Shewanellainoculated MFCs, as shown in Figure 49A.771 It is found that the Fe3O4 nanospheres significantly enhance the cell adhesion 1887

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Figure 50. (A) (a) Illustration image for the preparation of GOA-GFB electrode. SEM images of bacterial inoculated anode surfaces, GOA-GFB: 2 months (b), 9 months (c), and 18 months (d); unmodified GFB: 2 months (e), 9 months (f), and 18 months (g). (h) Reproducible cycles of cell voltage produced by different anodes with an external resistance of 500 Ω. Reproduced with permission from ref 794. Copyright 2016, Elsevier. (B) (a) GO reduction and self-aggregation into a hydrogel complex in the Geobacter sp. strain R4 inoculated with intact (upper) and autoclaved (lower) inocula. (b) SEM image of the R4-RGO complexes after 30 days. (b) Appearance of the R4-RGO (c) and R4-graphite felt (d) complexes after 30 days. (e) Changes in electricity in the R4-RGO (green) and R4-graphite felt (purple) complexes. (f) CV curves obtained by the R4-RGO (green) and R4-graphite felt (purple) complexes. Reproduced with permission from ref 770. Copyright 2016, Nature Publishing Group.

carbon paper, carbon felt, and carbon cloth).791 It is noteworthy that the flexible RGO-Ni electrodes-based MFC device can produce an optimal volumetric power density of 661 W m−3 (calculated from the volume ratio of anode material).792 In order to further improve the electrical conductivity of FGNs hybrid electrodes in MFC, the Cui group has found that stainless-steel can be integrated into the 3D graphene foam. The composite anode can generate a 14 times maximum power density than that of a pure graphene sponge-based anode.476 Another important index is the cost of the designed anode, it has been evaluated to be at least 1 order of magnitude lower than currently used graphite-based anode. In these earlier studies, the power densities of 2D and 3D FGNs-based MFCs are nearly 2 orders of magnitude lower than many other conventional power sources/converters. To further improve the power density, Ren group has developed a CVD coated 3D foam to push the limit of MFC power density to over 10 000 W/m3, Figure 49C.793 An extremely dense and thick biofilm from the Geobacter sulfurreducens (G. sulf urreducens)-enriched culture on the surface 3D graphene foam was achieved. Therefore, the electrode can generate a power density of 5.61 W/m2/11 220 W/m3 and an areal/volumetric current density of 15.51 A/m2/31 040 A/m3, respectively. The power density of 3D graphene-based MFC is nearly 1−3 orders of magnitude higher than that of PV (indoor), TE, PE, and lithium manganese dioxide batteries; meanwhile, the power density is

comparable with that of Ni−Cd, lead-acid, PV (outdoor), and lithium ion batteries. To evaluate the long-term performance of the FGNs-based electrode, Feng et al. have constructed a GO aerogel modified graphite fiber brush (GOA-GFB), and the MFC performance was tested for 18 months, Figure 50A.794 Within the incubation of 18 months, the power generation continuously increased to 53.8 ± 6.0 W/m3. This study also suggested that the high specific surface area of GOA could benefit the bacteria growth and promote the extracellular electron transfer. Meanwhile, the electrochemically active bacteria will simultaneously reduce the GO into RGO during incubation. Yoshida et al. have made a more systematically study to figure out how the microorganism influence the GO reduction and aggregation, Figure 50B.770 Interestingly, they found that the bacteria in the GO enriched environment self-aggregated into a conductive hydrogel complex, and GO was biologically converted to RGO. The isolated RGO-Geobacter sp. strain R4 hydrogel complex can continually generate electricity at >1000 μA/cm3 for more than 60 days, which is better than using a commercial electrode, graphite felt. It is believed that the proposed formation of conductive RGO/exoelectrogens-based hydrogel complex by a simple put-and-wait process will enable more practical applications in designing industrial-level MFC devices. Seeking to fabricate FGNs-based low-cost and high-power density MFC devices is always significantly important for generating sustainable power and also treating wastewaters. On 1888

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Table 8. Examples and Performances of FGNs-Based Electrodes and Other Carbon-Hybridized Electrodes in MFCs FGNs-based electrode materials

maximum power density

graphite 26 mW/m2 electrochemical oxidized carbon cloth ∼939 mW/m2 nitrogen doped carbon nanoparticles loaded on 298.0 mW/m2 carbon cloth Nitrogen doped porous carbon foam 96 mW/m3 3D ordered macroporous carbon 822 mW/m2 CNT-stainless steel spin-spray LbL CNT CNT coated textile CNT-chitosan hydrogel CNT/PANI composite films graphene-coated stainless steel graphene-coated stainless steel crumpled graphene particles RGO-hybridized biofilm on carbon cloth GO-polypyrrole-graphite felt chitosan and vacuum-stripped graphene

147 mW/m2 830 mW/m2 1100 mW/m2 132 mW/m2 42 mW/m2 2668 mW/m2 2143 mW/m2 3.6 W/m3 ∼843 mW/m2 1326 mW/m2 1530 mW/m2

3D monolithic graphene frameworks

897.1 mW/ m2 17.9 W/m3

3D graphene−nickel foam graphene-sponge-stain steel graphene-based 3D foam

661 W/m3 1570 mW/m2 394 W/m3 786 mW/m2 with 0.4 mm-thick, 2935 mW/m2 with 2 mm-thick ∼768 mW/m2

3D graphene/PANI

microorganism

feed

mixed mixed S. oneidensis MR-1

wastewater wastewater sodium lactate

801 802 803

S. oneidensis MR-1 mixed

804 805

S. oneidensis MR-1 mixed Shewanella putrefaciens

Luria broth medium anaerobic sludge and sucrose acetate acetate wastewater and glucose wastewater glucose peptone wastewater wastewater lactate lactate glucose and yeast extract glucose and yeast extract lactate wastewater lactate

S. oneidensis MR-1

lactate

219

mixed G. sulf urreducens mixed mixed E. coli E. coli mixed mixed S. oneidensis MR-1 S. oneidensis MR-1 P. aeruginosa (ATCC 9027) E. coli

ref

806 798 807 808 809 810 811 523 508,772 82 475 767 792 476 812

applications. In this review, we have summarized the recent advancements in the construction of 2D and 3D conductive, bioactive and bioadhesive architectures for diverse biological applications in cellular signal detection, implant coating, stem cell engineering, tissue regeneration, and MFC. It is believed that the design of FGNs hybrid architectures have a promising future and will draw interests across a broad range of fields. Despite the great efforts that have been taken to design FGNs-based composites, such as thin film coating, oriented porous hydrogel, 3D foam or 3D printing scaffolds, challenges still exist. On the one hand, more research is needed to further reveal the inherent physical and chemical properties of FGNsbased materials and to design more tunable methods in order to obtain nanostructured thin film coatings and to construct hierarchical porous foams. On the other hand, more potential applications for these FGNs hybrid architectures need to be explored. Particularly in therapeutic or biological fields, many applications are still restricted to drug/gene delivery in cancer therapy. Recent advancements have shown that electrically conductive properties endow FGNs-based composites with a promising potential for cardiovascular and neurodegenerative treatments. FGNs’ large surface area confers them the ability as carriers to concentrate growth factor and many other kind of ECM proteins to promote cell adhesion, thus improving the cells’ survival and proliferation in stem cell therapy.

the other hand, designing milli- to microliter scale MFCs devices also emerged as important avenue to provide unique on-chip power source for implantable electrodes or in lab-on-achip applications.795−797 The microsized MFCs made from CNT or porous carbon had achieved exciting results, which usually exhibited high surface area-to-volume ratios, short electrode distances, and fast response times.798−800 Therefore, using the FGNs-based electrode to design microsized MFCs will be the next step to significantly boost the performance of these devices. In the above sections, the design of FGNs-based electrode materials in MFC has been briefly discussed. Compared with many other structured carbon electrodes, including graphite, carbon paper, carbon cloth, carbon nanoparticles, carbon foam, CNT, as well as conductive polymers/CNT, FGNs-based electrode materials exhibit obvious advantages in many ways. In Table 8, we have summarized some typical examples for each category in terms of materials, surface area, pore structure/size, power density, microorganism, and feed. It reveals that FGNsbased electrodes have a better power density than other types of carbon electrodes; both the 2D and 3D FGN-based electrodes performed better in MFCs.

6. OUTLOOK AND FUTURE DIRECTIONS FGNs have been attracting more and more attention as an emerging platform in the fields of chemistry, material science, and biomedical engineering due to their tunable mechanical properties, high surface area, remarkable electronic and thermal conductivity, as well as easy chemical functionalization. Beyond their applications in nanomedicine for drug/gene delivery, phototherapy, and bioimaging, FGNs have shown excellent interaction and adhesive properties for protein, mammalian cells, and microbials, which make FGNs and FGNs hybrid architectures potential platforms for multifunctional biological

6.1. FGNs for Cellular/Pathogen Detection and Tissue Recording

The facile construction and cell compatibility, combined with good electrochemical, optical, and mechanical properties make FGNs ideal electrode platforms for future clinical applications. However, much room is still available to enhance the electrode performances in specific disease-related diagnosis and tissuerecording. Further investigations should focus more on the mechanisms and selectivity behind the FGNs-cell/pathogen 1889

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needed to further improve the performance of FGNs hybrid anode electrodes. In summary, the future FGNs-based 3D architectures with ordered macropores for bacterial adhesion and diffusion, hierarchical nanoporous and conductive structures for quick electron transfer, as well as fast formation of bacterial film show the most promising properties for electrode materials.

interaction to achieve more specific electrode interfaces for fast, low-cost, highly selective and sensitive detection of pathogens and cancer cells. Developing graphene-based nanoscopic electrodes or implantable devices for label-free and fast detection or online monitoring of biomarkers or cellular signaling is also of critical importance, especially for the in situ neural and cardiac recording. 6.2. FGNs for Stem Cell Engineering

AUTHOR INFORMATION

The FGNs hybrid architectures have been achieved in different 2D and 3D forms, like multilayer coating, micro/nanofabrication, free-standing films, and even 3D foams. These materials have shown great potential for various applications in stem cell engineering and tissue regeneration. Both the extraordinary mechanical and electrical properties of FGNs allow them to direct and regulate stem cell growth and differentiation into targeted tissues, such as the nerve, bone, cartilage, skin, and muscle. However, the underlying mechanisms and signaling pathways for the adhesion and differentiation of stem cell on FGNs-based substrates are still not clearly understood. Further studies are needed to uncover the possible principles at the cellular/subcellular level and to provide new clues for stem cell-based therapy. Furthermore, the design of FGNs hybrid substrates, thin films, or 3D scaffolds, which have been interfaced with different nanomorphologies and mechanical and electrical stimulations, are both intriguing and necessary to further reveal the nanostructure−stem cells interactions.

Corresponding Author

*E-mail: [email protected] or [email protected]. Tel: +49-30-838-52633. Fax: +49-30-838-452611. ORCID

Arne Thomas: 0000-0002-2130-4930 Rainer Haag: 0000-0003-3840-162X Notes

The authors declare no competing financial interest. Biographies Chong Cheng is a DRS and AvH postdoc researcher in Freie Universität Berlin. He obtained his BS degree in Biomedical Engineering, Sichuan University. Then, he pursued his Ph.D. degree under the supervision of Prof. Changsheng Zhao. From 2013, he had been doing research works at University of Michigan, Ann Arbor with Prof. Nicholas A. Kotov as Joint-Training Ph.D. student. After finishing his Ph.D studies, he joined the group of Prof. Dr. Rainer Haag as a DRS POINT and Alexander von Humboldt postdoctoral researcher in the Institute of Chemistry and Biochemistry, Freie Universität Berlin. Since 2010, his publication includes over 60 papers on biomaterial and chemical journals. His current research interests focus on designing graphene nanomaterial based conductive and bioactive architectures for tissue regeneration, stem-cell therapy, and biological electrodes.

6.3. FGNs for Implant Coating and Tissue Regeneration

The specific properties of FGNs have facilitated recent developments in biomedical implants and tissue regeneration therapy, such as artificial organs or implantable vascular, bone, or skeletal muscle. FGNs-functionalized composites have improved physical properties and better cell adhesion and proliferation. Most current research on the FGNs−cell interaction and bioactivity on FGNs and their composites are still focused on the in vitro studies, but the results from in vitro 2D or 3D cell culture conditions may be significantly different from the physiological environment. Therefore, clear in vivo biological studies, especially longer than 6 months, of these materials are needed to evaluate their toxicity and future potential. Since FGNs are nonbiodegradable materials, longterm and systematically histological studies of a wide range of tissues and organs will be important to evaluate health risks, which is critical before these FGNs can be used for implantable applications.

Shuang Li is a Ph.D. candidate in chemistry at Technische Universität Berlin. She received her Bachelor degree at Sichuan University, and then she moved to Shanghai Jiao Tong University for Master’s degree studies from 2011 under the supervision of Prof. Yuezeng Su and Prof. Xinliang Feng. During Master period, she took part in the ERC grant 2DMATER at the Max Planck Institute for Polymer Research in Mainz, Germany in 2013. After finishing the Master study, she became a research scholar from 2014 at University of Michigan, Ann Arbor in the group of Prof. Nicolas A. Kotov. Now, she is a Ph.D. candidate in the group of Prof. Arne Thomas. Her current research focuses on synthesis of porous carbon and graphene based nanocomposites and their applications as advanced electrode materials.

6.4. FGNs for Electrodes in MFC

Arne Thomas is a professor of inorganic chemistry at Technische Universität Berlin. He studied chemistry in Gieben, Marburg, and Edinburgh and received his Ph.D. from the Max Planck Institute for Colloid and Interfaces in Potsdam/Golm. After a postdoctoral stay at the University of California, Santa Barbara, as an AvH fellow, he rejoined the MPI for Colloids and Interfaces as a group leader. In 2009 he became a Professor for Inorganic Chemistry at the Technische Universität Berlin where he had been leading the department of Functional Materials. His research focuses on porous materialsfrom mesoporous inorganic/carbon materials to microporous organic frameworks.

The performance of MFC equipment is usually determined by bacterial activity, extracellular electron transfer efficiency between the bacteria and electrode, conductivity of the electrode, and biocompatibility or bioactive properties (which determine the loading amount of the bacteria) of the electrode materials. From the perspective of electrode materials, designing more conductive, unique, low-cost and bacteriaadhesive nanostructured carbon materials are major concerns. 3D FGNs hybrid architectures with opened pore structure and a specific pore size that allow bacteria to easily diffuse and adhere are of great importance for electrodes. Meanwhile, the conductivity of these GO or RGO-based architectures is sometimes not sufficient to meet the requirements of current electrode materials. Therefore integration of a highly conductive current collector, for example, stainless steel, is

Nicholas A. Kotov is a Joseph B. and Florence V. Professor of Engineering at the University of Michigan. His works is mainly devoted to nanoscale preparation and utilization of advanced composites made by the layer-by-layer assembly and other nano1890

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structured thin films for military/civilian application and to selforganization of nanoscale particles into complex systems. He is particularly interested in biomimetic aspects of composites, tissue engineering with nanomaterials, implantable biomedical devices, and nanoscale chiral systems. His publications include 300+ papers devoted to the mechanical, electrical, and biological properties of nanocomposites; self-organized nanoscale processes; tissue scaffolds and neural electrodes; and optoelectronic materials. He is serving as an Associate Editor for ACS Nano. His awards include: 2012 AICHE Stine Award, 2012 Kennedy Family Award, and 2014 Materials Research Society Fellow.

E. coli FBS FETs FGNs GelMA G-NFs GNRs GO GO-Car GOCF

Rainer Haag is a professor of organic chemistry at Freie Universität Berlin. He obtained his Ph.D. with A. de Meijere at the University of Göttingen in 1995. After postdoctoral work with S. V. Ley, University of Cambridge (U.K.), and G. M. Whitesides, Harvard University, Cambridge, MA (U.S.A.), he completed his habilitation at the University of Freiburg in 2002. He then became associate professor at the University of Dortmund and in 2004 was appointed full Professor of Organic and Macromolecular Chemistry at the Freie Universität Berlin. His main research interests are the mimicry of biological systems by functional dendritic polymer based synthetic nano- and microstructures, multivalent architectures, and carbon nanomaterials and their biological applications in nanomedicine, including drug/protein carriers, anti-inflammation, bacterial/virus blocking, and tissue regeneration, in which area he published over 370 papers. Since 2017 he is a board member of the journal Angewandte Chemie.

GOQDs GQDs GSHF HA HIV hADMSCs hADSCs hASCs hBMSCs hNSCs hRGO Ig iPSCs ITO KGM LB LbL ManCD MFCs mPEG MSCs NIR NGF NSC PAA PANI PAH PCL PDMS PECL PEDOT PEI PEM PEO PLA PLC PLGA PLL PMA PMAA PMMA PPO PPy PS PSS PVA PVP QCM qRT-PCR

ACKNOWLEDGMENTS The authors gratefully acknowledge financial assistance from Deutsche Forschungsgemeinschaft (DFG) through grants from the Collaborative Research Center (SFB) 765 and 1112, Helmholtz Virtual Institute on “Multifunctional Biomaterials for Medicine”, Unifying Concepts in Catalysis (UniCat) and Berlin Graduate School of Natural Sciences and Engineering (BIG-NSE). C.C. acknowledges the support of the China Scholarship Council (CSC, in University of Michigan, Ann Arbor), DRS POINT Fellowship of Freie Universitat Berlin, and Alexander von Humboldt Fellowship. Dr. Lang Ma is acknowledged for the assistance in image processing. Dr. Pamela Winchester is sincerely acknowledged for language polishing in the manuscript preparation. ABBREVIATIONS 2D two-dimensional 3D three-dimensional AFM atomic force microscopy AG4 adamantyl-functionalized graphene derivatives AGO amine-functionalized graphene oxide anti-EpCAM epithelial-cell adhesion-molecule antibody BFG bovine fibrinogen BSA bovine serum albumin CLEAR carbon-layered electrode array CMG chemically modified graphene CNTs carbon nanotubes CTC circulating tumor cell CVD chemical vapor deposition DMEM Dulbecco’s modified eagle medium DPV differential pulse voltammetry dsDNA double-stranded DNA DWCNT double-walled carbon nanotube ECM extracellular matrix

RGO 1891

Escherichia coli fetal bovine serum field-effect transistors functional graphene nanomaterials methacrylated gelatin reduced graphene oxide sheets coated nanofibers scaffolds graphene nanoribbons graphene oxide carrageenan-functionalized graphene oxide graphene oxide-incorporated collagen-fibrin composite film graphene oxide quantum dots graphene quantum dots graphene-based self-supporting hydrogel film hydroxyapatite human immunodeficiency virus human adipose-derived mesenchymal stem cells human adipose-derived stem cells human adipose-derived stem cells human bone marrow stromal cells human neural stem cells holey reduced graphene oxide immunoglobulin induced pluripotent stem cells indium tin oxide konjac-derived glucomannan Langmuir−Blodgett layer-by-layer heptamannosylated β-cyclodextrin microbial fuel cells methoxy poly (ethylene glycol) mesenchymal stem cells near-infrared nerve growth factor neural stem cell poly(acrylic acid) polyaniline poly(allylamine hydrochloride) polycaprolactone polydimethylsiloxane poly(epsilon-caprolactone) poly(3,4-ethylenedioxythiophene) polyethylenimine polyelectrolyte multilayer poly(ethylene oxide) poly(lactic acid) poly(lactic acid-poly epsilon-caprolactone) poly(lactic-co-glycolic acid) poly-L-lysine phorbol 12-myristate-13-acetate poly(methacrylic acid) poly(methyl methacrylate) polypropylene oxide polypyrrole polystyrene poly(sodium 4-styrenesulfonate) poly(vinyl alcohol) poly(vinyl pyrrolidone) quartz crystal microbalance quantitative real-time reverse transcriptase polymerase chain reaction reduced graphene oxide DOI: 10.1021/acs.chemrev.6b00520 Chem. Rev. 2017, 117, 1826−1914

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ROS

reactive oxygen species chemically reduced poly (vinyl alcohol)/graR-PVA/GO phene oxide rBMSCs rat bone marrow stromal stem cells S. cerevisiae Saccharomyces cerevisiae SF silk fibroin SBF simulated body fluid SPR surface plasmon resonance S. oneidensis Shewanella oneidensis TCPS tissue culture polystyrene Tet-TA 4-arm polypropylene oxide-poly (ethylene oxide)-tyramine TGF-β3 transforming growth factor-β3 THF tetrahydrofuran Tf transferrin TRGO thermal reduced graphene oxide XPS X-ray photoelectron spectroscopy ZGNRs zigzag graphene nanoribbons

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