Conductive Polymers: Opportunities and Challenges in Biomedical

Conductive Polymers: Opportunities and Challenges in Biomedical...

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Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

Conductive Polymers: Opportunities and Challenges in Biomedical Applications Toktam Nezakati,†,‡,∥ Amelia Seifalian,⊥ Aaron Tan,§,⊥ and Alexander M. Seifalian*,# †

Google Inc.., Mountain View, California 94043, United States Radiology Institute and §Biomaterials & Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Palo Alto, California 94305, United States ∥ Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, London NW3 2QG, United Kingdom ⊥ UCL Medical School, University College London, London WC1E 6BT, United Kingdom # NanoRegMed Ltd. (Nanotechnology and Regenerative Medicine Commercialization Centre), The London Innovation BioScience Centre, London NW1 0NH, United Kingdom

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‡

ABSTRACT: Research pertaining to conductive polymers has gained signiﬁcant traction in recent years, and their applications range from optoelectronics to material science. For all intents and purposes, conductive polymers can be described as Nobel Prize-winning materials, given that their discoverers were awarded the Nobel Prize in Chemistry in 2000. In this review, we seek to describe the chemical forms and functionalities of the main types of conductive polymers, as well as their synthesis methods. We also present an in-depth analysis of composite conductive polymers that contain various nanomaterials such as graphene, fullerene, carbon nanotubes, and paramagnetic metal ions. Natural polymers such as collagen, chitosan, ﬁbroin, and hydrogel that are structurally modiﬁed for them to be conductive are also brieﬂy touched upon. Finally, we expound on the plethora of biomedical applications that harbor the potential to be revolutionized by conductive polymers, with a particular focus on tissue engineering, regenerative medicine, and biosensors.

CONTENTS 1. Introduction 2. Conjugated π Conductive Polymers 2.1. Polyacetylene 2.1.1. Properties and Structure 2.1.2. Polyacetylene Synthesis 2.1.3. Compound and Composites 2.2. Polythiophene 2.2.1. Properties and Structure 2.2.2. Polythiophene Synthesis 2.2.3. Compound and Composites 2.3. Polypyrrole 2.3.1. Properties and Structure 2.3.2. Polypyrrole Synthesis 2.3.3. Compound and Composites 2.4. Polyphenylene 2.4.1. Properties and Structure 2.4.2. Compound and Composites 2.5. Polyaniline 2.5.1. Properties and Structure 2.5.2. Polyaniline Synthesis 2.5.3. Compound and Composites 3. Conductive Composite Biopolymers 3.1. Modiﬁed Biopolymers with Conjugated π Conductive Polymers © XXXX American Chemical Society

3.1.1. Polythiophene 3.1.2. Polypyrrole 3.1.3. Polyaniline 3.2. Modiﬁed Polymers with Carbon-Based Nanoparticles 3.2.1. Carbone Nanotubes 3.2.2. Fullerene 3.2.3. Graphene 3.2.4. Nanodiamond 3.3. Modiﬁed Polymers with Alloys 4. Modiﬁed Natural Polymers for Conductivity 4.1. Chitosan 4.2. Collagen 4.3. Fibroin 4.4. Other Polymers with 3D Network Structure 5. Fabrication of the 3D Scaﬀold Using the Conductive Polymer 5.1. Electrospinning 5.2. Deposition 6. Biomedical Applications of Conductive Polymers 6.1. Tissue Engineering and Regenerative Medicine

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Chemical Reviews 6.1.1. Neural System 6.1.2. Cardiovascular Disorders 6.1.3. Wound Healing with a Conductive Graphene Nanocomposite 3D Scaﬀold 6.2. Biosensors 6.2.1. Neural System 6.2.2. DNA 6.2.3. Retinal 6.2.4. Metabolic Markers of Stress 6.3. Protein Corona 7. Conclusion and Future Perspective 7.1. Ongoing Development of Conductive Polymers Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

Review

potential of CPs to be used for the development of surgical implants and medical devices, including tissue engineering (TE) and regenerative purposes, will be discussed, with a speciﬁc emphasis on neural and cardiovascular systems. Another remarkable application of CPs is in the ﬁeld of electrically induced targeted drug release systems. An electrical potential applied to stem cells or mature cells can stimulate their adhesion, growth, migration, and diﬀerentiation. The potential of CPs as biosensors will also be highlighted, especially in the neural system and ophthalmic system and as metabolic markers of stress. Overall, this review will provide an authoritative account of the synthesis, modiﬁcations, and properties of CPs with an emphasis on biomedical applications. Of late, an exciting direction in nanomedicine is concerned with elucidating the response of living cells to CPs.2 The application of CPs in TE may improve the performance of drug-eluting stents by addressing late-onset stent thrombosis and delayed stent re-endothelialization.2 Appropriate materials conjugated polymers have been investigated for interfacing prosthetic device electrodes with neural tissue. Recently, the focus has been on the development of conjugated polymers which consist of biological components; this would improve electrode implantation and consequently further improve the tissue response.3 The clinical applications of CPs are vast; importantly, they could help address many currently unmet clinical needs. This includes the following: (1) In lagophthalmos, patients experience an inability to blink completely. Since blinking is required to create a moist environment for cells of the exterior part of the eye, lagophthalmos may cause corneal drying, dysfunction, and ulceration. (2) CPs may be used in the development of nerve conduits to stimulate nerve regeneration. Such enhancement of nerve growth is required in post-trauma and in organ transplantation. (3) CPs may be a key component in synthetic scaﬀolds that support the successful regeneration of myocardial tissue or use as a pacemaker. (4) CPs can be used for deep brain stimulation for treatment of neurological disorders such as Parkinson’s disease. Metallic implants such as stainless steel suﬀer from lack of biocompatibility and integration with surrounding tissue; hence, it is hoped that biocompatible CPs will overcome this problem. Our group is currently developing biocompatible CPs based on graphene for coating implants used in deep brain stimulation implants. Similarly, a research team at Rice University achieved encouraging results with the use of carbon nanotube ﬁbers to stimulate the brain of a patient with Parkinson’s disease. Besides these above-mentioned applications, there remain many other potential uses of CPs, from biosensors and bioactuators to drug delivery systems and neural prosthetics.4−7

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1. INTRODUCTION Conductive polymers (CPs) are recognized as a class of organic materials with unique electrical and optical properties similar to those of inorganic semiconductors and metals. CPs can be synthesized using simple, versatile, and cost-eﬀective approaches. They can be readily assembled into supramolecular structures with multifunctional capabilities by using simple electropolymerization processes.1 A diverse array of methodologies have been developed to modify and tune the CPs to integrate and interface them into biomedical applications, including biomaterials and biosensors. Such novel innovations are coveted in various ﬁelds of biomedicine such as bioengineering, regenerative medicine, and biosensors, as they could potentially lay the foundation for future breakthroughs. CPs have demonstrated promising capabilities to induce various cellular mechanisms, which broaden their unique applications in the biomedical ﬁeld. Moreover, they are attractive for various biomedical applications due to their intelligent response to electrical ﬁelds from diﬀerent types of tissues, including muscle, connective tissue, epithelium, and nervous tissue. CPs have been used to enhance the electrical sensitivity, speed, and stability of various biomedical devices and their interfaces with biological tissues. There are various types of CPs known to interact with biological samples, while retaining their biocompatibility; thus, one can expect that CPs could be qualiﬁed as viable candidates for use in numerous biological and medical applications. There are a large numbers of CPs, and their classiﬁcations are based on their types of electric charge, such as delocalized π electrons, conductive nanomaterials, and ions. In this paper, diﬀerent types of conjugated π CPs and their unique properties and their synthesis routes will be discussed in depth. The ﬁve main types of CPs that will be presented are polyacetylene, polythiophene, polypyrrole, polyphenylene, and polyaniline. A section on conductive composite polymers that we will elaborate on includes conjugated π CPs, conductive nanoparticles (NPs), carbon-based NPs, and alloys. The methodologies used for converting natural polymers such as chitosan, collagen, ﬁbroin, and gelatin into CPs will also be discussed. Furthermore, various polymer fabrication techniques will be explained. Finally, a comprehensive analysis of the

2. CONJUGATED π CONDUCTIVE POLYMERS Conjugated π polymers are a class of materials with electrons held in their backbones.8 Delocalized π-electrons move freely within the unsaturated backbone to construct an electrical pathway for mobile charge carriers.9,10 Polyacetylene (PA), polythiophene (PT), poly[3,4-(ethylenedioxy)thiophene] (PEDOT), polypyrrole (PPy), polyphenylene, and polyaniline (PANi) are some of the most widely used CPs in 3D tissue engineering scaﬀold construction for the development of human organs, and their chemical structures are depicted in Figure 1.11 Table 1 provides a summary of conjugated π B

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

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conductive polymers, including their formulas, electrical conductivities, and applications.

Figure 2. Polyacetylene development. Reprinted from ref 12. Copyright 2005 American Chemical Society.

NaBH4, and results show stabilities to oxygen and water.20 Developing and synthesizing polyacetylene could also be obtained by other methods of polymerization radiations such as glow discharge, ultraviolet, and Y-radiation. Use of radiation methods could be beneﬁcial, since they could avoid the use of catalyst and solvents. 2.1.3. Compound and Composites. This section explains the use of diﬀerent materials for hybridization with polyacetylene to improve the conductivity, such as dihexadecyl hydrogen phosphate,21 quaternized cellulose NPs,22 and Au NPs.23 Polyacetylenes are also called acetylene black (AB) or polyacetylene black depending on the preparation method. It is possible that AB derives other substitutions, which does not inﬂuence the physical properties such as conductivity and color. AB is a carbon nanomaterial which is a speciﬁc subtype of carbon black and is produced by the controlled combustion of acetylene under pressurized air. ABs are usually used as substitutes for graphitic powder in the preparation of carbon paste electrodes,24−26 and are dispersed in chitosan solution to modify glassy carbon electrodes.27 An acetylene black− dihexadecyl hydrogen phosphate (AB−DHP) ﬁlm-coated glassy carbon electrode (GCE) was also constructed to detect 2-chlorophenol28 and erythromycin.21 With the physical inclusion of enzymes, quaternized cellulose NPs (QCs)/acetylene black (AB)/enzyme composite electrodes have been constructed in the electrode matrix bulk. This has been used for hydrogen peroxide (H2O2) and glucose amperometric detection. The new composite material combines the unique and attractive electrocatalytic behaviors of QCs and acetylene black with excellent biocompatibility, electric conductivity, and a large speciﬁc surface area. The modiﬁed electrodes were electrochemically characterized, and bioelectrocatalytic reactions were performed. The resulting composite ﬁlm promotes the glucose oxidase (GOD) direct electron transfer and hemoglobin (Hb) immobilization in the ﬁlms eﬀectively with fast electron transfer rates. The prepared enzyme/QCs/AB composite ﬁlm indicated high electrocatalytic performance for H2O2 and glucose with a quick response, a broad linear range, good sensitivity, and excellent stability.22

Figure 1. Chemical structures of π-conjugated polymers.

2.1. Polyacetylene

2.1.1. Properties and Structure. PA is, for all intents and purposes, considered to be a Nobel Prize-winning macromolecule.12 PA is a conjugated polymer whose functional derivatives demonstrate multifaceted properties that have been extensively reviewed in the literature. Some of its useful features include electrical conductivity, photoconductivity, gas permeability, supramolecular assemblies, chiral recognition, helical graphitic nanoﬁber formation, and liquid crystal.12−19 The primitive discovery of electrical conductivity in the doped form has generated much interest in CPs, which engendered an exciting ﬁeld of research on synthetic metals. The chemical structure of PA is a linear polyene chain [−(HCCH)n−]. Its backbone provides an important opportunity for decoration with pendants due to the presence of repeated units of two hydrogen atoms. Each repeated unit of hydrogen could thus be replaced by one or two substitutes to yield monosubstituted or disubstituted PAs, respectively (Figure 2).12 2.1.2. Polyacetylene Synthesis. Acetylene only or other monomers could be used in a number of methods to develop and synthesize polyacetylene. One of the methods is named Ziegler−Natta catalysis and involves the use of titanium and aluminum in the presence of gaseous acetylene. By changing the temperature and amount of catalyst, this method could be a beneﬁcial way to develop polyacetylene while monitoring the structure and watching for the ﬁnal polymer products. Note that there is a possibility that metal existing in the monomer’s triple bonds could occur. Studies show that the polyacetylene could be synthesized by substituting the catalyst with CoNO3/ Table 1. Conjugated π Conductive Polymers conjugated π conductive polymer

abbreviation

formula

electrical conductivity (S/cm)

polyacetylene polythiophene

PA PT

[C2H2]n [C4H4S]n

105 100−103

polypyrrole

PPy

[C4H2NH]n

2−100

poly(p-phenylene) polyaniline

PPP PANi

[C6H4]n [C6H4NH]n

10−3−102 10−2−100

applications biosensors,26 colchicine detection,27 bioelectrodes30 biosensors,55,64 enzyme immobilization,70 voltammetry of roxithromycin,71 conducting biomaterials76 modulate cellular activities,86−88 nerve regeneration,107 biomedicine,108 biosensors,110 bacterial detection111 dental applications,131 cell alignment141 neural application,161 bioelectrodes168 C

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observations suggested that a tip-growth mechanism involving the Au NPs as the nucleation sites was in operation. By decreasing the reaction temperature, C2H2 decomposition was assisted via liquid-phase K metal. Acetylide and hydride intermediates were proposed to have been formed in the reaction. In addition, further decomposition of acetylide intermediates led to the growth of solid-phase CNC. The results of electron ﬁeld emission (EFE) indicated a ﬁeld enhancement factor (β) of 1852 and a turn-on ﬁeld (Eto) of 3.78 V μm−1. Furthermore, the current density (J) was as high as 43 mA cm−2 at 6.87 V μm−1.23 The modiﬁed electrode displayed high sensitivity and eﬃcient electrocatalytic oxidation of monoamine neurotransmitters and their metabolites. The detectability level was 0.1 nmol L−1, and the linear range improved to 4 orders of magnitude (r > 0.998).31 In conjunction with in vivo microdialysis sampling, the described electrode method successfully measured lower levels of monoamine neurotransmitters and their metabolites in the lesion side of the striatum of unilateral 6-hydroxydopamine-lesioned rats, compared to the intact side of the striatum or in the striatum of control rats.31

The analysis of the electrochemical behavior of colchicine in AB−DHP composite ﬁlm-coated GCEs has revealed noteworthy results29 Colchicine is an alkaloid produced from Colchicum autumnale seeds, meadow saﬀron, or autumn crocus and dried corn, and its molecular structure is illustrated in Figure 3.29 Colchicine is used to treat gout, and reduce hepatic

Figure 3. Colchicine chemical structure. Reprinted with permission from ref 29. Copyright 2006 Elsevier.

ﬁbrous tissue formation in primary biliary cirrhosis and other cirrhotic conditions. By controlled combustion of acetylene under pressurized air, acetylene black was produced from graphitic powder.29 The colchicine electrochemical response in modiﬁed GCEs coated with an AB−DHP ﬁlm was signiﬁcantly improved due to its high peak current in comparison with an unmodiﬁed GCE, which showed a low electrochemical signal. The development of a sensitive voltammetric range of 1.0 × 10−7 to 4.0 × 10−5 mol L−1 for colchicine determination was also noted. A low value of 4.0 × 10−8 mol L−1 for 4 min of aggregation was achieved with a signal-to-noise ratio of 3 dB for the colchicine detection limit. Colchicine detection in human urine samples was hence one of the suggested applications of the electrode.29 The eﬀect of pulsed electric ﬁeld (PEF) processing on polyacetylene and sugar extraction, the total carotenoid content, and the color change in carrot purees has also been reported; the puree redness increased at 0.25 kV cm−1 for 10 ms (7.5 J kg−1), which correlated with the carotenoid increment. In PEF-treated samples, falcarindiol-3-acetate (FaDOAc) and falcarindiol (FaDOH) concentrations were detected, which were higher compared to those of the untreated purees at 0.25 kV cm−1 for 6 ms (4.5 J kg−1). Furthermore, the β-glucose and sucrose concentrations at 1 kV cm−1 for 2 ms (29 J kg−1) increased by 43% and 48%, respectively. In addition, the concentrations of fructose and αglucose contents when a potential of 1 kV cm−1 for 6 ms (86 J kg−1) was applied increased to 52% and 78%, respectively. On the basis of the results, the carrot puree sugar content and polyacetylene could be enhanced by PEF pretreatment processing.30 Water-soluble silver salt and poly(pyridylacetylene) (PPyA) were mixed, producing a AgX (X = Br and I) and PPyA suspension, which could be uniformly casted due to its stability in the dark at 25 °C.19 Due to a photochemical reaction, an in situ polymer matrix of Ag NPs was produced through ultraviolet (UV) light exposure. The Ag particle size, composite conductivity, and surface morphology could be tuned by Ag+ content adjustment. UV light absorbed by PPyA and polymer degradation due to the photogenerated halogen will occur. Therefore, a highly porous ﬁlm of Ag NPs is formed by the photochemical process.19 K and Au metals were combined through chemical vapor deposition (CVD) to act as catalysts that would promote C2H2 thermal decomposition; this ultimately resulted in the demonstrable growth of carbon nanocoils (CNCs). Their

2.2. Polythiophene

2.2.1. Properties and Structure. Polythiophene is interesting for its stable conductivity and high electrical conductivity (103 S cm−1), and its conductivity varies with the type of dopant and polymerization.32−34 As CPs are based on conjugated systems, they are by nature nontransparent and refractory, polythiophene being a prime example.35 Previous studies have evaluated the eﬀect of the length of conjugated sequences in polythiophene on conductivity. Speciﬁcally, it was reported that oligomers consisting of 11 thiophene units have conductivity similar to that of higher molecular weight polythiophene.36 Consistent with this is the ﬁnding that short oligomers of thiophene have polymer properties, with conductivity and carrier mobility increasing as a function of the conjugation length up to the hexamer of thiophene.37 Transparency is one of the main characteristics based on the application where electrical conductivity is important, such as photographic ﬁlms coated with antistatic coatings, which should be higher than 90%. CP transparency could be increased by dilution, which inﬂuences conductivity. There are diﬀerent methods for polythiophene dilution, such as block copolymerization,38 alkyl side chain grafting onto the conjugated backbone,39,40 or blending with a transparent polymer, 41,42 and producing composites via thiophene polymerization absorbed in an insulating polymer.43 In addition, plasma polymerization,44 electrochemical procedures,39 and thin layer polythiophene deposition could be conducted. Plasma polymerization provides the possibility to achieve very thin pinhole-free layers, which attach ﬁrmly to almost any substrate without the use of any solvents.45,46 To obtain semiconducting ﬁlms, electrochemical polymerization of PEDOT, a conjugated polymer with high conductivity on a neural electrode, could be performed.47,48 PEDOT could interface electrically with neurons; however, it lacks the chemical functionality to covalently bind biological molecules. Two functionalized carboxylic acids, 3,4(ethylenedioxy)thiophenes (EDOTs), were also evaluated;49 however, the long linkers to the acid group decrease their solubility in water (the preferred polymerization solvent).3 D

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oxide).74 In addition, PEDOT in the presence of EDOT-OH, C2-EDOT-COOH, C4-EDOT-COOH, C2-EDOT-NHS, and EDOT-N349 indicated better conductivity. The use of counterions in addition to polyanion poly(sodium 4-styrenesulfonate), sodium chloride (NaCl), lithium perchlorate (LiClO4), (PSSNa), sodium phosphate monobasic monohydrate (NaH2PO4·H2O), and ions in PBS (i.e., KH2 PO 4, NaCl, and Na 2HPO 4 ) has been extensively investigated. It was observed that the polyanion PSS− was incorporated into PEDOT in comparison to Cl− and ClO4− anions by using the ion mixtures.66−69 The correlation of cell proliferation and adhesion of PEDOT thin ﬁlms with physiochemical properties and doping for stent application has also been investigated.2 Tosylate anion (TOS) or poly(styrenesulfonate) (PSS) was used for doping the PEDOT for ﬁlm fabrication by spin coating and vapor phase polymerization. For biofunctionalization and reducing immunogenicity, PEDOT:TOS PEGylation with RGD peptides was conducted to induce cell proliferation.2 The integrin-binding tripeptide motif RGD is a sequence within ﬁbronectin that mediates cell attachment, and it also is found in numerous other cell-attachment proteins. PEDOT:TOS demonstrated high cell adhesion, due to its hydrophilicity and nanotopography, which positively inﬂuences cytocompatibility. Furthermore, PEDOT:TOS PEGylation increases hydrophilicity and improves conductivity.2 One of the eﬃcient ways of improving biocompatibility and mechanical properties in biometallic implants is through surface modiﬁcation with a protein-resistant polymer. The initiation of −Br group containing PEDOTs by electropolymerization has also been studied.70 2,2′-Bipyridine, polyethylene glycol methacrylate (POEGMA), [2(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (PSBMA), poly((oligoethylene glycol methacrylate), and zwitterionic poly([2- (methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide) were grafted by surface-initiated electropolymerization after the CP was deposited. PSBMA-grafted PEDOTs and POEGMA protein resistance were conﬁrmed by quartz crystal microbalance (QCM).70 The feed content of the monomer PEDOT-Br which contains the initiator in the monomer mixture solution for electropolymerization is responsible for regulating the density of brushes, which in turn regulates the protein-binding characteristics displayed by the surface. Additionally, surface adherence of the cells is also hindered by the polymer-grafted PEDOTs.70 The monomer EDOT-Br, capable of initiating atom transfer radical polymerization (ATRP), was synthesized by esteriﬁcation of hydroxmethyl-functionalized EDOT

As a highly conductive polymer, PEDOT could be polymerized either by electrochemical polymerization or by oxidative chemical polymerization (Figure 4). As a biomaterial

Figure 4. Poly[3,4-(ethylenedioxy)thiophene] (PEDOT) and poly(sodium 4-styrenesulfonate) (PSSNa).

tissue interfacing agent, PEDOT has been used for ionic and electrical conductivity.50,51 Most of the previously studied conductive conjugated biomaterial polymers were focused on PPy.52−55 In comparison to PPy, PEDOT possesses superior chemical56−58 and thermal59 stability and has been postulated for possible use as an interfacing agent. The electrical and morphological properties of PEDOT polymer ﬁlm are aﬀected by counterion incorporation. Thus, counterion processes for incorporation could be used to improve the understanding of its fundamental properties. Biological buﬀers such as phosphate-buﬀered saline (PBS) solution can be used, especially for applications such as implant coatings50 and biosensors,60−64 applications required for biological incorporation. For electrochemical polymerization, PEDOT could also be doped with other counterions.56,65 2.2.2. Polythiophene Synthesis. Polythiophene can be developed electrochemically and chemically. By obtaining a conductive ﬁlm on the anode with a solution of thiophene and an electrolyte, the electrochemical polymerization of polythiophene results. Polythiophene polymerization’s main beneﬁt is that it does not require isolation and puriﬁcation, but it could be irreversible and decompose. In chemical synthesis and development, there is a better monomer selection and better synthesis by using proper catalysts. 2.2.3. Compound and Composites. This section explains the use of diﬀerent materials for hybridization with polythiophene to improve the conductivity, such as tosylate anion, poly(styrenesulfonate),2 sodium chloride, lithium perchlorate, sodium phosphate monobasic monohydrate,66−69 Br,70 poly(sodium 4-styrenesulfonate),69 poly(styrenesulfonic acid)/Au,71 methyl- or benzyl-capped diethylene glycol, tetraethylene glycol,72 alkyl side chains,73 and poly(ethylene

Figure 5. Atom transfer radical polymerization (ATRP) initiator synthesis. Reprinted from ref 70. Copyright 2013 American Chemical Society. E

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Figure 6. Carboxylic acid-functionalized 3,4-(ethylenedioxy)thiophene (EDOT acid) synthesis. Reprinted with permission from ref 3. Copyright 2013 Elsevier.

Figure 7. RM molecular structure. Reprinted with permission from ref 76. Copyright 1994 Springer

neurons was enhanced between 3-fold and 9-fold by the PEDOT−PEDOT acid−peptide ﬁlms. Functionalized copolymer ﬁlms of PEDOT−PEDOT acid with regulated bioactivity can be formed with the help of the EDOT acid monomer.3 Thus, it was possible to develop carboxylic acid-functionalized EDOT with direct attachment of the acid group to EDOT acid. An experiment was conducted on the electrochemical polymerization capability of this monomer together with the interaction between the RGD peptide and carboxylic acids. RGD has been the focus of ample research, despite not exclusively enhancing neuron adhesion, and its primary function is to show the attachment of EDOT acid-containing

(EDOT-OH) with 2-bromoisobutyryl bromide in the presence of triethylamine as shown in Figure 5.70 The covalent binding of peptides to the conjugated polymer ﬁlm surfaces was achieved through the synthesis of the carboxylic acid-functionalized EDOT acid monomer. The PEDOT−PEDOT acid is a copolymer ﬁlm characterized by stability and electrical conductivity, which resulted from the copolymerization of EDOT acid with the EDOT monomer. Furthermore, the peptide-functionalized PEDOT ﬁlm was the resultant product of the binding of the peptide GGGGRGDS to PEDOT−PEDOT acid.3 The importance of the peptide in supporting biological activity was conﬁrmed by the fact that, compared to controls, the adhesion of primary rat motor F

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Figure 8. Oligoethylene glycol-functionalized thiophene monomer syntheses. Reprinted from ref 72. Copyright 2012 Americal Chemical Society.

conjugated polymers to bioactive peptides.3 EDOT acid was synthesized as shown in Figure 6.3 The investigation targeted counterions such as polyanion poly(sodium 4-styrenesulfonate) (PSSNa), as well as small anions such as lithium perchlorate, sodium chloride, and sodium phosphate monobasic monohydrate. The investigation also addressed an ion mixture and phosphate-buﬀered saline (PBS) solution. In the case of these mixtures, it was observed that the role of the counterion during electrochemical polymerization of PEDOT in PBS solution was fulﬁlled by the chlorine anion from sodium chloride. Such behavior is of great signiﬁcance, due to the potential for use in biomedical applications that has been displayed by PEDOT, the synthesis of which occurs in the presence of PBS or an ion mixture. Consequently, an analysis was conducted of diﬀerent mixtures of PSSNa, lithium perchlorate, sodium p-toluenesulfonate (TosNa), and PBS counterions. Findings revealed that, during the use of ion mixtures, PEDOT usually integrated the polyanion PSS− rather than CIO4− and Cl− anions. Results derived from analytical methods such as electrochemical impedance spectroscopy, cyclic voltammetry, and scanning electron microscopy reinforced these ﬁndings.69 A one-step chemical synthesis was undertaken to prepare a poly[3,4-(ethylenedioxy)thiophene]−poly(styrenesulfonic acid)/Au (PEDOT−PSS/Au) nanocomposite characterized by high solubility. This nanocomposite can serve as a biomaterial for enzyme immobilization thanks to its exceptional aqueous compatibility and biocompatibility. This system involved the incorporation of the redox enzyme horseradish peroxidase (HRP) with the PEDOT−PSS/Au nanocomposite with the observation of direct HRP electron transfer. Furthermore, the exceptional electrocatalytic ability of H2O2 was demonstrated by the HRP/PEDOT−PSS/Au-modiﬁed electrode, and the value of the formal Michaelis−Menten constant (Kapp m ) was 0.78 mmol L−1. Additionally, the linear relation between the response currents and the H2O2 concentration was satisfactory, with a 2.0 × 10−7 to 3.8 × 10−4 mol L−1 linear range.71 A technique exhibiting simplicity, sensitivity, and reliability was created to determine the voltammetry of roxithromycin (RM) at the surface of the developed PEDOT-modiﬁed Au electrode. Thus, cyclic voltammetry and diﬀerential pulse voltammetry were used to examine how RM behaved electrochemically at the modiﬁed electrode surface. The investigation focused on how the RM response was aﬀected by experimental parameters such as PEDOT-modiﬁed solid electrodes, supporting electrolytes, nanomodiﬁed materials, buﬀer solution, pH values, and scan rates. If circumstances allow it, RM can be quantiﬁed with the as-synthesized modiﬁed electrodes, with a 0.08−20 μM linear range, 0.9921 μA μM−1 sensitivity, and 0.0267 μM detection limit. The

developed modiﬁed electrode was highly stable, sensitive, and reproducible. Acceptable results were obtained from the voltammetric assessment of RM content in capsule samples based on the as-synthesized modiﬁed electrode, with an acceptable recovery range of 98.9−102%. Additionally, these results conﬁrmed the potential of the as-synthesized PEDOTmodiﬁed Au electrode for use in macrolide antibiotic electrochemical determination and analysis.75 A derivative of macrolide antibacterial erythromycin, RM displays similar antibacterial action in vitro.76 As shown in Figure 7, the structure of this semisynthetic macrolide antibiotic consists of a 14-membered lactone ring with two sugars. Its main use is in treating sensitive strain-induced infections of the respiratory tract, urinary system, and soft tissue.77,78 Furthermore, compared to erythromycin, RM is chemically more stable, has robust activity and a broad in vivo distribution, and displays higher antibiotic concentrations in the serum when administered orally.75,76 The preparation and description of a new copolymer, 5,5‴bis(hydroxymethyl)-3,3‴-dimethyl-2,2′:5′,2″:5′,2‴-quaterthiophene-co-adipic acid polyester (QAPE) has been investigated to contribute to endeavors geared toward the development of conducting polymers with biocompatibility and biodegradability. The system was intended to simultaneously integrate electroactive quaterthiophene units and biodegradable ester units in an alternating sequence and to mediate simpliﬁed synthesis of the polymer based on a polycondensation reaction. Conventional chemical and spectroscopic analyses demonstrated that the integration of the ester groups in the polymer did indeed occur between the quaterthiophene subunits. Furthermore, the conserved electroactivity of the quaterthiophene units following integration in the QAPE polymer framework was conﬁrmed by the redox activity of the QAPE determined by cyclic voltammetry and novel red-shifted peaks of absorption associated with doping. The ﬂuorescence signal detected at wavelengths related to the quaterthiophene subunit for degradation samples was indicative of the biodegradable nature of the polymer. Moreover, the harmless eﬀect of the QAPE polymer on Schwann cells (SCs) was conﬁrmed by in vitro cytocompatibility analyses performed over a period of 2 days.79 Grignard metathesis (GRIM) polymerization or reductive coupling polymerization can be used to eﬀectively prepare and polymerize a set of methyl- or benzyl-capped oligoethylene glycol-functionalized 2,5-dibromo-3-oxythiophenes. The equivalent polymers can thus be produced in acceptable quantities and with narrowly distributed molecular weights.72 After they are puriﬁed, poly(oxythiophene)s synthesized via diﬀerent polymerization techniques show varying colors, and this variation was proven by spectroelectrochemical studies to be G

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due to discrepancies in their doping mode. Cell compatibility assays conducted in vitro showed that the polymers do not have high cytotoxicity. Furthermore, strong attachment and proliferation on spin-coated ﬁlms have been demonstrated by NIH3T3 ﬁbroblast cells.72 Methyl- or benzyl-capped diethylene glycol (EG2) and tetraethylene glycol (EG4) containing dibromothiophene monomers were synthesized in reasonable yield as shown in Figure 8. OEG-substituted oxythiophenes were formed when the 3-bromothiophene was ﬁrst reacted with oligoethylene glycol. Following methylation or benzylation, the oxythiophenes were subjected to dibromination, producing m1− m4 in good yields (55−80%). 1H and 13C nuclear magnetic resonance spectra and mass measurements certiﬁed the monomer molecular structures. GRIM and reductive coupling polymerization were then applied to monomers m1−m4 (Figure 9). The reaction of the monomers with iPrMgCl, a

Figure 10. Polythiophene structure. Reprinted from ref 73. Copyright 2008 American Chemical Society.

thiophene (PPT) layers was aﬀected by power, pressure, pulse time, duty cycle, and location in the reactor. Of these factors, pressure was the only one to considerably impact conductivity within the employed ranges. An association could be made between these results and the inﬂuence of deposition factors on thiophene monomer fragmentation. The layers were made more conductive as thiophene did not fragment signiﬁcantly at high pressure. Fragmentation can be diminished with the help of a pulsed plasma, the eﬃciency of which is greatest when the oﬀ time is selected, which enables reloading of the reactor with new monomer.46 It is essential for fragmentation during deposition to be kept to a minimum; otherwise, plasmapolymerized (PP) layers retaining the conjugated monomer structure cannot be attained. Thus, plasma polymerization was conducted with various methylated and halogenated thiophenes serving as monomers, and the response of fragmentation during deposition to the substitute(s) was examined. Results revealed that fragmentation during deposition was limited in the case of the methylated thiophenes but high in the case of halogenated thiophenes. Furthermore, for a particular substitute, substitution on the 3-position was associated with higher fragmentation of thiophene derivatives than substitution on the 2-position. In fact, fragmentation of disubstituted thiophenes was constantly more limited compared to that of monosubstituted thiophenes. Additionally, more conjugated structures were present in the PP layers of methylated thiophenes thanks to the limited fragmentation. Hence, following iodine doping, these PP layers displayed higher conductivity.80 A PEDOT with electrical conductivity was used to produce nanobiointerfaces. The electropolymerization of thin (80%) and conductivity (10−6 S cm−1). An assessment was conducted regarding the extent to which the conductivity of these plasma-polymerized H

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Figure 11. Poly(acrylic acid) grafting from the PBrEDOT backbone: (1) tBA, acetone, CuBr, PMDETA, 60 °C, (2) 1% methanesulfonic acid in DCM. Reprinted from ref 81. Copyright 2013 American Chemical Society.

Figure 12. PEDOT synthesis and fabrication: (a) PEDOT schematic illustration, (b) heterocyclic PEDOT synthesis, (c) NIR-induced MSC detachment schematic. Reprinted from ref 82. Copyright 2013 American Chemical Society.

dichloromethane (DCM), followed by shaking in a beaker containing 10 mL of DCM and 0.1 mL of methanesulfonic acid for 1/4 h. DCM and ethanol were subsequently used to rinse the samples.81 Another synthetic protocol that merits consideration involves the use of solution-casting polymerization (SCP) to prepare PEDOT-coated cell culture surfaces. Harvesting of cells when exposed to an NIR source was induced as a result of the PEDOT thin ﬁlms becoming absorbed in the NIR region. It was possible to quantitatively regulate proliferation and harvesting of human mesenchymal stem cells (hMSCs) by using electrochemical doping to modulate NIR absorption of the PEDOT ﬁlm or by developing PEDOT with a thin ﬁlm thickness in the range of 70−300 nm. Both cell harvesting and patterning can be temporally and spatially regulated with this light-triggered cell detachment technique underpinned by PEDOT ﬁlms. Furthermore, even though NIR increased the temperature, the survival and proliferation of the harvested stem cells were unaﬀected, and their inherent properties and ability of multilineage diﬀerentiation were maintained. The PEDOT ﬁlms did not display any photodeterioration when they were exposed to NIR; therefore, the PEDOT surface may be employed for recurrent hMSC culture and detachment or for eﬀectively extracting or eliminating a particular subset from a nonuniform population when diﬀerent tissue-derived cells are cultured.82 Figure 10 provides a simpliﬁed representation of

ily available on the market. Afterward, the modiﬁed monomer was subjected to electropolymerization onto large-area electrodes coated with gold, serving as a support for the grafting of poly(acrylic acid) brushes displaying a pH response.81 Surfaceinitiated ATRP enabled the grafting of tert-butyl acrylate (tBA), resulting in development of poly(acrylic acid) (PAA) brushes (Figure 11). Following the addition of 10 mL of tBA and 15 mL of acetone to a ﬂask, the mixture was subjected to nitrogen bubbling for a minimum of 60 min. Subsequently, the mixture was frozen in liquid nitrogen, followed by the addition of 50 mg of CuBr under a nitrogen atmosphere. The next step was sealing and defrosting of the ﬂask. A syringe was then used to add 70 μL of PMDETA to the mixture, which was subsequently stirred for 1 h under a nitrogen atmosphere at a temperature of 60 °C. Acetonitrile was used to dry the CP ﬁlm samples (PBrEDOT or PEDOT as negative control), which were then introduced to small ﬂasks with a round bottom that were sealed, evacuated, and ﬁlled back with nitrogen. The samples in the ﬂasks were then enriched with the solution consisting of tBA and the catalyst complex and introduced to a water bath at 60 °C which was shaken at 60 rpm for an interval of 2−20 h. The following step was rinsing the samples with acetone with the brushes in tBA form or performance of acid hydrolysis of the tert-butyl group to obtain the PAA brushes. In the latter case, tetrahydrofuran was used to rinse the samples for 5 min, which were further rinsed with acetone and I

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Figure 13. Quarter thiophene β-sheet structure: (a) POCl3, DMF, dichloroethane, reﬂux, 3 h, (b) K2CO3, methanol/THF, room temperature, overnight, (c) [Cu(CH3CN)4]PF6, Cu0, DCM, room temperature, 24 h. (Thr-Val)pro refers to a pseudoproline unit, (Val-O-Thr) refers to the switch unit, and aPhe stands for p-azido-Phe. Reprinted from ref 74. Copyright 2011 American Chemical Society.

the product of partially functionalized symmetrically didodecyl-substituted quaterthiophene combined with a PEO−βpeptide conjugate. Three repeats of Val and Thr were included in the peptide sequence. In aqueous and organic media, these repeats produce stable β-sheets. Due to their aggregation tendency during preparation and workup, the sequences that form β-sheets are considered to be diﬃcult sequences. To avoid such aggregation and to also regulate the self-construction process, two strategies were adopted. The ﬁrst strategy involved the integration of a pseudoproline unit into the peptide which was then transformed into a Val-Thr repeat through acidic deprotection. The other strategy involved the use of a switch ester moiety which introduced a β-ester link between Val5 and Thr6, and thus brieﬂy created a defect in the innate amide backbone. The switch ester unit (OfN-acyl transfer, inset in Figure 13) can be reorganized and the innate amide backbone restored through a promotion of alkaline conditions to replace the acidic conditions supporting the switch defect. The ligation site in a peptide side chain can be deﬁned by introducing a pazidophenylalanine (aPhe), which also facilitates quaterthiophene adhesion via Cu(I)-catalyzed Huisgen cycloaddition, the high chemoselectivity and synthetic quantiﬁcation of which make it conducive to peptide conjugation. Furthermore, a possible secondary-structure-breaking glycine was inserted between the p-azidophenylalaline and β-sheet sequence to

the PEDOT-coated cell culture surface and NIR harvesting. SCP facilitated the coating of PEDOT ﬁlms 70−300 nm thick on Petri dishes made of polystyrene or ITO glass. P-doping with tosylate was applied to pure PEDOT ﬁlms (SP) which were colored transparent blue (Figure 12). The preparation of surfaces coated with partially doped PEDOT (P1P and P2P) and dedoped PEDOT (neutral PEDOT, NP) was undertaken through cyclic voltammetry-based SP surface electrochemical dedoping by terminating the potential at +0.4, −0.2, and −1 V, respectively (Figure 10).82 Experiments were conducted on hybrid compound synthesis consisting of a poly(ethylene oxide) (PEO)-functionalized βsheet peptide sequence covalently bound to an alkylated quaterthiophene moiety.74 Experiments have revealed that the above-mentioned compound produces stable ﬁbrillar aggregates that can be seen by transmission electron microscopy as well as atomic force microscopy. Such techniques fostered the creation of a theoretical methodology for the use of all-atom MD simulations alongside experimental data integration in the model to explore potential intermolecular organizations and their properties. Thus, a number of ﬁbrillar aggregates with varying molecular organizations were used to conduct largescale atomistic simulations. Comparison of the simulation results with experimental data permitted the development of a potential model for how individual molecules in the aggregates were organized.74 The T−P hybrid compound (Figure 13) was J

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Figure 14. Py protonation. Reprinted from ref 112. Copyright 2010 American Chemical Society.

make the obtained hybrid more ﬂexible. Additionally, to make the hybrid more soluble and to hinder possible lateral interactions of ﬁbrillar aggregates, a PEO chain was supplied to the hybrid at the N-terminus.74

nanocomposite, including the high stability and dispersibility even in viscous polymer, has garnered attention due to its unique physicochemical properties dedicated to the nanoeﬀect.99,101−103 The PPy processability and functionality of PPy are signiﬁcantly improved through copolymerization with other monomers with self-stabilized functional groups.104−112 A research group found that electrochemical polymerization leads to nanosized PPy sheet formation on electrodes. Although the size and morphology of the PPy sheet are manageable, the electropolymerization is not appropriate for mass production.113 This method of productively synthesizing nanostructured PPy without any surfactants or external stabilizer thus still faces challenges.112 An investigation of PC-12 cell growth on PPy revealed exciting ﬁndings: PPy sheets subjected to electrical stimulation (ES) showed approximately twice the cell growth of that on PPy without ES.114,115 This makes CPs particularly enticing in nerve conduit construction, and highlights the possible role of ES in nerve regeneration.115 Four primary kinds of ﬁbronectin (FN) interactions have been identiﬁed, namely, interactions without adhesion, random adhesion, desorption, and protein development followed by surface detachment.90 The surface adhesion density was indicated by FN attachment to PPy/hyaluronic acid to be markedly reduced, occurring mostly in the nodule structures rather than the margins of polymer morphology. On the other hand, the surface adhesion density was indicated by PPy/ chondroitin sulfate to be substantially greater, so much so that the topography was virtually concealed by the adhesion distribution. It is plausible that interactions with chondroitin sulfate and hyaluronic acid at the surface of the polymer facilitate FN adhesion as polymer doping is essential for conductivity; moreover, as a result of the input from electrostatic attraction among FN and the dopant sulfate/ anionic groups, FN adhesion may also point to particular interactions.90 PPy NP nanocomposites were investigated and nanocarbon precursors were synthesized via unstirred oxidative pyrrole polymerization with no template in acidic aqueous media at 0 °C.112 As the HCl and HNO3 concentration rises from 0 to 3.0 M, the bulk PPy conductivity increases, before subsequently decreasing. Electrical conductivities of 0.037 and 0.068 S cm−1 are obtained in polymerization media of 0.5 M HCl and 0.35 M HNO3, respectively. Although the doping level would be higher in a higher concentration of acidic medium, the lower

2.3. Polypyrrole

2.3.1. Properties and Structure. One of the biocompatible electrically conducting polymers is PPy, which has the potential to be applied in applications in biomedicine due to its impressive conductivity, outstanding redox properties, biocompatibility, easy synthesis, and environmental stability.83−85 It can be used for neural implants, biosensors, and molecular memory devices. PPy possesses an amorphous structure and is insoluble.86 PPy could modulate cellular activities, including deoxyribonucleic acid (DNA) synthesis by ES,87 migration,88 and cell proliferation in biological environments. 2.3.2. Polypyrrole Synthesis. Polypyrrole was ﬁrst obtained by Weiss and colleagues in 1963 as a highly conductive polymer material from pyrolysis of tetraiodopyrrole. Development, synthesis, and polymerization of polypyrrole are achieved from many repetitions of pyrrole’s oxidation of ferric chloride in methanol. Polymerization would be obtained by peeling the ﬁlm from the anode. 2.3.3. Compound and Composites. This section explains the use of diﬀerent materials for hybridization with polypyrrole to improve the conductivity, such as myocytes,89 ﬁbronectin,90 titanium,91 bovine leukemia virus (BLV) protein (gp51),92 poly(ethylene terephthalate) (PET),93 biotin, alginate, biotinylated GOx,94 silk ﬁbroin,95 chlorpromazine (CPZ)-incorporated heparin (Hep),96 and tosylate ion.97 Cultured cardiac myocytes with external stimulation via a microelectrode coated by PPy have been studied.89 To construct a sheet, myocytes were electrically conjugated on the electrodes and demonstrated synchronized beating upon triggering. The threshold charge of a myocyte sheet of 0.8 cm2 was about 0.2 μC, which is approximately comparable to membrane depolarization of 250 mV.89 The absence of the required strength in pristine PPy ﬁlms restricts the broad application of this material. Construction of composite CPs was accomplished by incorporating the PPy with various polymers. It has been shown that, by mixing polylactide98,99 and poly(vinyl alcohol) (PVA)100 with PPy, PPy nanocomposites can be constructed. Considering that the PPy/ PVA nanocomposite would inevitably lose the required strength in the adjacent water, some of the solvents could uniformly disperse the PPy into polylactide solution and cause homogeneity and a low percolation threshold. Thus, the PPy K

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conjugation to biotinylated Py substrate and copolymerization and oxidation of Alg−Py and Py−B−Av−B−GOx (Figure 15). A simultaneous and stoichiometric modiﬁcation in the innate conductivity inﬂuencing the electrical signal was caused as Py was oxidized with the contribution of H2O2.94

PPy electrical conductivity could be illustrated by diﬀerent coupling modes and corresponding spatial structures depicted in Figure 14.112 Static repulsion and uniform nucleation are explained as PPy NP self-stabilization and formation mechanisms. A mixture of (NH4)2S2O8 oxidant and 2.0 M HNO3 medium maximized the yield of PPy NP synthesis to ∼87% and resulted in a high electrical conductivity of 21 S cm−1 and smaller diameter of 62 nm. In addition, at the graphitization temperature of 2300 °C in argon, the electrical conductivity could increase to 370 S cm−1.112 To develop a titanium-modiﬁed surface capable of greater antibacterial action and biocompatibility, an investigation was undertaken on the inﬂuence of the electrolyte type employed in PPy ﬁlm electrodeposition on the Ti6Al7Nb alloy. To this end, a potentiostatic electrochemical method was used to prepare the polypyrrole coatings from pyrrole and lithium perchlorate (LiClO4) based on both aqueous and nonaqueous solutions. The ﬁlm stability and surface characteristics, synthesis variables, and biological medium interaction were found to be correlated. Furthermore, biocompatibility and antibacterial action were heavily inﬂuenced by the physical and chemical qualities of the PPy ﬁlms under consideration, which have a direct connection with the doping level.91 PPy was studied as a matrix for label-free electrochemical immunosensors. Bovine leukemia virus (BLV) protein (gp51) embedded in PPy obtained through electrochemical synthesis (PPy/gp51) was the basis of the immune-sensing system model indicated. Interaction was observed between this PPy/ gp51 layer and gp51 antibodies (anti-gp51-Ab) occurring in large amounts in the blood serum of cattle infected with BLV. The protein complex PPy/gp51/anti-gp51-Ab was the outcome of this interaction. The agents employed in interaction with PPy/gp51/anti-gp51-Ab and development of the protein complex were horseradish peroxidase (HRP)-labeled secondary gp51 antibodies (Ab*).92 Detection and characterization of bacterial bioﬁlms were undertaken with the help of an electrochemical approach employing PPy-enhanced ﬂexible bioﬁlm sensors underpinned by poly(ethylene terephthalate) (PET) organic substrates.93 Py sheets served as functionalization material on electrodes made of gold to decrease the impedance, therefore elevating the electrochemical signal detection. Owing to the versatile PET substrates, the sensors can not only be introduced in geometrically complex systems, but also be developed through cost-eﬀective roll-to-roll manufacturing. The early and later phases of bioﬁlm development are respectively associated with a rise and fall in charge transfer resistance.93 To illustrate that a classical model system (e.g., monitoring of glucose presence) could result in enhanced performance, the electropolymerization of pyrrole−biotin (Py−B) in conjunction with alginate−pyrrole (Alg−Py) has been studied. To assemble the sensor, biotinylated glucose oxidase (B−GOx) was conjugated to Py−B via avidin (Av) bridges and subsequently polymerized alongside Alg−Py. This setup had markedly lower performance when it incorporated unmodiﬁed alginate rather than Py-modiﬁed alginate. H2O2 oxidation was applied to measure the glucose analyte concentration of the model, revealing intensiﬁed current conductivity of the surface of the electrode, which thus reduced the response time and increased sensitivity based on an enzyme load that was not signiﬁcantly high.94 There are two aspects underpinning the biosensor fundamental operation, namely, a close biotin− avidin binding aﬃnity promoting biotinylated GOx enzyme

Figure 15. Schematic illustration: (A) Alg−Py, (B) B−Py, and (C) biosensing matrix reaction mechanism. Reprinted with permission from ref 94. Copyright 2009 Elsevier.

Electrospinning was applied to attain scaﬀolds assembled by silk ﬁbroin micro- and nanoﬁbers. Furthermore, PPy coating of ﬁbroin ﬁber meshes was conducted by chemical polymerization. The high electroactivity presented by these coated meshes enabled anions to be stored and delivered during reactions of oxidation/reduction undertaken in aqueous solutions. Both hMSCs and human ﬁbroblasts (hFb’s) could adhere and proliferate based on the support provided by uncoated and PPy-coated materials. Moreover, compared to the PPy-coated meshes, the ﬁbroin meshes displayed greater bioactivity.95 To improve the PPy surface, plasma immersion ion implantation (PIII) was utilized as well.116 Despite not using chemical linking molecules, this method provided sustained covalent binding of tropoelastin, the cell-adhesive protein. Tropoelastin was obtained from the untreated surface through the process of elution and promoted cell attachment and dissemination on the surface treated with PIII, based on the diﬀerential binding persistence. Collagen I was employed to demonstrate that the above approach was applicable to other extracellular matrix (ECM) proteins and, despite necessitating more extensive washing conditions, produced results comparable to those of tropoelastin. This method permitted coarse cell attachment, patterning, and dissemination to tropoelastin and collagen, in particular on the PPy areas subjected to PIII treatment.116 Researchers have investigated high-yield PPy synthesis based on a biocatalytic technique and the oxidizer H2O2 in mild L

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Figure 16. Gold nanoparticles which attached to DNA origami structures, and metallized to provide conductive nanowires. Reprinted from ref 121. Copyright 2012 American Chemical Society.

aqueous environments.117 The redox mediator 2,2′-azinobis(3ethylbenzthiazoline-6-sulfonic acid) (ABTS) diammonium salt was employed to oxidize the PPy. A peroxidase substrate of high eﬃciency, ABTS produced a radical cation through enzymatic oxidation, which subsequently undertook the chemical oxidation of pyrrole. The polymer spectroscopy indicated by the pyrrole biocatalytic polymerization was the same as that indicated by chemically synthesized PPy.117 Other conducting polymer nanomaterials besides PANi have been synthesized via chemical oxidation on DNA scaﬀolds, including PPy and polythioprine derivatives.118 For instance, 2,5-bis(2-thienyl)pyrrole was covalently linked to speciﬁc nitrogenous bases in DNA strands,119 and hybridization of the unmodiﬁed bases resulted in the alignment and selfassembly of cyclic or linear pyrrole-derived structures. This was followed by enzymatic oxidation to yield cyclic or linear conductive oligomers with chemical and optical characteristics similar to those of thiophene-like polymers. The DNA-directed synthesis of CPs confers DNA nanostructures with dopant-dependent conductivity and enables the nanostructures to function as electronic boards on which conductive patterns may be organized. The DNA scaﬀold endows CPs with electrical functions, such as Schottky emission-dominated conduction and the rectiﬁcation eﬀect.120 Another advantage of using these scaﬀolds is the generation of a DNA-supported polythiophene porous structure that facilitates ion diﬀusion; DNA templates may hence play a role in the development of supercapacitors.118 A method to produce conductive DNA origami templates was developed by attaching gold nanoparticles to DNA strands, followed by a metallization process (Figure 16).121 The gold nanoparticles were densely arranged, with intervening gaps of 4.1 nm. Subsequent metallization helped to ﬁll these gaps, ultimately forming continuous nanowires. Electrodes were then patterned using electron beam lithography, with the resistance of each metallized structure measured as 2.4 kΩ. A biosensor was used to employ immobilized DNA on a nanostructured CP on a platinum electrode.122 PPy nanoﬁbers, with diameters of 30−90 nm, were synthesized by pyrrole polymerization with the assistance of normal pulse voltammetry (NPV). Double-stranded DNA was physically absorbed onto the PPy nanoﬁber sheet. The proposed technique indicated a good dynamic range for the spermidine determination. However, Ca2+ ions were depicted to be electrostatically bound to DNA and weaken the DNA−spermidine interaction.122

A new method for the treatment of water by use of PPy/ cellulose ﬁber was developed, for the purpose of Cr(VI)contaminated water detoxiﬁcation.123 The composite has a high impact on detoxiﬁcation of Cr(VI). The incorporated adsorptive/reductive detoxiﬁcation of Cr(VI) by engineered cellulose ﬁbers leads to a novel commercial conductive ﬁber application.123 The surface properties are the main factors in the elucidation of cellular interactions on the surfaces of biomaterials. The elasticity and distribution of surface charge were correlated well with the knotty morphology of PPy−hyaluronic acid (PPy−HA), and were sensitive to electrochemical charging. In fact, a considerable alteration in adhesion has been noted, based on the electrochemically charged positive surface.124 One study suggested that using positively charged PPy−HA as a coating material might improve the stem cell response.124 The synthesis of chlorpromazine (CPZ)-incorporated, heparin (Hep)-doped PPy (PPy−Hep−CPZ) was reported (Figure 14).96 One of the major sedative antipsychotic drugs for patients who suﬀer from schizophrenia is CPZ, which controls the psychomotor disturbances and excitement, as well as diminishing manic behavior.125 The bioactive sulfated polyelectrolyte Hep is employed as a doping anion polymer due to its polyanionic nature (Figure 17). In addition, as a

Figure 17. Structures of CPZ and Hep molecules. Reprinted with permission from ref 96. Copyright 2014 Elsevier.

cation exchanger, it could interact with CPZ. However, its cumbersome and multicharged structure hinders Hep trapped in PPy and on redox switching from being substituted from the polymer. By contrast, CPZ is capable of movement into the polymer due to its higher mobility and can preserve the charge equilibrium.96 The redox enzyme GOx from penicillin Vitale selfencapsulation within CP/PPy was investigted.126 The PPy polymerization was initiated by a GOx catalytic action product, H2O2, which acts as an oxidator for free radical generation. GOx began to generate H2O2 and the lactone of gluconic acid M

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nanoconﬁnement, which involves reducing the size of a polymer to the nanometer scale to modify its kinetic and thermodynamic properties. Pan and co-workers134 in 2014 redesigned a stiﬀ and brittle PPy from its rigid conjugated-ring backbone into a microstructured conducting polymer (EMCP), which is elastic and ultrasensitive with rapid respond to force. This was achieved by making interconnected hollowsphere structures of PPy that were prepared through a multiphase synthesis technique. The hollow-sphere structure allows the PPy to elastically deform and recover upon the application and release of external pressure (Figure 19a). Their

in the presence of dissolved oxygen and glucose, which was hydrolyzed to gluconic acid (Figure 18). The presence of

Figure 18. Glucose oxidase coating by PPy schematic illustration. Reprinted with permission from ref 126. Copyright 2005 Elsevier.

entrapped GOx within PPy was determined by a basic PPycoated GOx NP application in biosensor design. The optimal conditions for PPy polymerization are a high concentration of H2O2 and a low pH.127 PPy polymerization self-assembly begins under favorable conditions, and the CP covered the GOx. Due to high nitrogen protonation, enzyme coverage could be speciﬁed by electrostatic interactions between the PPy backbone (positively charged) and glycoprotein GOx (negatively charged).126,128−131 Tosylate ion release and conductivity were also investigated by researchers.97 The impedance of the oxidized tosylatedoped PPy ﬁlm gradually increases and the conductivity decreases after overoxidation. On the basis of the results, to improve the bioactive materials, tosylate-doped PPy ﬁlms were grown directly in the sol−gel matrix or on the metal alloy surface. Overoxidation resulted in the degraded material form under a biological oxidizing environment.97 The development of PPy ﬁlms with various resistances as conductive surfaces was undertaken to investigate the eﬀect of substrate-mediated ES.132 Dark yet transparent, the PPy ﬁlms permitted the visualization of surface cells. They supported the culturing of stromal cells from rat bone marrow, which underwent diﬀerentiation into osteoblasts following treatment with osteogenic medium. Up-regulated osteogenic markers were displayed by these cultured cells, while the rapid pace of cell diﬀerentiation promoted by the PPy ﬁlms was demonstrated by an assay on alkaline phosphatase activity. Furthermore, the favorable eﬀect of the PPy ﬁlms on osteogenesis was indicated by alizarin red staining and calcium analysis. Additionally, to determine how osteogenesis was aﬀected by ES, a constant electric ﬁeld was applied to the PPy ﬁlms. Thus, it was found that calcium was deposited more eﬀectively in the extracellular matrix in the presence of ES, in contrast to the untreated group. Moreover, surface cell stimulation was underpinned by larger currents due to the reduced resistance of the PPy ﬁlms, enhancing mineralization levels. Such ﬁndings accentuated the higher electroactivity with modulated electrical resistance of the proposed system, which could advance ES research on tissue repair since it is amenable to direct coating to develop transparent medical devices.132,133 Nanoconﬁnement is based on the reduction of the size to the nanometer scale to modify kinetic and thermodynamic properties. In polymer nanoconﬁnement, nanosized and slender ﬁbers of a conducting polymer are encased within a soft and stretchable material, known as an “elastomer”. Due to its small size, the conducting polymer can bond well with the surrounding elastomer over a large surface area. The resulting blend of polymers can thus transport electrical charge eﬃciently. This technique could result in highly stretchable polymer semiconducting ﬁlms using a technique known as

Figure 19. Elastic microstructured conducting polymer (EMCP): synthesis and microstructure. (a) Structural elasticity of the hollowsphere-structured PPy. (b) Interphase synthesis mechanism of PPy hydrogels with hollow-sphere microstructures. (c) PPy hydrogel in the tube. (d) SEM image of the PPy ﬁlm, scale bar 10 mm. (e) TEM image of PPy revealing its interconnected hollow-sphere structure, scale bar 1 mm. Reprinted with permission from ref 137. Copyright 2015 Wiley-VCH Verlag GmbH & Co.

application of EMCP was the development of a pressuresensing device that mimics and surpasses the subtle pressuresensing properties of natural skin, for human−computer user interfaces or robotics. The EMCP thin ﬁlm was developed using PPy gel precursor and casting in a glass Petri dish. Figure 19b schematically shows the multiphase reaction mechanism employed to achieve the hollow-sphere morphology of the PPy. After puriﬁcation with deionized water, the PPy gel became a hydrogel (Figure 19c). The SEM image (Figure 19d) shows the 3D honeycomb foam morphology of the dried PPy ﬁlm. Furthermore, the high-magniﬁcation SEM image of PPy reveals its interconnected hollow-sphere structure (Figure 19e). At the University of Texas at Austin, researchers135 have developed a conductive self-healing polymer. They developed N

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Figure 20. Nanoconﬁnement eﬀect for developmnet of the stretchability of a polymer semiconducting ﬁlm: (A) 3D schematic of the desired morphology composed of embedded nanoscale networks of polymer semiconductor to achieve high stretchability, which can be used to construct a highly stretchable and wearable TFT, (B) chemical structures of semiconducting polymer DPPT-TT and SEBS elastomer, (C) three model ﬁlms of DPPT-TT for investigation of the nanoconﬁnement eﬀect. Reprinted with permission from ref 138. Copyright 2017 American Association for the Advancement of Science.

amino or carboxyl groups,142 poly-L-lysine,143 and (diphenylamino)-s-triazine.144 Also discussed are methods such as ﬂuorination145 and sulfonation.146 A study was conducted on the electrochemical technique capable of activating nucleophilic ﬂuorination of cationic intermediates to initiate 18F-ﬂuorination on an automatic platform controlled remotely. An intermediate model molecule for the positron emission tomography (PoET) probe (3,4dihydroxy-6-[18F]ﬂuoro-L-phenylalanine), tert-butyloxycarbonyl (Boc)-protected catechol, was the focus of the conducted nucleophilic electrochemical ﬂuorination (Figure 21). The

morphology-controlled nanostructured conductive hydrogels with polypyrrole (PPy). They used a general supramolecular strategy to prepare morphology-controlled nanostructured hydrogels with PPy by using a dopant counterion, copper phthalocyanine-3,4′,4″,4‴ -tetrasulfonic acid tetrasodium salt (CuPcTs). The CuPcTs acts as both the cross-linker gelator and protonic dopant for the PPy hydrogel and self-assembles the PPy chains into a nanostructure via a steric eﬀect. Application of a disk-shaped liquid crystal molecule enhances the conductivity, biocompatibility, and permeability of the polymer hydrogel. In addition, when the supramolecular gel is incorporated into the polymer hydrogel, forming the hybrid gel, the mechanical properties and viscoelasticity of the conductive polymer signiﬁcantly increase.136 Its current application is in the electronic industry such as in mobile phones, but it also has a biomedical application due to its biocompatibility. Smart, thermally responsive polymer has many applications, including in biomedicine and the robotic and industrial sectors. Shi and co-workers137 have developed a thermally responsive polymer using conductive hydrogels cross-linked by phytic acid in a poly(N-isopropylacrylamide) matrix. The interpenetrating binary network structure provides a porous microstructure, which allows a continuous path of the electron, making the polymer highly electrically conductive. Due to the interaction between two hydrogel networks used in this composite, the mechanical properties were signiﬁcantly improved. This kind of polymer has been emerging for many applications, and the immediate aim of this group was the potential applications in stimulus-responsive electronic devices. In summary, polymer molecules when trapped in thin layers or tubes or when on the free surface will have properties diﬀerent from those of the bulk. This is due to the fact that conﬁnement can prevent crystallization and also give the chain molecules more scope for motion.138 They can retain their conductive properties even when subjected to large deformations, with an application such as stretchable electronic skin (Figure 20).

Figure 21. Redox potential reactions of (a) di-tert-butyl 1,2phenylenedicarbonate (1) and (b) di-tert-butyl 4-tert-butyl-1,2phenylenedicarbonate (6). Reprinted with permission from ref 145. Copyright 2014 Elsevier.

2.4. Polyphenylene

achievement of ﬂuorination was mediated by potentiostatic anodic oxidation in acetonitrile whose composition included Et3N·3HF and additional supporting electrolytes. Precursor and Et3N·3HF concentrations, supporting electrolyte type, temperature, time, and applied potentials were among the factors aﬀecting the eﬀectiveness of radio ﬂuorination. 4-tertButyl-diBoc-catechol (0.1 M) was subjected to electrolysis for 1 h in an acetonitrile solution of 0.033 M Et3N·3HF and 0.05 M NBu4PF6, resulting in 10.4 ± 0.6% (n = 4) radio

2.4.1. Properties and Structure. Polyphenylene is one of the CPs and contains an aromatic ring in its structure. An insoluble powder, it has shown interesting thermal, chemical, and electrical properties. 2.4.2. Compound and Composites. This section explains the use of diﬀerent materials for hybridization with polyphenylene to improve the conductivity, such as ZnO NPs,139 silicate platelets,140 polystyrene (PS) mixtures,141 O

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Figure 22. Dendrimer polyphenylene scaﬀold. X is either H or R. Reprinted from ref 143. Copyright 2009 American Chemical Society.

ﬂuorination eﬃciency and up to 43 GBq mmol−1 speciﬁc activities. The mediation of electrochemical oxidation and ﬂuorination by the tert-butyl functional group was clariﬁed with density functional theory (DFT).145 A study was also conducted on the physiochemical properties of the poly(phenylene sulﬁde) derivative (PPSNH2) combined with various compositions of ZnO NPs.139 No surfactants or coupling agents were required for the dissemination of the NPs in the matrix. The role played by the NPs as nucleating agents for PPS-NH2 crystallization was certiﬁed by the fact that an increase in ZnO loading elevated the temperature of crystallization and the crystallinity level. At 8.0 wt % content, the NPs signiﬁcantly increased the original 80 °C degradation temperature by diminishing water intake and making the matrix more stable thermally. Furthermore, in contrast to the considerable increase in rigidity, strength, ﬁrmness, and glass transition and heat distortion temperatures, the added ZnO caused a reduction in the thermal expansion coeﬃcient, due to the fact that the matrix amino groups and the NP hydroxyl moieties displayed powerful hydrogenbonding interactions. Exposure to multiple steam sterilization cycles did not aﬀect the tensile features of the nanocomposites. Furthermore, the capability of NPs to protect the matrix against wear was proven by the almost 100-fold decrease in the wear rate associated with the nanocomposite bearing the greatest loading.139 Moreover, the synthesis of sulfonated poly(2,6-dimethyl-1,4phenylene oxide) (sulfonated PPO) was undertaken with diﬀerent levels of sulfonation.146 Membrane preparation by solvent casting involved the combination of the solutions with organically modiﬁed montmorillonite (MMT). In the case of membranes lacking MMT, the increase of the sulfonation level to 40% elevated the ion exchange capability to 2.59 mequiv g−1, water absorption to 21%, and proton conductivity to

0.0182 S cm−1. In comparison to Naﬁon (40500), a membrane selectivity of around 63500 was displayed by a sulfonated PPO/MMT membrane with 27% sulfonation and 2.0 wt % MMT loading. Moreover, in the case of single-cell DMFC in a methanol feed (5 M), the power density of this membrane also exceeded that of Naﬁon (125 mW cm−2 vs 108 mW cm−2).146 Covalent binding of the polymer on the surface of the silicate platelets permitted the synthesis of poly(N-isopropylacrylamide)-tethered nanosilicate platelets (NSP-PNiPAAm).140 This compound was used to pulverize poly[2methoxy-5-((2′-ethylhexyl)oxy)-1,4-phenylenevinylene] (MEH-PPV) to enable its dispersion in water; at 37.5 °C, MEH-PPV exhibited thermoresponsive qualities, with the CP particle size within the range of 50−100 nm. Furthermore, compared to 45 °C, a temperature of 4 °C was associated with a markedly higher photoluminescence (PL) emission. In keeping with the PL measurement, the PL emission was orange in color when exposed to ultraviolet light due to its coating as a ﬁlm. Thus, hydrophobic conjugated polymers can be easily manipulated through this method of CP dissemination in water with NSP-PNiPAAm present and subsequent ﬁlm development.140 An investigation has also been conducted on the behavior of poly(2,6-dimethyl-1,4-phenylene ether) (PPE) ﬁlms and their polystyrene (PS) mixtures.141 According to empirical research, appropriate PS weight fractions may be added to augment the favorable electret performance of pure PPE. A correlation exists between such a cooperative electret behavior and morphological blend factors such as packaging density and occurrence of PS microheterogeneities in the PPE/PS matrix.141 In addition, polyphenylene dendrimers (PPDs) coupled by peptides seem to be both a practical and a promising option.142 The functionalized cyclopentadienones that were prepared P

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characteristic time did not undergo any signiﬁcant alterations. On the other hand, a temperature increase caused a reduction in the accompanying relaxation modulus, as anticipated.150 The surface wettability of (diphenylamino)-s-triazinebridged p-phenylenevinylene polymer (DTOPV) can change in the presence of UV light, thereby also aﬀecting its ﬂuorescence quenching. For example, the patterned polymer has been exposed to UV light via a photomask.144 The photopatterning empirical work focused on the surface of a polymer ﬁlm that represented a synthesized DTOPV depicted in Figure 23, which used the Wittig polycondensation

equipped polyphenylene dendrimers with amino or carboxyl groups due to their Diels−Alder cycloaddition with diﬀerent core molecules. Furthermore, the shape persistence and monodispersity-deﬁning PPDs were illustrated by the functionalized molecules produced in this way. The ﬁrst approach involves the application of R-amino acid N-carboxyanhydride (NCA) polymerization to graft polylysine portions from the dendrimer surface.142 The second approach entails activation of protected polypeptide C-terminal carboxyl groups followed by their attachment to the amino groups on the PPD surface. The third approach involves adding the cysteine sulfhydryl group to the maleimide functions on the surface of the dendrimers to bind the cysteine-terminated, unprotected peptide sequences to the polyphenylene dendrimers. Additionally, a dendritic scaﬀold with various anchor groups on its margins can be created through Diels−Alder cycloaddition of appropriately functionalized cyclopentadienones to a desymmetrized core molecule. The development of innovative multiple antigen conjugates displaying shape persistence and polyfunctionality is directly dependent on such methods.142 Ample research has focused on the mechanism of selfconstruction and the related molecular dynamics. One report noted that the core size (generation), functionality, and polypeptide length caused a set of poly-L-lysine-functionalized polyphenylene dendrimers to melt.143 The grafting of poly-Llysine chains was done straight from the surface of the ﬁrstand second-generation amino-functionalized polyphenylene dendrimers (PPDs) comprising pentaphenylbenzene units and a stiﬀ perylenediimide core. A speciﬁc number of functional groups can not only be placed into an outlined volume element, but also have their orientation manipulated through the use of this type of dendrimer as a polymerization macroinitiator.147−149 Ring-opening polymerization of ε[(benzyloxy)carbonyl]-L-lysine-N-carboxyanhydride (Lys(Z)NCA) enabled poly-L-lysine to be grafted from the PPD surface. The polypeptide length can be regulated by this reaction process through the quantity of Lys(Z)-NCA it contains. Lysine ε-amino group deprotection was the next process after grafting. The numbers of poly-L-lysine chains of diﬀerent lengths varied among the obtained polypeptide−PPD conjugates (Figure 22).143 Furthermore, various secondary structures could be appropriated by the constrained poly-Llysines from their linear equivalents. Three mechanisms were identiﬁed by the dynamic investigation to support polypeptide movement, namely, glass transition, a process progressing at a slow pace and related to R-helical segment relaxation, and a glassy state whose source could be determined with methods of site-speciﬁc solid-state NMR.143 Quasi-static (QS) and dynamic nanoindentation (NI) were employed to study the temperature-based mechanical properties of poly(p-phenylenevinylene) (PPV) in the temperature range of 25−100 °C. Over this range, a decline from approximately 4.40 to 3.64 GPa was observed in the reduced modulus. Furthermore, every measurement temperature produced plasticity indices that did not exceed the crucial value of 0.875, deﬁning material “sink-in” instead of “pile-up”. The lowest plasticity index value was recorded at approximately 70 °C, with a nonmonotonic trend being exhibited. Moreover, generalized Maxwell viscoelastic models were employed to examine the indentation stress relaxation data derived at various temperatures. This examination highlighted a relaxation mode deﬁned by a characteristic relaxation time of around 0.5 s. Within the 25−100 °C temperature range, the

Figure 23. DTOPV structure and photo-oxidation. Reprinted from ref 144. Copyright 2009 American Chemical Society.

method.151,152 To achieve a 140 nm polymer ﬁlm of 140 nm thickness after solvent removal, the polymer solution was spincoated in chloroform.144 Fibronectin exists in the form of a dimer comprising two polypeptide subunits which are closely similar and which are connected by two C-terminal disulﬁde bonds.153,154 By contrast, gelatin and collagen consist of polypeptide strands connected by multiple hydrogen bonds, and therefore, they are considered to be hydrophilic.155,156 These hydrophilic proteins owe their preferential location on the area exposed to UV to the interplay with the photooxidized DTOPV surface. Meanwhile, the adhesion proteins also interact with cells based on the mediation provided by integrins.157 Therefore, the presence of hydrophilic proteins is important for the adhesion and culture of hMSCs. Figure 24 indicates the cell adhesion model with collagen.144 The exposed area of the polymer showed biocompatibility and selective hMSC adhesion. Overall, this approach permitted patterning and cell alignment along the patterns of curved, linear, and diﬀerent letter shapes.144 2.5. Polyaniline

2.5.1. Properties and Structure. One of the most promising conjugated CPs is PANi, due to it preparation simplicity, high electrical conductivity, and great environmental stability.158 These properties make PANi suitable to be employed on diﬀerent sensor applications, such as pH switching electrical conducting biomaterials,159 electrically active redox biopolymers, and matrixes for nanocomposite CP preparation.160,161 Thus, tremendous development in PANi-based nanocomposite biopolymer preparation has been done. PANi is the only CP which by protonation or charge transfer doping can regulate the electrical properties. Due to control of the electrical,162 magnetic,163 mechanical,164 and thermal165,166 properties of the organic−inorganic nanoQ

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Figure 24. Cell adhesion and patterning on a photo-oxidized DTOPV surface model. Reprinted from ref 144. Copyright 2009 American Chemical Society.

β-cyclodextrin by adopting a molecular stance in the examination of the interaction between PANi and cyclodextrin.168 The synthesis of dual-layered PANi selenium−tellurium (Se0.5Te0.5) sheets from a lyotropic liquid crystalline (LLC) template with Brij56 surfactant is another pragmatic option.169 The band gap of Se0.5Te0.5/PANi dual-layer sheets was approximated to be about 0.9 eV, and the band gap of Se0.5Te0.5 sheets was estimated to be 1.4 eV, showing that incorporating PANi into Se0.5Te0.5 enhances its electron transfer.169 The PANi coated with platinum electrode, formed by in situ polymerization, was proposed for neural applications.170 The outcome of the PANi stability by in vitro ES indicated that the PANi coated with Pt induced less peroxidation and adsorbed fewer retinal fragments when compared to the uncoated Pt electrode. In addition, the surface of PANi coated with Pt tended to accumulate retinal fragments in contrast to the uncoated PANi, the scar formation and inﬂammation of which may decrease over time. Finally, the coated PANi exhibited favorable properties such as intactness and stale NPs after 6 months by ES, compared to the uncoated PANi, for which after a month corrosion occurred.170 PANi NPs have also been polymerized on the Pt electrode surface to form nanostructured sheets.174 PANi ﬁlms covered the electrode surface thoroughly. No cracks appeared on these ﬁlms following ES for one month in a 0.9% solution of sodium chloride. To ensure durable performance, a compact ﬁlm can be employed to coat an electrode because it serves as a protective membrane on the Pt surface. By comparison to the case without ES, ES caused a 1.7-fold increase in the protein quantity assimilated on PANi ﬁlms, according to the time frame associated with both human plasma ﬁbronectin (FN) and bovine serum albumin (BSA) adsorption. Furthermore, PANi ﬁlms were observed to be less conductive due to protein adsorption, which may be explained in terms of the protein barriers surrounding them.174 Another relevant proposition involved the synthesis of PANi in an acidic aqueous environment undertaken via aniline (C 6 H 5 NH 2 ) by oxidant ammonium peroxydisulfate [(NH4)2S2O8] with chain-terminating agent 1,4-phenylenediamine present, which is illustrated in Figure 26.171,175,176 PANi-jute was treated with alkali through immersion in 1 M ammonium hydroxide (NH4OH) for 5 min to ensure that it was fully deprotonated. To adapt the solution to a neutral pH, distilled water was subsequently used to wash the products. Afterward, the PANi-jute ﬁber of blue-black color was placed in an oven to dry at a temperature of 40 °C.171 Furthermore,

composites compared to the organic polymers, they are considered among the most important nanocomposite materials.167 Figure 25 shows the chemical structure of

Figure 25. PANi chemical structure. Reprinted from ref 168. Copyright 2012 American Chemical Society.

PANi. It is polymerized on the basis of the aniline monomer, and can be found in one of three idealized oxidation states, which aﬀect its conductivity. The partially oxidized structure called emeraldine is also of interest and is shown in Figure 25, where m and n in the ﬁgure are in a 1:1 ratio.168 After being doped with acid, it becomes a CP which is very stable at room temperature. Pernigraniline and leucoemeraldine are oxidized and reduced forms, respectively, and demonstrate poor conductivity, even after doping. 2.5.2. Polyaniline Synthesis. Polyaniline can be obtained from a three-component-state physical mixture of leucoemeraldine [(C6H4NH)n], emeraldine [([C6H4NH]2[C6H4N]2)n], and per-nigraniline [(C6H4N)n]. Emeraldine [([C6H4NH]2[C6H4N]2)n] is doped with acid and is in the most stable and conductive of the three states of the physical mixture used to obtain polyaniline. Developing and synthesizing the polyaniline is easy, but on the contray, the mechanism is not as easy. In the process, the oxidant ammonium persulfate is required. Each component is dissolved in acid and slowly mixed. An exothermic reaction results. 2.5.3. Compound and Composites. This section explains the use of diﬀerent materials for hybridization with polyaniline to improve the conductivity, such as cyclodextrin, β-cyclodextrin ring,168 lyotropic liquid crystalline (LLC) materials,169 platinum,170 oxidant ammonium peroxydisulfate,171 ATQD,172 and methyl orange (MO).173 Molecular dynamics were employed to create simulations of various β-cyclodextrin ring orientations on one PANi chain in the form of an alternating emeraldine. An implicit solvent medium equivalent to the experimental conditions provided the simulation context. The cyclodextrins repulse one another when the directions in which the larger β-cyclodextrin toroid openings are oriented are the same. In contrast, the βcyclodextrin rings are attracted to each other and create ring pairs or stacks when the β-cyclodextrin orientation on the chain is alternated. Such simulations illustrate how external chemical action on polyaniline can be impeded with the help of R

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ATQD electroactivity, which was comparable to that of PANi in terms of the two diﬀerent reversible oxidative states displayed. The adhesive oligopeptide cyclic Arg-Gly-Asp (RGD) (ATQD-RGD) was used to achieve the covalent alteration of the aromatic amine terminals of the ATQD selfassembled monolayers (SAMs). As expected, in both control and electroactive surfaces, neurite extension was considerably enlarged by the nerve growth factor (NGF).172 As illustrated in Figure 27, a three-neck round ﬂask with an anhydrous THF content was used to mix equal molar amounts of the puriﬁed emeraldine base form of the aniline trimer (EBAT) and triethoxysilylpropyl isocyanante (TESPIC) with magnetic stirring before 24 h of reﬂuxing at a temperature of around 67 °C under a N2 atmosphere. The obtained solution of a wine-red color was allowed to cool at ambient temperature, and thereafter, nonpolar solvent n-hexane was added to it; to permit full precipitation, the reaction system was then transferred to a dry ice−acetone bath for 12 h. Vacuum ﬁltration through ﬁlter paper was used to aobtain the dark violet solid, which generated about 85% yield after being washed with n-hexane (300 mL) and vacuum-dried for 3 days at ambient temperature. Moreover, n-hexane/ethanol was used as the eluant, and silica was then used for solvent evaporation.172 Methyl orange (MO) was used to alter natural silk ﬁbroin (SF) ﬁbers, and a composite displaying a core/shell coaxial-line structure was formed through in situ oxidation.173 Oxidation of aniline monomers during the ﬁrst polymerization phase results in cation radicals serving as seeds with active growth. The cation radicals can be assimilated in high amounts by the MOmodiﬁed SF surface through electrostatic attraction and based on the input of −SO3−. Therefore, aniline monomers are oxidized and polymerized not in solution, but on the ﬁber surface because the latter contains greater quantities of cation radicals. The phenomenon is demonstrated by the color alteration from yellow to deep green exhibited by the ﬁber, whereas the solution color stays transparent during the initial reaction moments. Composite ﬁbers are ultimately formed by selective polymerization on the MO-modiﬁed SF surface, with the PANi nanolayer providing a complete and homogeneous cover of the SF (Figure 28).173 To manipulate the PANi

Figure 26. PANi synthesis scheme. Reprinted with permission from ref 171. Copyright 2009 Elsevier.

polyaniline, the short-chain polymer obtained through synthesis on the PANi-jute ﬁber surface, was assessed in terms of how it performed in eliminating hexavalent chromium [Cr(VI)] in an aqueous medium based on ﬁxed-bed column studies. To this end, the variable parameters employed were inﬂuent pH, column bed depth, inﬂuent Cr(VI) concentrations, and inﬂuent ﬂow rate. Electrostatic attraction of acid chromate ion (HCr4−) with PANi-jute protonated amine group (NH3+) revealed that the total chromium removal had an ideal pH of 3. Total chromium absorption by PANi-jute rose from 4.14 to 4.66 mg g−1 when the column bed depth was enhanced from 40 to 60 cm, causing the throughput volume of 9.84 L to increase to 12.6 L at the point of exhaustion. Moreover, at 10% breakthrough, the adsorption rate constant was 0.01 L mg h−1, while the dynamic bed capacity was 1069.46 mg L−1. Following ignition, nontoxic Cr(III) was the form in which the assimilated total chromium was recovered from PANi-jute, with a weight decrease of over 97%, thus reducing the issue of solid waste discard.171 A one-step coupling reaction followed by column chromatography-based puriﬁcation was employed to extract N-(4-aminophenyl)-N′-(4′-((3-(triethoxysilyl)propyl)ureido)phenyl)-1,4-quinonenediimine) (ATQD), an electroactive silsesquioxane precursor, from the emeraldine form of amino-capped aniline trimers.172 Analysis indicated that protonic acid doping ensured the preservation of the inherent

Figure 27. (A) ATQD, (B) EBAT, and (C) TSUPQD synthetic scheme. Reprinted from ref 172. Copyright 2007 American Chemical Society. S

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Figure 28. Natural SF/PANi (core/shell) coaxial ﬁber formation. Reprinted with permission from ref 173. Copyright 2013 Elsevier.

Figure 29. PANi ﬁlm polymerization. Reprinted with permission from ref 177. Copyright 2011 Elsevier. Reprinted from ref 178. Copyright 2006 American Chemical Society.

coating density on the composite ﬁber, the reaction time must be regulated. There are views that the development of a PANi shell coated on the SF ﬁbers is determined by MO. The composite ﬁber was observed to depict acceptable biocompatibility, proliferation, and cell adhesion when L929 cells were chosen as a model and grown on a ﬁbrous substrate.173 The in situ free radical polymerization method has also been employed to synthesize an Fe0.01Ni0.01Zn0.98O NP (FNZP) composite and PANi.167 The sol−gel method was applied to perform the synthesis of iron/nickel-codoped zinc oxide NPs. Optimal photodegradation eﬃciency against methylene blue dye (MB) was obtained for nanocomposites. Improved electrical conductivity was also observed. Furthermore, the optical density technique was used to examine how eﬀectively the prepared NPs and nanocomposites acted against Escheria coli bacteria.167 The PANi modiﬁcation electrode reactor has also been investigated regarding its ability to extract ﬂuoride from aqueous solutions.177 The control of ﬂuoride absorption and elution through manipulation of the PANi ﬁlm potential is the idea underpinning this reactor. The outcomes indicated that PANi extraction of ﬂuoride was signiﬁcantly inﬂuenced by terminal potential values, ideal extraction taking place at 1.5 V. The accelerated ﬂuoride extraction velocity was reﬂected by the fact that there was a fast intensiﬁcation in ﬂuoride

extraction capacity within 5 min, the capacity becoming balanced within 10 min. Research on ﬂow cell breakthrough also assessed the feasibility of treating tap water contaminated with ﬂuoride with the PANi reactor for ﬂuoride extraction. The outcomes suggested that ﬂuoride may be eﬀectively removed from water through the electrically controlled anion exchange by the PANi-modiﬁed electrode reactor.177 PANi polymerization and ﬂuoride ion absorption and elution alongside oxidation and PANi reduction are illustrated in Figure 29. Polymerization of free aniline monomers took place in HCl solution, with doping of Cl− in the PANi ﬁlm. Morphological transformation in nitrogen atoms caused PANi chains to lose electrons in the process of electrochemical anion exchange. Consequently, F− ion doping of secondary PANi occurred at an appropriate anodic voltage. Fluoride levels were reduced as a result of anion exchange mediating elution into solution of some Cl− ions in the PANi ﬁlm and removal of F− ions from solution via secondary doping. The recurrent usage of the PANi electrode was ensured through renewal of the PANi ﬁlm in HCl solution at a particular negative voltage for dedoping of F− ions.177,178 DNA nanostructures have numerous characteristics that make them suitable scaﬀolds for synthesizing nanostructured polyaniline. First, the negatively charged phosphodiesterase backbone of DNA provides the counterionic charge necessary T

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Figure 30. Self-assembled DNA templates facilitate catalytic growth of conductive PANi: (A) PANi NDA-guided growth (pictorial, AFM images), (B) DNA-templated PANi absorption spectra. Reprinted from ref 183. Copyright 2013 American Chemical Society.

to the radical form. The DNAzyme interacted with the template eﬃciently, allowing the aniline radicals to promptly diﬀuse to and dimerize at the negatively charged regions; paradirected polyaniline was eventually formed through successive reactions. The growth of PANi was preferentially initiated around the catalytic region before spreading over the template surface as depicted in Figure 30A. This is an example of siteselective polymerization. The strong DNA−polyaniline coupling eﬃciently transferred chirality from the DNA duplex to polyaniline, as evidenced by the right-handedness of the synthesized polyaniline. The molecular spectra of PANi were determined by the charge density of the template, which was in turn inﬂuenced by the template conﬁguration as shown in Figure 30B. In summary, this study found that the shape of polyaniline can be controlled on 2D and 3D origami surfaces by manipulating the position of catalytic DNAzyme sites.

for synthesizing polyaniline with an extended conjugate molecular structure. Second, the shape of the DNA templates can be programmed to generate diﬀerent morphological forms of polyaniline. For instance, 1D polyaniline nanowires were produced around the duplex structure of linear calf thymus DNA templates.179 At pH values below the pKa of aniline, the aniline was catalytically oxidized by horseradish peroxidase (HPA) with H2O2 acting as the oxidant. This eventually yielded the emeraldine form of alanine, which displayed reversible doping−dedoping behavior as well as inducible electrical activity. The use of enzymatic polymerization allows ﬁne regulation of the reaction kinetics and ensures overall eﬃciency of the reaction by producing a high yield of PANi/ DNA structures from the initial substrates.180 The growth of polyaniline on DNA self-assemblies as opposed to linear DNA templates deserves special consideration. The limited negatively charged area of self-assembled DNA can drastically decrease the percentage yield of conductive PANi. Two strategies have been proposed thus far to surmount this problem. The ﬁrst method covalently incorporates aniline monomers into contiguous bases of a single DNA strand,181 which then hybridizes with another strand, thereby promoting constant interaction between aniline and the negatively charged DNA duplex. A second strategy conjugates a catalyst such as HRP to the nucleic acid strands participating in self-directed DNA assembly. With H2O2 present, conductive polyaniline is then produced around the DNA molecule.182 However, the modiﬁcation of multiple strands with HRP can potentially cause undesirable crosslinking of the DNA nanostructures. As such, an alternative method involves use of a heparin-complexing DNA strand which mimics HRP function and assembles with the complexes to form discrete catalytic nanostructures. Using this concept, an HRP-like DNAzyme was linked to DNA monomers which then assembled into a 1D nanostructure via hybridization of their sticky ends.183 The DNAzyme was ﬁrst oxidized to an intermediate by H2O2 before itself oxidizing aniline monomers

3. CONDUCTIVE COMPOSITE BIOPOLYMERS Due to their biological behavior in critical substitution and restoration, polymeric tissue engineering scaﬀold materials have been broadly investigated in TE.184−186 Among the TE scaﬀold materials that have been employed in recent decades due to their excellent biodegradability and biocompatibility, there are a considerable number of synthetic and natural biopolymers, including polyurethane,187 poly(ε-caprolactone) (PCL),188 chitosan (CS),189,190 collagen,191 polylactide (PLA),192−194 alongside their composites.195−198 New biomaterials displaying particular target functions subject to external control or adjustment by surrounding stimulation, such as light,199 electrical signal,200 magnetic power,201 and pH changes,202,203 have recently been investigated. 3.1. Modiﬁed Biopolymers with Conjugated π Conductive Polymers

CPs are an innovative series of materials that have the same mechanical and processing qualities of organic polymers while also displaying the electrical and optical features of metal and U

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semiconductors.204,205 Among these polymers, the ones that have so far attracted the greatest attention for both their scientiﬁc and their commercial potential are chemically stable polythiophene, polypyrrole, and PANi, alongside their corresponding derivatives.206−210 3.1.1. Polythiophene. By oxidative polymerization of the parent monomers aniline and EDOT in p-toluenesulfonic acid (p-TSA) aqueous solutions, bilayer nanostructured PANi and PEDOT CP composites have been successfully produced.210 Initially, PANi nanoﬁbers were produced in the p-TSA solution using ammonium persulfate (APS) as the oxidant. Then the PANi nanoﬁbers were coated by PEDOT through EDOT oxidative polymerization, eventually forming the PEDOT/ PANi bilayer nanoﬁbers. The PEDOT/PANi nanocomposite electrical conductivity at room temperature was 2 orders of magnitude greater than that of the PANi nanoﬁbers. In addition, on a glassy carbon electrode, PEDOT/PANi nanocomposites indicated stronger electrocatalytic activity for the ascorbic acid oxidation in comparison with PANi nanoﬁbers.210 On the basis of the weight ratios 20:80, 40:60, and 60:40 TPU:P3TMA, nanomembranes have also been produced by spin-coating mixtures of a thermoplastic polyurethane (TPU) and polythiophene (P3TMA) derivative. An increase in P3TMA concentration enhances the TPU:P3TMA swelling capacity and hydrolytic and enzymatic deterioration. Furthermore, the behavior of TPU:P3TMA blends is considered to be similar to that of biodegradable materials because the occurrence of enzymes in the hydrolytic environment enhanced blend degradation substantially. In contrast, TPU:P3TMA nanomembranes promote cell attachment and viability by acting as bioactive platforms. The substrate supporting the nanomembrane determines to a great extent the assimilation of type I collagen, which on the other hand is largely unaﬀected by the chemical character of the polymeric material from which the nanomembrane is made. Nevertheless, the content of the nanomembrane interacting with the protein was identiﬁed to determine the type of arrangement taking form (e.g., ﬁbrils or pseudoregular honeycomb networks), based on in-depth microscopic analysis of adsorbed collagen morphology and topography. TE applications in biomedicine may beneﬁt from scaﬀolds constructed of TPU:P3TMA nanomembranes displaying electroactivity.211 P4VP-b-PS block copolymer iodination was employed to produce poly(4-vinylpyridine)-block-poly(4-iodostyrene), P4VP-b-PS(I), block polymers212 which can construct polymer brushes with PS(I) chains of moderate stretch, due to their strong attachment to various polar substrates, including a metal oxide, glass, or Si wafer surfaces. Graft copolymer planar brushes are the outcome of Kumada catalyst-transfer polycondensation (KCTP) from the P4VP-b-PS(I) brushes and are associated with emanation of ∼10 nm grafts of poly(3hexylthiophene) (P3HT) from the PS(I) chains attached to the surface. Mainly due to the heightened excluded volume interplays, P3HT grafting provides signiﬁcant PS(I) backbone stretching. P4VP25-b-PS(I)350 brush patterning has been achieved through particular P4VP block assimilation to polar surfaces.212 KCTP permitted the transformation of the P4VP25-b-PS(I)350 brush of microscopic structure to the patterned P4VP-PS(I)-g-P3HT brush.212 Furthermore, a quasi-structured hexagonal array was formed on Si wafer by P4VP75-b-PS(I)313 micelles derived from selective PS(I) block solvent. Even when it was carefully rinsed with diﬀerent

solvents, this array was maintained by the P4VP75-b-PS(I)313 monolayer. However, despite the fact that the original arrangements were demolished by the P3HT grafted from the nanostructured P4VP75-b-PS(I)313 brush, the particulate morphology in the resulting sheet was preserved. New materials and sensors reacting to stimuli may be used to explore this investigated path to CP-structured brushes in greater detail.212 3.1.2. Polypyrrole. Due to their integration of the physicochemical characteristics of organic polymers with the electrical characteristics of metals, electrical CPs have attracted a signiﬁcant amount of attention in the recent decade. Among the most well classiﬁed CPs is PPy, which is used in industry because it is easy to prepare and is environmentally stable in the long term. Figure 31 indicates the conjugated PPy

Figure 31. PPy reduction and oxidation states. Reprinted with permission from ref 99. Copyright 2004 Elsevier.

molecular backbone is positively charged; to obtain charge neutrality, it incorporates anionic counterions (dopants). When the molecular chains of PPy incorporate cations to maintain charge neutrality or release the dopant anions, it will be reduced. This leads to a loss of conductivity. The PPy main chain reaction with water or oxygen may result in conjugation and an irreversible loss of the PPy ring, causing a further deterioration in conductivity.99 To improve PPy surface biocompatibility, heparin (Hep) has been functionalized onto conductive PPy.213 Heparin was applied as the doping anion, which is a bioactive polyelectrolyte.213 To determine the capacity of PCL fumarate−PPy (PCLF− PPy) scaﬀolds for preservation of material characteristics required for use as conductive nerve conduits, their electrical characteristics have been investigated in a physiological setting.214 At a temperature of 37 °C, the mechanical characteristics demonstrated by the PCLF−PPy scaﬀolds were acceptable, permitting ﬂexibility and suturing. The scaﬀolds were electrically stable, showing a surface resistivity of 2 kΩ during ES application. In cases with ES, there was considerable enhancement in the proportion of cells containing neurite, neurite length and number of neurites in each cell, as indicated by in vitro investigation. Furthermore, the alignment of extending neurites appeared to occur in the applied current direction. These results indeed suggest that the material characteristics required for nerve conduits are manifested by the PCLF−PPy scaﬀolds. In addition, a signiﬁcant eﬀect on directing and enhancing neurite extension was observed to occur when an electrical current was passed through these scaﬀolds, making them even more relevant to treatments for severe nerve injuries in the future.214 Using FeCl3 as a catalyst, in situ oxidative polymerization from an aqueous solution of PPy at ambient temperature could be conducted to coat silk fabrics with PPy subjected to doping with electrical CP. 215 With an increase of the PPy concentration and the reaction time, the polymer percentage deposited on the fabrics increased in the reaction system. The silk molecular conformation and the intrinsic crystalline V

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Figure 32. (A) Polycaprolactone fumarate and PPy chemical structures. (B) PCLFePPy chemical composition. Reprinted with permission from ref 216. Copyright 2010 Elsevier.

Figure 33. Linear and hyperbranched copolymers of PCLs and CCAP synthesis. Reprinted from ref 217. Copyright 2010 American Chemical Society.

preformed PCLF scaﬀolds (Mn = 7000 or 18000 g mol−1), which gave rise to interpenetrating networks of PCLF−PPy. To study its impact on electrical conductivity and to enhance the chemical composition for cellular compatibility, PCLF− PPy was synthesized with various anions, including naphthalene-2-sulfonic acid sodium salt (NSA), dodecylbenzenesulfonic acid sodium salt (DBSA), dioctyl sulfosuccinate sodium salt (DOSS), potassium iodide (I), and lysine. PPy percentage bulk compositions from 5% to 13.5% result in PCLF−PPy conductivity of 6 mS cm−1.216 Figure 32 illustrates the PCLF−PPy polymer developed into three-dimensional conﬁgurations of complexity (e.g., single-

structure were not aﬀected by polymerization. In comparison to uncoated PPY, PPy-coated silk fabrics were much more thermally stable, because of the PPy layer protection against thermal degradation. Coated PPy with silk fabrics displayed interesting electrical characteristics. In addition, its resistance decreased exponentially with the increase in PPy concentration or reaction time.215 In one study in which PCLF−PPy was prepared and characterized in vitro, it was found that the neurite expansion not only of PC12 cells but also of dorsal root ganglia (DRG) was promoted by PCLF−PPy composite materials.216 The synthesis of these materials was based on Py polymerization in W

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Figure 34. Experimental protocol schematic illustration. Reprinted with permission from ref 218. Copyright 2010 Elsevier.

to provide hyperbranced and linear copolymers with biodegradability and conductivity, as shown in Figure 33. Compared with PCLs, lower crystallinity and better hydrophobicity were indicated by the aniline pentamer (EMAP) copolymer in its emeraldine state that had been subjected to doping. In contrast to linear copolymers, the hyperbranched copolymers were more conductive, possibly as a result of the systematic way in which peripheral EMAP segments were arranged, which facilitated the formation of conductive networks. Hence, the macromolecular architecture not only enhances but also regulates polymer conductivity.217 The modiﬁcation of polyacrylonitrile (PAN) sheets was studied with polymerization of PANi in potassium dichromate, which functions as the oxidizing agent. Here, PAN and (PAN/PANi)-1−3 composite surface resistances and grafting eﬃciency were monitored while varying the concentration of aniline. The grafting of the PAN sheet with PANi of diﬀerent surface densities and displaying conductivity was undertaken to ensure that the enzyme had suﬃcient interaction and ample activity yield. The grafting method associated with interaction of biological macromolecules was applied to achieve the functional sheet surface (Figure 34). Before grafting polyaniline on the PAN ﬁlm surface, polymer casting was undertaken to synthesize the PAN membrane. The obtained polyaniline-grafted polyacrylonitrile ﬁlms were cost-eﬀective and exhibited high loading capacity, making them suitable for immobilizing uricase in a reversible manner. This could be used to detect uric acid in biological ﬂuids.218 The results also indicated that the composite sheet surface resistance was in the range of 0.97−6.32 kΩ/cm. By increasing the PANi concentration on the PAN sheets, the composite sheet resistivity decreased. The increase in the grafted ﬁbrous PANi surface concentration increases the adsorbed enzyme. A PANi concentration of 2.4% was associated with the highest value for an enzyme immobilized on the composite sheet of around 216 μg/cm2. Over the course of a day,

lumen and multilumen nerve conduits) and overcoming diﬃculties of processability in PPy. The PCLF physical characteristics are retained by PCLF−PPy, decreasing the poor mechanical characteristics of PPy, while also incorporating electrical conductivity into the resultant scaﬀold. In vitro investigation using DRG and PC12 cells indicated that neurite extension, proliferation, and cell attachment are supported by PCLF−PPy prepared with DBSA or NSA, which warrants future investigation involving ES.216 In a solution of PDLLA, Py emulsion polymerization and subsequently precipitation were conducted to investigate the biodegradable conductive nanocomposite underpinned by poly(D,L-lactide) (PDLLA) and PPy NPs. The analysis of the electrical stability of the composite consisting of 5 wt % PPy was conducted in a cell culture medium for 1000 h with an applied voltage of 100 mV. Diﬀerent dc’s were used to provide stimulations to the ﬁbroblasts undergoing culturing on composite membranes. The aggregations developed by the PPy particles assembled into PDLLA-incorporated microdomains and networks. The material conductivity improved by 6 orders of magnitude by increasing the PPy concentration to 17%. The PPy/PDLLA membrane with 3% PPy displayed a decrease in surface resistivity to 1 × 103 Ω sq−1. PPy/PDLLA indicated better electrical stability compared to the PPy-coated polyester fabrics. By increasing the PPy concentration in PPy/ PDLLA, in 100 h, the membrane preserved 80% of the original conductivity, while in 400 h it preserved 42% of the original conductivity; this was followed by the addition of MEM solution in a proportion of 5% and 0.1%, respectively, for the polyester fabrics coated with PPy. Under 100 mV, electrical conductivity was sustained by the membrane with 5% PPy concentration in a cell culture medium for 1000 h. Electrical stimulation was applied to promote ﬁbroblast development.99 3.1.3. Polyaniline. The design of macromolecular architecture to improve the conductivity of the degradable polymer has been considered. The “A2+Bn (n = 2, 3, 4)” strategy was used to prepare branched PCLs and carboxylcapped aniline pentamer (CCAP) through coupling reactions, X

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Figure 35. PLAAP copolymer schematic and structure. Reprinted from ref 203. Copyright 2008 American Chemical Society.

Figure 36. PUD scheme. Reprinted with permission from ref 221. Copyright 2013 Elsevier.

batchwise assay was conducted, reusing the immobilized uricase 24 times. The development of the system of immobilized uricase enzyme was eventually achieved, and the system was employed to detect uric acid in samples of human serum.218 Employing potassium dichromate as an oxidizing agent, chemical polymerization of PANi has been used to modify the PAN surfaces.219 The purpose of this procedure was to provide insight into the response of the PAN/PANi composite surface resistance and grafting eﬃciency to the aniline concentration. Values of 8.0 and 0.5 kΩ/cm were obtained for the CP surface

resistance. There was a decline in the electrical resistance of composite ﬁbers which was directly proportional to the increase in the load of grafted PANi on the PAN ﬁbers. In contrast, composite ﬁbers with increasing PANi amounts heightened the immobilization eﬃciency and immobilized invertase activity (from 1.0 mg/mL invertase solution at pH5.5). Composite ﬁbers with 2.0% PANi had the highest quantity of immobilized enzyme of around 76.6 mg/g. The free enzyme was related to an ideal pH of 5, whereas the ideal pH for the immobilized invertase was in the range of 5−7. Furthermore, after being stored for two months at 4 °C, the Y

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Figure 37. Enzyme immobilization schematic illustration. Reprinted with permission from ref 222. Copyright 2010 Elsevier.

enhanced by such alterations compared to that of uncoated PU.220 As shown in Figure 36, a three-step reaction facilitated the preparation of aqueous cationomeric polyurethane dispersions (PUDs).221 Prepolymers were obtained from the reaction of isophorone diisocyanate (IPDI) with polyols, speciﬁcally, polypropylene glycol-400, polypropylene glycol-1000, and polypropylene glycol-2000. The chain extension of these prepolymers was achieved through reaction with N-methyldiethanolamine (N-MDEA). PUDs were derived from quarternization and self-emulsiﬁcation with deionized water. New conductive composites were developed for the ﬁrst time ever by mixing PUDs with 2, 4, and 6 wt % polyaniline−DBSA water dispersions. A conductivity range of 1.2 × 10−5 to 3.7 × 10−5 S cm−1 was obtained. Standard accelerated tests were then applied to assess the capability of these composites to protect mild steel panels against corrosion.221 The process of PUD preparation was as follows. Dry nitrogen was used to ﬂush a three-necked, moisture-free ﬂask with a round bottom, which was then charged with a measured IPDI and PPG-400 amount. Cross-linking was enhanced through the addition of a small quantity of TMP. During heating at 70−75 °C for an interval of 3−4 h, the ﬂask’s contents were stirred energetically. Simultaneously, the standard n-dibutylamine titration technique was applied to monitor NCO values at regular times. When a suitable NCO value of 1.3−1.5% was attained, the reaction temperature was reduced to 60 °C. This was followed by charging of the viscous prepolymer with a measured NMDEA amount dissolved in a small quantity of MEK solvent. The reaction temperature was again raised to 70−75 °C, and the mixture was stirred for an additional 2 h before it was left to cool to ambient temperature. A measured quantity of standard hydrochloric acid was subsequently used to neutralize the cooled, thick polyurethane solution, resulting in quaternary nitrogen cationomeric centers emerging along the backbone of the polymer. Addition of a measured quantity of water and energetic stirring led to the self-emulsion of the neutralized PU, producing a dispersion of white color with solid content in a proportion of 30%. The same procedure was undertaken with the polyols PPG-1000 and PPG-2000. Therefore, PUDs were diﬀerentiated into PUD-400, PUD-1000, and PUD-2000.221

free enzyme and immobilized invertase displayed 7% and 83% of the original activity, respectively.219 Condensation polymerization of hydroxyl-capped poly(Lactide) (PLA) and carboxyl-capped aniline pentamer (AP) was used in one study to produce the multiblock copolymer PLAAP, an electroactive and biodegradable polymer.203 A 32 MPa tensile Young’s modulus, 95% rate of breaking elongation, and 3 MPa tensile strength are the mechanical characteristics possessed by the PLAAP copolymer. Empirical research has shown that rat neuronal pheochromocytoma PC-12 cells diﬀerentiated faster when electrical signal stimulation was applied to this copolymer.203 A discussion of the synthesis techniques has already been provided. To summarize, the precursors hydroxyl-capped poly(L-lactide) (PLA) and carboxyl-capped aniline pentamer (AP) were subjected to condensation polymerization with a 1:1 feed molecular ratio; the concentrated NMP solution in which this was conducted contained DCC and DMAP as the condensating agent and catalyst, respectively. The lengthy and multiblock PLAAP copolymer chain (Figure 35) was the result of the combination of the hydroxyls and carboxyls on each end of PLA and AP with one another and with ester bonds.203 In another study, PU was coated with PANi and Ag NPs (PANi−AgNP).220 After they were incubated for 48 h, the modiﬁed sheets indicated that 3T3 L1 cells died in a proportion of 23% and 18%, respectively, in comparison to 41% cell death with pristine PU. The proinﬂammatory cytokine genes, TNF-α and IL-6, were expressed at a heightened level, indicating that inﬂammatory response was produced by all surfaces. However, compared to pure PU, modiﬁed ﬁlms were associated with values that were lower by 20%. Furthermore, in comparison to uncoated PU, the PANi− AgNP-coated surface revealed a signiﬁcant reduction in the adhesion of Pseudomonas and Bacillus bacterial cells, by 90.6% and 50.5%, respectively. Adhesion was further diminished when the CFU counts on the NP-coated PU decreased, causing a reduction in the content of assimilated carbohydrate and protein on the polymer surface. Moreover, the bioﬁlm of the PU surface coated with PANi−AgNP was 20% less thick. The surface is endowed with conductivity when PANi and PANi + AgNP are used to coat PU, making it viable for use in electrochemical sensors. Surface biocompatibility is also Z

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Figure 38. Surface grafting of polylactide (PLA) ﬁlms with aniline tetramer (AT). Reprinted from ref 223. Copyright 2012 American Chemical Society.

biomedical applications as well.224 In one study, the polymer was endowed with radical scavenger qualities through introduction of a conductive moiety given by 2-methoxyaniline (mAn) into poly(maleic anhydride-alt-butyl vinyl ether) grafted with monomethoxy polyethylene glycol 2000 MW (PEG) and 2-methoxyethanol (VAM41−PEG) in proportions of 5% and 95%, respectively. To increase the reaction yield as much as possible, several reaction schemes were assessed. The DPPH• radical assay was applied to prove that the scavenger activity of the modiﬁed polymer intensiﬁed. Furthermore, mouse embryo ﬁbroblast cell line balb/3T3 clone A31 was employed to evaluate the cytotoxicity on the mAn-modiﬁed polymeric matrix. Findings revealed that the cytocompatibility of the VAM41−PEG polymeric structure was unaﬀected by mAn insertion.224

Conductive PANi was chemically polymerized to alter the PAN membrane surfaces.222 An examination was also conducted on the response of the grafting eﬃciency to aniline concentration. The composite membrane became less electrically resistant with the increase in the grafted PANi amount on the PAN membrane. GOD was immobilized in a reversible manner with the help of the composite (PAN/PANi)-1−5 membrane. As the PANi content of the composite membrane increased, the immobilized GOD displayed higher immobilization eﬃciency and activity. The composite PAN/PANi-5 membrane with 2.1% PANi had a maximum immobilized enzyme quantity of around 251 μg cm-2. In contrast to the free enzyme which exhibited original activity loss after 3 weeks, immobilized GOD retained its original activity in a proportion of 66% even after it was stored for two months at 4 °C.222 A two-step process was used to synthesize conductive (PAN/ PANi)-1−5 composite membranes. The ﬁrst step involved the application of the standard casting technique to synthesize the PAN membrane in CaCl2-containing DMSO solution. The second step entailed PANi graft polymerization on the PAN membrane through the transfer of aniline-sorbed membrane into the polymerization environment with potassium dichromate acting as an oxidant (Figure 37).222 To make polyester ﬁlms more hydrophilic and electroactive, covalent surface functionalization has been explored.223 For instance, a “grafting form” technique was applied to photograft acrylic acid and maleic anhydride on a polylactide (PLA) surface, to make the surface more hydrophilic. Afterward, the PLA surface was endowed with electroactivity via coupling of conductive aniline oligomer. Maleic anhydride, acrylic acid, and aniline tetramer (AT) were used to modify the surface, resulting in a medium PLA surface displaying hydrophilicity.223 After being soaked in 10% (w/w) maleic anhydride (Ma) solution in ethanol, PLA ﬁlms activated by benzophenone were subjected to 10 min of nitrogen puriﬁcation. The reaction was then started by positioning the mixture under a UV lamp (Osram Ultra-Vitalux 300 W lamp). The ﬁlms were removed from solution after 5 h, and the unreacted Ma was extracted by thoroughly washing the ﬁlms with ethanol. The sample was then placed in a vacuum oven to dry for 2 days. Figure 38 illustrates the reaction process.223 The antioxidant action exhibited by free radical scavenger biocompatible polymers has made them relevant for

3.2. Modiﬁed Polymers with Carbon-Based Nanoparticles

Carbon has attracted a lot of interest in biomedical research communities; this was further encouraged by awarding of the Nobel Prize in Physics in 2010 to Geim and Novoselov for their groundbreaking work on the 2D structure of graphene. Carbon-based nanomaterials demonstrate unprecedented physical and chemical properties, including enhanced thermal, electrical, mechanical, and optical performance. Carbon exists in many diﬀerent structural conﬁgurations, including graphite, carbon nanotube, diamond, and amorphous carbon; these conﬁgurations have entirely diﬀerent properties. In recent years, graphene has been intensely researched for medical applications due to its unique biophysical and chemical properties. 3.2.1. Carbone Nanotubes. Carbon nanotubes (CNTs) harbor unique properties, which makes them a promising material for biomedical applications.225,226 The development of volatile organic compound (VOC) sensors was achieved by using conductive biopolymer nanocomposites (CPCs) prepared through solution mixing to disperse multiwalled CNTs (MWCNTs) as a ﬁller with conductivity in poly(lactic acid) (PLA) serving as a matrix.227 The method of spray layer-by-layer (sLbL) was used to create CPC transducers, while various organic vapors (e.g., chloroform, methanol, toluene, and water) with physical features such as solubility, polarity, and molecular size were used to assess the chemoresistive properties of the obtained sensors. PLA/CNT CPC well correlated to the solubility parameters AA

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toward vapors, which indicated that chloroform responded highly to sensors.227 A study was conducted on the eﬀect exerted on silica layer development by functionalized single-walled carbon nanotubes (SWCNTs).228 This involved employing pure SWCNTs and carboxylic SWCNTs (C-SWCNTs); the growth and crystalline formation of silica on the C-SWCNTs were caused by the hydrolysis and chemical bonding between C-SWCNTs and silica precursors.228 Diﬀerent types of possible mechanisms could be proposed, based on the obtained silica on the CSWCNTs: (a) C-SWCNT coated by partial silica, (b) two CSWCNTs coated by partial silica, (c) C-SWCNT bundle coated by partial silica, (d) C-SWCNT silica encapsulation, (e) two-stranded C-SWCNT silica encapsulation, and (f) CSWCNT bundle silica encapsulation. The six silica growth models are depicted in Figure 39.228

Figure 40. (A) Device scheme and assembly. (B) DNA−CNT nanowire and HRP probe hybridization. Reprinted from ref 229. Copyright 2011. American Chemical Society.

occurred, ﬁlling the sensing space among adjacent CNTs. Enzymatic metallization was triggered by device exposure to suitable reagents; once the analyte was detected, this process determined conductive links among interrupted CNT wires, while also amplifying the signal considerably.229,230 Investigations have been conducted on a ﬂexible method of patterning MWCNTs on all types of substrates.231 The method uses layer-by-layer (LBL) assembly to achieve the multilayer construction of MWCNT suspensions with antagonistic charges on the patterned poly(dimethylsiloxane) (PDMS). Thereafter, the pattern is transferred to diﬀerent substrates, such as a transparent glass slide, silicon wafer, and polymeric substrate, exhibiting ﬂexibility and conductivity. Accurately adjustable in thickness, the transferred MWCNT pattern had a capacitor behavior that was augmented as the growing ﬁlm became thicker. The patterned MWCNT electrodes displaying high surface functionality were shown to have potential for use as glucose-sensitive biosensors.231 Due to the electrostatic contact among MWCNT-COO− moieties with negative charge and the positively charged MWCNT-NH3+ moieties (Figure 41), LbL assembly permitted the construction of MWCNT ﬁlms straight on a micrometer scale patterned PDMS stamp.231 An artiﬁcial antibody to troponin T (TnT) was synthesized by molecular imprint (MI) on the surface of an MWCNT.232 This was achieved by ﬁlling the vacant spaces by polymerizing under mild conditions acrylamide (monomer) in N,N′methylenebis(acrylamide) (cross-linker) and ammonium persulfate (initiator) and attaching TnT to the MWCNT surface. The produced biomaterial was able to discriminate and

Figure 39. Silica nanorods from C-SWCNT schematic illustration. Reprinted from ref 228. Copyright 2010 American Chemical Society.

Highly sensitive fabrication of eﬀective and simple conductometric devices could be oﬀered by hybrid biocatalyzed CNT nanowire-based detection methods. One study reported an interesting technique of DNA detection based on conductivity, in which CNT−DNA nanowire devices and oligonucleotide-functionalized enzyme were employed as probes.229 Creating a system of interrupted CNT wires underpinning the link between two electrodes, the DNAlinked CNT wire motif is fundamental to this design. The linking junction between DNA and CNTs supplied sensing capability, after which enzymatic metallization was used to perform ampliﬁcation and thus elicit a conductometric response.229 By covalent bonding at the terminus, the gap between the SWCNT sensing surfaces was bridged with singlestranded DNA (ssDNA) that leads to network formation of CNT wires and ssDNA linked between two gold electrodes (Figure 40). A double-stranded DNA (dsDNA) construction was achieved through selective bindings occurring at the ssDNA junction, in the presence of the ssDNA, among adjacent CNTs. An oligonucleotide-functionalized enzyme (horseradish peroxidase, HRP) and the CNT linking the capture strand at one end probe at the other end (Figure 40B) were complemented by the neighboring recognition sequences of the ssDNA analyte. Therefore, when the device was immersed in the probe and analyte solution, the hybridization of the enzyme probe with the analyte recognition domain AB

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Figure 41. MWCNT multilayer pattern transfer process schematic. Reprinted from ref 231. Copyright 2010 American Chemical Society.

protein linking to the CNT surface and ﬁlling the vacancy with a proper rigid structure followed by removing the protein. Figure 42A depicts the reaction for TnT covalent attachment to the MWCNT. On the MWCNT surface, the carboxylic acid groups are activated by N-ethyl-N′-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDAC). A highly reactive O-acylisourea intermediate was obtained, which reacts quickly with N- hydroxysuccinimide (NHS) to form a more stable ester (succinimidyl intermediate). An amide bond was created among TnT and MWCNTs when the ester, with any readily available amine group on TnT, underwent nucleophilic substitution. Subsequently, to inhibit ester groups that did not react, TnT−MWCNT was subjected to 30 min of incubation in Tris solution. Piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES) solution (pH 7.0) was used to wash the material obtained, which was afterward allowed to stand for 45 min in acrylamide (AAM) (vinyl monomer) and then in N,N′methylenebis(acrylamide) (NNMBA) (cross-linker), which were prepared in the same buﬀer (Figure 42B). In the case of polymerization, the APS was added, followed by washing the modiﬁed MWCNTs. By reaction with Oac, the attached protein was removed. After washing, ﬁltering, and conditioning the imprinted MWCNTs in 10 mM phosphate buﬀer, pH 8.0, for 1 h, the pH was increased from 1.2 to 8.0 to facilitate peptide/amino acid removal.232 Of relevance here is a study which measured direct and alternating current conductivities in a broad angular frequency, 2π × 10−3 s−1 < ω < 2π × 107 s−1, and temperature range, 133 K < T < 323 K, in PCL/MWCNT nanocomposites as a function of the weight concentration (0 wt % ≤ p ≤ 3 wt %).233 The percolation threshold was indicated at 0.3 wt % concentrations. The tunneling conduction existence was observed, and its temperature independency indicated the presence of a tunnel eﬀect, through energy barriers made by the polymer chains.233 The electropolymerization of thioaniline-modiﬁed glucose and aniline-functionalized CNTs GOx on a thioaniline monolayer-modiﬁed Au electrode yields a CNT/GOx composite cross-linked by the redox-active bisaniline units.234 The CNT conductivity matrix and the bisaniline electrontransfer properties led to the eﬀective electrical wiring of the enzyme units with the electrode, and to the eﬃcient bioelectrocatalytic oxidation of glucose. The conditions to synthesize the three-dimensional CNT/GOx composite and the parameters inﬂuencing the bioelectrocatalytic functions of the modiﬁed electrode are discussed.234 The CNT/GOx composite electrode was constructed with the technique demonstrated in Figure 43. Oxidative cleavage

rebind TnT among other interfering species. Biomaterial ability to rebind TnT was conﬁrmed by including it as an electroactive compound in a PVC/plasticizer mixture coating a gold, silver, or titanium wire. MI-based membranes coated by gold wire dipped in HEPES buﬀer of pH 7 indicated anionic slopes of 50 mV decade−1. The detection limit of this system was 0.16 μg mL−1. Both MWCNT and nonimprint (NI)MWCNT could not recognize the template. The authors also observed good selectivity against sucrose, creatinine, fructose, sodium glutamate, myoglobin, thiamine, and urea.232 Figure 42 illustrates the plastic antibody synthesizing process, which is

Figure 42. (A) CNT protein attachment via diimide-activated amidation process. (B) Imprinting step with protein removal. Reprinted with permission from ref 232. Copyright 2011 Elsevier. AC

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Figure 43. (A) CNT modiﬁcation with the electropolymerizable aniline functionalities. (B) GOx modiﬁcation with the electropolymerizable thioaniline functionalities. Reprinted from ref 234. Copyright 2009 American Chemical Society.

Figure 44. MWCNT−PVBTEAC synthesis. Reprinted from ref 235. Copyright 2011 American Chemical Society.

was applied to the SWCNTs, and the covalent binding of 2-(4 aminophenyl)ethylamine (1) to the CNTs was achieved with the produced carboxylic acid residues derived from the CNTs (Figure 43A). Furthermore, the GOx lysine residues were

primary modiﬁed with bifunctional 6-maleimido-N-hydroxysucinimide hexanoic acid ester (2), enabling covalent binding of thioaniline to GOx, after which thioaniline (3) was used to replace the maleimide residue (Figure 43B).234 AD

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Surface-initiated polymerization and subsequent quaternization were initiated to functionalize MWCNTs with various loads of poly(vinylbenzyl)triethylammonium chloride (PVBTEAC) with the purpose of synthesizing amphiphilic MWCNT polymer hybrids.248 The amphiphilic MWCNT− PVBTEAC hybrid of 4 wt % indicated a 7−8 order of magnitude increase in conductivity compared to that of MWCNTs. A 15 mL volume of CH2Cl2 and 50 mg of MWCNTs (50 mg) were mixed in a 100 mL round-bottomed ﬂask and then dispersed by ultrasonication for 10 min. This was followed by dissolving 0.25 g of tetrabutylammonium bromide (TBAB) in 5 mL of acetic acid and 5 mL of H2O. A 0.065 g mass of KMnO4 was dissolved in 5 mL of H2O, and the solution was added to the mixture. The resultant mixture was subjected to energetic stirring for 2 days at 25 °C. Thereafter, 1000 mL of deionized water was used to dilute the mixture, and a 0.2 μm Teﬂon membrane was employed to ﬁlter the obtained product under vacuum. MWCNT−PVBTEAC was synthesized in three diﬀerent stages: (1) 3-MPTMS tethering to MWCNT-OH, (2) VBC functionalization on MWCNT−3-MPTMS, and (3) MWCNT−PVBC quaternisation (Figure 44).235 A process for synthesizing ionically self-assembled polyelectrolyte-complex-based CNT ﬁbers using a noncovalent stabilization of CNT aqueous dispersions was described.236 Due to the presence of the CNT interconnected network embedded inside the ﬁbers, conductivity was reported at 45 S cm−1 for SWCNTs and 80−90 S cm−1 for MWCNTs. The self-assembled polyelectrolyte−CNT ﬁbers have potential applications in biosensors and ﬂexible electronics.236 Moreover, the increase of the MWCNT content in the polyimide (PI)-based solution cast to 30 wt % and high electrical conductivity of 38.8 S cm−1 was studied by using novel poly(amic acid) (PAA) containing a rigid backbone with hydroxyl pendant groups.237 The percolation threshold occurred at 0.48 wt %. At the same time, it was shown that uniform MWCNT/PI composite coatings can be deposited onto glass and aluminum substrates.237 The PAA was synthesized from 3,3′-dihydroxy-4,4′-diaminobiphenyl (HAB; 97%) and 3,3′,4,4′-biphenyltetracarboxylic dianhydride (BPDA) (Figure 45a), to achieve the highest possible molecular weight and stoichiometric amounts of these compounds used. Between the CNTs and polymer, more contacts are enabled by high molecular weight; this will increase the dispersion eﬃcacy of CNT.238,239 The dianhydride and biphenyldiamine attached to a rigid and unbent PAA backbone were polymerized, and via π−π interaction, they facilitate the dispersant molecules stacking onto the conjugated MWCNT surface,240 to promote PAA adsorption. The hydroxyl and carboxyl groups provide the functionalized MWCNTs with good solubility in organic solvents and a polymer matrix precursor. The 1H NMR spectrum of PAA in deuterated dimethyl sulfoxide (DMSO-d6) is exhibited in Figure 45b, which conﬁrms its successful synthesis with the characteristic aromatic proton peaks at δ 7.1−7.2 ppm (peaks b and c) and 7.8−8.3 ppm (peaks d, f, g, and h), the phenolic hydroxyl and −NH proton peaks at δ 9.7−9.9 ppm (peaks a and e), and the carboxyl proton peak at δ 13.0 ppm (peak i).237 1 H NMR signal broadening is due to the CNT π interaction.237,241−243 The use of tungsten disulﬁde inorganic nanotubes (INTWS2) to fabricate advanced poly(ether ether ketone) (PEEK) biomaterials was investigated through a melt processing

Figure 45. (a) Poly(amic acid) (PAA) synthesis and MWNT/ polyimide composite fabrication. (b) PAA and MWNT/PAA 1H NMR spectra. Reprinted from ref 237. Copyright 2011 American Chemical Society.

technique.244 The results showed that, without surfactants or modiﬁers, inorganic nanotubes could be eﬃciently incorporated into the biopolymer matrix, which provides a homogeneous dispersion. Furthermore, the increase in concentration of INT-WS2 without modifying the crystalline structure of PEEK in the nanocomposites changes the crystallization behavior. These nanocomposites could be a possible candidate for biomedical applications, especially for orthopedic implants.244 For saccharides detection, the poly(aniline boronic acid) (PABA)-functionalized SWCNT nonenzymatic sensor has been studied.245 The research involved the electrochemical polymerization of 3-aminophenylboronic acid (3-APBA) in the presence of ﬂuoride on the surface of SWCNTs. They also evaluated the D-glucose and D-fructose detection by the chemiresistive sensors. The sensing performance could be optimized by varying the condition of sensor synthesis through charge-controlled electropolymerization. The optimized sensors indicated sensing response for concentration with a wide range and detection limits of 3.46 and 2.92 mM for D-glucose and D-fructose, respectively.245 AE

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Figure 46. Electrical conductivity variance. Reprinted from ref 246. Copyright 2013 American Chemical Society.

into the PCL matrix, which may introduce additional advantageous properties. Figure 47 shows the synthetic route for fullerene and POSS double-end-capped PCL (FPCLP). Chloro-ended PCLP was

A conductive polyurethane (PU) elastomer could be fabricated by in situ polymerization with surface hydroxylmodiﬁed MWCNTs.246 A signiﬁcant increase in the conductivity of PU/MWCNT elastomers was provided by in situ polymerization with MWCNTs. Conductivity enhancement of PU/MWCNT elastomers and the MWCNT orientation is caused by stretching. As pressure sensor electrodes, the PU/ MWCNT elastomers exhibited good sensitivity.246 Figure 46 illustrates the change mechanism that was proposed. The randomly distributed and initially coiled MWCNTs in the PU orientate and extend along the stretching direction when the PU/MWCNT ﬁlm is stretched, during cycle 1. This causes them to make contact, forming conductive channels in the process. By releasing the PU/MWCNT, the MWCNTs relax, and the stretching induces conductive channels to partially dissociate. Therefore, the conductivity returned, but was improved compared with its initial state. In cycle 2, the processes of orientation and disorientation of MWCNTs in PU/MWCNT were repeated.246 Coaxial electrospinning from a nonvolatile, nonﬂammable ionic liquid (IL) solvent, 1-methyl-3-methylimidazolium acetate ([EMIM][Ac]) was used to prepare MWCNT− cellulose ﬁbers.247 The gel solution provided by dispersion of MWCNTs into IL was electrospun by a cellulose sheath solution dissolved in IL to from an MWCNT−cellulose ﬁber sheet, and the ﬁbers were then subsequently collected in a coagulation bath containing ethanol−water. The MWCNT− cellulose ﬁber had a coaxial structure, which consisted of insulating a sheet and a conductive core. The MWCNT− cellulose ﬁber sheet showed enhanced conductivity due to a conductive pathway of bundled MWCNTs. By increasing the MWCNT concentration in ﬁbers, the ﬁber sheet conductivity increased to 10.7 S m−1 at 45 wt % MWCNT.247 3.2.2. Fullerene. A fullerene or buckyball can be described as a nanoscale sphere or ellipsoid molecule characterized by the fact that carbon atoms are its only constituent elements. In 1985, Smalley et al.248 received the 1996 Nobel Prize in Chemistry for the discovery of the ﬁrst fullerene, buckminsterfullerene (C60). An investigation was conducted on how PCL was aﬀected by the crystallization behavior of fullerene and polyhedral oligomeric silsesquioxane (POSS) double-end-capped PCL as well as by POSS and fullerene moiety aggregation.249 The results showed that, compared to POSS crystallization, PCL crystallization was more aﬀected by fullerene moiety aggregation. Thus, the acquisition of multifunctional qualities by PCL depends on eﬀectively integrating POSS and fullerene

Figure 47. Fullerene and POSS double-end-capped PCL synthesis. Reprinted with permission from ref 249. Copyright 2008 Wiley-VCH Verlag GmbH & Co.

obtained by reacting PCLP with chlorobutyryl chloride in dry dichloromethane for 24 h at ambient temperature, in the presence of pyridine as the catalyst. Furthermore, azide-ended PCL was obtained by reacting chloro-ended PCLP with sodium azide in dry DMF for 24 h at 65 °C, in the presence of tetrabutylammonium iodide as the catalyst. Finally, FPCLP was obtained by reacting azide-ended PCLP with fullerene in chlorobenzene at a temperature of 135 °C. There are reports that the use of biocompatible poly(ether imide) enabled the creation of electroactive artiﬁcial muscles based on fullerenol. 250 Brieﬂy, the synthesis of ionic networking membranes was undertaken by uniformly disseminating polyhydroxylated fullerene (PHF) NPs into a sulfonated poly(ether imide) (SPEI) matrix by incorporating a solvent. The proton conductivity and water absorption depicted by the PHF−SPEI nanocomposite membranes were higher in comparison to those of pure SPEI membranes. These two properties are crucial for ionic polymer actuators of high performance. PHF and SPEI are promising materials for catheters and stents due to their excellent biocompatibility.250 Fullerene has many applications, including medicine,251 for heat resistance,252 as light-activated antimicrobial agents,253 as AF

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Figure 48. POSS−PCL/graphene nanocomposite schematic. Reprinted with permission from ref 266. Copyright 2014 Elsevier.

proton conductors,254 for superconductivity,255 and for biocompatibility.250,256 Incorporation of fullerenes into a polymer matrix has ben shown to improve the proton conductivity, thermomechanical stability, and suppression of the thermo-oxidative degradation of the host polymer.257−260 For practical applications, due to the powdery form of fullerenes, it is reinforced into the polymer matrix to obtain a smart material. Several techniques for linking fullerenes with polymers have been described,260,261 including physical blending.262 However, low miscibility and the poor adhesion of fullerene (C60) in common organic solvents typically prevent it from being well-dispersed in a polymer matrix. Functionalization of fullerene with hydrophilic groups has been proposed to overcome these diﬃculties. It has been shown that promoting strong adherence and dispersion in the polymer matrix would enhance its physicochemical properties.250 Due to their exceptional proton conductivity, hydrophilicity, and biocompatibility, fullerenol NPS and derivatives may contribute to nanobiomaterial development and applications in biomedicine. Antioxidants, free radical sponges, and photosensitizers are just some of their possible applications. However, the feasibility of these applications depends mainly on the transport features. Measurements and reports have been conducted on the electrochemical impedance of aqueous solution of the fullerenol types C60(OH)22−26 and C60(OH)18−22(OK)4.263 The impedance data supplied sample conductivity, and a nonlinear concentration-dependent conductivity was found for C60(OH)18−22(OK)4. The obtained experimental data may be explained in terms of movement as a function of concentration, which justiﬁes electrophoretic and relaxation eﬀects.263 3.2.3. Graphene. Graphene is a two-dimensional (2D) honeycomb, mono- or multilayer, with sp2 hybridization. It harbors unique electrical, chemical, optical, and mechanical properties.225,264−266 The attention paid to graphene is largely due to the contribution that it could make to various areas of biomedicine, including biological or molecular imaging, drug/ gene267 delivery, and cancer treatment.268−270 Moreover, to promote particular functional or structural properties, modiﬁcations could be brought to the functional groups of graphene oxide (GO) during its preparation.271 Acute injuries to the nervous system and neurodegenerative diseases inevitably lead to neurite damage and neuron loss.272

To repair these damaged tissues, the development of eﬀective methods is necessary. Neurite growth and guidance of regenerating a nerve could be supported by fabricating biomimetic materials exhibiting particular physicochemical qualities. One study outlined an uncomplicated approach through which biomimetic GO composites could be created on the basis of covalent linking on GO surfaces of an acetylcholine-like unit ((dimethylamino)ethyl methacrylate, DMAEMA) or a phosphorylcholine-like unit (2-[(methacryloyloxy)ethyl]phosphorylcholine, MPC).273 On such composites, the manner in which nerve cells became attached, disseminated, and proliferated was explored with primary rat hippocampal neurons. The biomimetric qualities required for high biocompatibility are supplied by GO−DMAEMA and GO− MPC composites, with cell viability remaining intact. In comparison to control GO, GO−DMAEMA and GO−MPC composites displayed a higher neurite count and mean neurite length at 2−7 days following cell seeding. Furthermore, in contrast to GO groups, biomimetric GO composite groups had better growth-associated protein-43 (GAP-43) expression, as revealed by the application of Western blot to analyze GAP-43. Such enhancement may be conducive to neurite germination and development. These ﬁndings supply fundamental data for future GO usage in biomedicine.273 One study has proposed a technique for preparing multifunctional free-standing papers comprising reduced graphene oxide (rGO) that does not have detrimental eﬀects on the environment. According to the ﬁndings, in addition to restricting GO nanosheets in ionic liquids, cellulose was also successfully assimilated on the rGO basal planes. A natural polymer, cellulose is characterized by cost-eﬀectiveness, renewability, nontoxicity, and biodegradability. Therefore, functionalized graphene nanosheets (rGO−CL) displaying stability and water dispersibility could be prepared on a large scale with this simple and aﬀordable cellulose-based technique. In addition, the synthesis of highly ordered rGO−CL composite papers was achieved based on separated hybrid rGO−CL nanosheets that underwent ﬂow-direct construction. The obtained products were more conductive and had better biocompatibility and robust mechanical ﬂexibility. Thus, they have potential applications in biomedical scaﬀolds for tissue engineering, or as medical devices.274 AG

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1000 °C under ambient pressure, carbon was introduced into a nickel foam, and graphene ﬁlms were then precipitated on the nickel foam surface278−280 (Figure 49b). Due to the thermal expansion coeﬃcient diﬀerences of nickel and graphene, on the graphene ﬁlms wrinkles and ripples were formed.281 To avoid the breakdown of the graphene network (Figure 49c,d), a poly(methyl methacrylate) (PMMA) thin layer was deposited on the graphene ﬁlms prior to using a solution of hot HCl (or FeCl3) to wear away the nickel skeleton. A monolith of a graphene three-dimensional network displaying continuity and interconnectedness was obtained following the use of hot acetone to remove the PMMA layer (Figure 49e), even though the graphene skeleton shrank slightly. The interlinked 3D scaﬀold structure of the nickel foam template was derived by the GF copies, and no interruptions existed between the GF graphene sheets. Only a GF showing signiﬁcant distortion and not a freestanding GF can be prepared without using the PMMA support layer. In addition, due to the fact that evaporated acetone gave rise to a liquid capillary force, the GF was not as thick as the initial nickel foam, after it was removed from acetone.280 Furthermore, high GF porosity was caused by the fact that GF became thicker (from ∼100 to ∼600 μm), due to the GF lower shrinkage caused by increasing the thicker graphene sheet stiﬀness. This resulted in GF in GF/ poly(dimethylsiloxane) (PDMS) composites having a lower weight or volume fraction, preceded by a higher porosity GF.275 The reinforcement of functionalized graphene sheets (FGSs) and graphene with polycarbonate composites was achieved in one study using melt compounding.282 The composites were processed with various degrees of graphene orientation, through long-term annealing, injection, and compression molding. In both compression-molded and injection samples, a graphene ﬂow induced orientation was observed. As electrical conductivity and melt rheology measurements indicated, a smaller percolation threshold and reinforcement for rigidity were required for composites with the exfoliated FGSs. Also, they indicated better performance in suppressing the gas permeability of polycarbonate.282 Better cell attachment and dissemination were displayed by C2C12 myoblasts whose culture was undertaken on thermally reduced graphene (TR-graphene) ﬁlms of minimal thickness.283 Furthermore, myogenic gene and protein expression indicated that, by comparison to GO and glass slide surfaces, the ability of myoblast cells to diﬀerentiate on a TR-graphene substrate was considerably improved by ES. This highlights that ﬁelds such as cell-based research, bioelectronics, and biorobotics may beneﬁt from the use of graphene-based materials. Interestingly, it was shown that human neural stem cells (hNSCs) diﬀerentiated in a self-structured manner into neurons when they were stimulated with a pulsed laser on graphene ﬁlms.284 This prompted an analysis of how hNSC proliferation was aﬀected by GO and rGO sheets. Due to its hydrophilicity, higher cell proliferation on the GO was observed. In contrast, compared to GO, rGO was more conductive, as indicated by the intensiﬁed neuronal diﬀerentiation of cells.284 A new electrochemical electrode architecture has been proposed in the form of CVD-prepared 3D monolithic graphene foam displaying high conductivity and macroporosity.285 In addition to being extremely sensitive (619.6 μA mM−1 cm−2), a graphene electrode, serving as an

Useful insights have been provided by a study on a polymer showing electrical conductivity which has been synthesized through integration of a POSS nanocage into a modiﬁed PCL/ graphene hybrid nanocomposite.266 Brieﬂy, the uniform dissemination of multilayer graphene ﬂakes (8 nm) in POSS−PCL was undertaken at various concentrations by using stable dimethylacetamide (DMAc) to enable solution inclusion with POSS−PCL nanocomposites. The impedance spectroscopy results indicated that, compared to pure POSS− PCL, graphene-containing POSS−PCL with a concentration of 5.0 wt % or higher signiﬁcantly enhanced conductivity. The insulator POSS−PCL was transformed into a POSS−PCL/ graphene hybrid nanocomposite with conductivity due to the occurrence of the percolation threshold at 5.0 wt % graphene concentration.266 After introduction into a 250 mL roundbottom ﬂask at various concentrations (0.1, 2, 5, and 10 wt %), the graphene ﬂakes were subjected to 3 h of ultrasonication with the stable solvent DMAc. Moreover, ultracentrifugation was conducted for 5 h to mix POSS−PCL and various concentrations of DMAc-disseminated graphene ﬂakes. Following molding on a plate made of aluminum, the POSS−PCL/graphene solution was left in an oven heated to 60 °C for 12 h for solvent evaporation to yield the resultant nanocomposite ﬁlm. Figure 48 describes the schematic preparation.266 Template-directed chemical vapor deposition enabled graphene foams (GFs), which are 3D graphene macrostructures resembling foam, to be directly synthesized.275 The interlinked versatile graphene network incorporated into GFs serves as a rapid transport channel of high electrical conductivity charge carriers. It shows a very high electrical conductivity of ∼10 S cm−1, which is ∼6 orders of magnitude higher than that of chemically derived graphene-based composites with a ∼0.5 wt % GF loading, GF/poly(dimethylsiloxane) composites.276 GF/poly(dimethylsiloxane) composites are promising candidates for conductors that can be adjusted, folded, and stretched, given this singular network structure and the excellent GF electrical and mechanical qualities.275,277 Figure 49 illustrates GF synthesis and its integration with polymers. As a template for the growth of GFs, a porous structure of nickel foam was selected, with an interconnected 3D scaﬀold of nickel (Figure 49a). By decomposing CH4 at

Figure 49. GF and integration with PDMS synthesis: (a, b) graphene ﬁlms (Ni−G; b) and CVD growth applying nickel foam (Ni foam; a) as a scaﬀold, (c) as-grown graphene ﬁlm, (d) GF coated with PMMA(GF-PMMA), (e) free-standing GF, (f) GF/PDMS composite. Reprinted with permission from ref 275. Copyright 2013 Macmillan Publishers Ltd. AH

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electrochemical sensor for dopamine recognition, also has a lower detection limit (25 nM). It is indicated that the dopamine oxidation peak could be easily distinguished from that of uric acid, as interference with dopamine detection.285 The functional groups and suspension charge behavior of nitrogen-doped graphene (NDG) have been characterized in the absence of a highly toxic reagent, hydrazine.286 NDG materials showed good water dispersibility, which allowed their surface charge to be probed by measuring the ζ potential as a function of the suspension pH. The NDG-6 material held surface charges ranging from ζ = −50 mV to ζ = +20 mV, which was the widest range of surface charges measured on a colloidal graphene material.286 Functionalization of graphene with nitrophenyl through a covalent bond was investigated.287 Functionalized graphene indicated better electric transport compared to pristine graphene. A scattering and charge transfer eﬀect comparison of functionalized nitrophenyl groups indicated that due to its conductivity the latter one is dominant. Figure 50 depicts functionalized graphene with a (nitrophenyl)diazonium salt ((4-nitrophenyl)diazonium, 4-NPD) tetraﬂuoroborate.287

Figure 51. Implantable zinc−air battery scheme. Reprinted from ref 289. Copyright 2014 American Chemical Society.

to be 57.9 S m−1. The spiky Pt nanosphere decorated G/S ﬁlm used as a H2O2 electrode had a sensitivity of 0.56 mA mM−1 cm−2, a linear range of 0−2.5 mM, and an ultralow detection limit of 0.2 μM (S/N = 3).293 By enzyme immobilization, a glucose biosensor electrode was fabricated. The results indicated a 1 μM (S/N = 3) low detection limit and 150.8 μA mM−1cm−2 sensitivity for glucose detection. The silk ﬁber surface coated by a graphene ﬁlm suggested a new approach for developing tissue scaﬀolds, electrically conductive biomaterials, wearable biomedical devices, and bendable electrodes.293 Silk ﬁbers obtained by the Bombyx mori silkworm are composed of ﬁbrous proteins, called ﬁbroin, and sericin that surrounds the ﬁbroin ﬁbers. The silk ﬁbers show a natural shine and are white, after removal of the gluelike sericin proteins (Figure 52b). The ﬁbers became deep yellow after GO coating (Figure 52c), which suggests that the GO absorbent was successfully attached on the ﬁber surface. The GO sheets deposited on a mica substrate are measured to be 0.8−1.2 nm thick, with an average lateral width of 1.0 mm, demonstrating the complete exfoliation in water. GO chemical reduction converted the color of the ﬁber from yellow to black (Figure 52d). The graphene-coated silk ﬁbers are robust, and no graphene exfoliation is observed during bending, which suggests that the graphene ﬁlms obtained via polar−polar, hydrogen-bonding, and hydrophobic−hydrophobic interactions are ﬁrmly attached to the silk ﬁbers294,295 as illustrated in Figure 52a. Parts e and f of Figure 52 illustrate that while the surface of a pure silk ﬁber was very smooth without pleats, the ﬁber surface was covered by a wrinkled ﬁlm.293 Additionally, covalent coverage of the graphene surface with multidentate P(MMA-co-SEMA) copolymers or brushlike PMMA-SH by the thiolene click reaction was shown to be a feasible option.296 The covalent bonding of the polymer with graphene indicated superior conductivity and was not detrimental to sp2 hybridization. PMMA graphene-based composites attained ∼2 × 10−3 S cm−1 conductivity, using graphene as a ﬁller for P(MMA-co-SEMA), which was interfaced via graphene multidentate copolymer functionalization.296 Investigation was conducted on the synthesis of copolymers based on 2-(acetylthio)ethyl methacrylate (AcSEMA) and methyl methacrylate with diﬀerent compositions of AcSEMA and a thioacetyl-terminated PMMA homopolymer, obtained by atom transfer radical polymerization (ATRP).297 The ATRP provides low polydispersity due to its controlled radical polymerization,298 leading to a homogeneous coating. The thiolacetyl group in the homopolymer was located at the end of each chain, while the copolymer along the main chain

Figure 50. (Nitrophenyl)diazonium salts and graphene reaction. Reprinted from ref 287. Copyright 2011 American Chemical Society.

The interfacing of graphene sheets on the yeast cell surface has led to the electromechanical coupling of cells and sheets.288 After the interfacing, cells are viable. Due to the cell exposure to the alcohol, physiological stressing occurs, which leads to a change in cell volume which can be detected in electrical signals via graphene. The change in the cell volume leads to straining of the sheets, forming wrinkles, which reduces the electrical conductivity. Furthermore, the graphene sheets could diﬀerentiate between water, 2-propanol, and ethanol, which has potential ramiﬁcations on sensors and cell-based electrical devices.288 A high-performance cathode material for biocompatible zinc polymer batteries has been studied, utilizing bioﬂuids as the electrolyte.289 To control the graphene electrical conductivity and PPy redox capability, a PPy ﬁber/graphene composite was synthesized. This composite possesses a large speciﬁc surface area of 561 m2 g−1 and is highly conductive, 141 S cm−1. A PPy ﬁber/rGO cathode and Zn anode constructed for a battery delivered an energy density of 264 mW h g−1 in 0.1 M PBS.289 The Zn−air battery compared to the Mg−air battery harbors advantages due to the controllable Zn anode interface reaction in aqueous electrolyte.290 While the cathode material works as the oxygen reduction catalyst, via the redox reaction between the oxygen and zinc anode, the zinc−air battery is powered, which throughout the discharge process provides oxygen ions for zinc oxidation (Figure 51).289,291,292 A graphene silk composite (G/S) ﬁlm was fabricated via vacuum ﬁltration of a mixed suspension of GO and silk ﬁbers.293 By cyclic voltammetry electrodeposition, spiky structured Pt nanospheres were grown on the substrate. The conductivity of a single graphene-coated silk ﬁber was shown AI

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Figure 52. (a) Silk ﬁbroin hydrophilic segment molecular model illustration. (b−d) Photographs of silk ﬁbers after the sericin removal (b), GOcoated silk ﬁbers (c), and graphene-coated silk ﬁbers (d). (e, f) Graphene-coated silk ﬁber SEM images. Reprinted with permission from ref 293. Copyright 2014 Royal Society of Chemistry.

Figure 53. Multidentate synthesis (a) and brushlike (b) hybrid graphene. Reprinted with permission from ref 296. Copyright 2014 Royal Society of Chemistry.

radical-mediated reaction,303,304 with in situ −SAc hydrolysis (Figure 53).296 In the case of the homopolymer, typical polymer brushes should form a multidentate linkage to the graphene, since the copolymers have the “clickable” groups distributed along the chain (Figure 53). Therefore, the reaction mechanism consisted of ﬁrst hydrolysis in basic media from −SAc to a thiol moiety (−SH) and then the in situ formation of a thiyl radical (−S•) promoted by the thermal decomposition of AIBN.296 For fabricating conductive PET nonwoven fabrics using rGO, a dyelike approach has been investigated.305 PU was used

was randomly distributed with the thiolacetyl groups (−SAc) (Figure 53). The − SAc could be hydrolyzed to the respective thiol moiety (−SH) using a saturated solution of sodium methoxide in dichloromethane. In addition, it was shown that these polymers were able to undergo click reactions and in situ hydrolysis with radical thiolene attack with a thermal source in the presence of radicals such as azobis(isobutyronitrile) (AIBN) or double bonds by thiolene Michael addition.298−301 Graphene is considered a hyperconjugated alkene which is capable of reacting with thiol radicals.302 The homopolymer and copolymers with graphene have been coupled by a thiolAJ

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Figure 54. Nanoﬁller-cross-linked polyurethane block copolymer schematic. Reprinted with permission from ref 307. Copyright 2013 Royal Society of Chemistry.

ratio GMGO sheets were folded with a diameter smaller than 150 nm into the nanoﬁbers. The GMGO/PVA electrospun nanoﬁber thermal decomposition temperature and storage modulus increased by 20 °C and 50.5%, respectively, at 0.5 wt % compared with those of pristine PVA nanoﬁbers. Almost no cytotoxicity was observed on L929 cells.308 Figure 55 shows

as a middle adhesive layer, and due to the strong attraction between the adjacent components, the rGO could be immobilized and adsorbed on the PET surface. Conductive fabrics with structural stability were obtained in an aqueous dispersion of rGO. The composite due to the graphene homogeneous coverage on the PET surface by graphene depicted a low electrical percolation threshold, and the conductivity achieved was ∼2.0 × 10−5 S sq−1.305 PEDOT electropolymerization in the presence of GO was applied to achieve the electrochemical synthesis of a polymerbased nanocomposite showing biocompatibility and conductivity.306 GO could be easily integrated and uniformly dispersed all throughout the conducting polymer due to the high dissemination in aqueous solutions displayed by its constituent carboxyl groups with negative charge. After 1 day, PEDOT/GO ﬁlms were negligibly cytotoxic, and in comparison to the control PEDOT/PSS ﬁlm, they promoted neuron development with greater neurite length. This means that growing neurons received a positive growth signal from the PEDOT/GO ﬁlms. The PEDOT was “doped” by some GO carboxyl groups with negative charge, while PEDOT/GO functionalization with biomolecules was facilitated by other groups with free exposure on the composite surface. Covalent binding occurred between RNIAEIIKDI, a functional laminin peptide, and the PEDOT/GO surface, preserving its bioactivity by intensifying neurite outgrowth from neurons developed on the functionalized composite surface.306 Therefore, PEDOT/ GO is an interesting material for neural interfacing and biosensing, due to being functionalized from biomolecules, possessing low impedance and diminished permissiveness, and being nontoxic to neural development.306 Functionalized graphene can be incorporated as a crosslinker in the prepolymer through a reaction of poly(εcaprolactone)diol and 4,4′-methylene bis(phenyl isocyanate).307 The composite depicted 95% shape retention, 97% shape recovery, a fast electroactive shape recovery rate, and enhanced shape recovery force, highlighting its potential to function as a graphene-based actuating device.307 Figure 54 illustrates the nanoﬁller-cross-linked PU block copolymer synthesis.307 Glycine-modiﬁed GO (GMGO) and its derivative, nanogold-deposited GO (AuGO), have been embedded into PVA nanoﬁber matrixes by electrospinning.308 The 2D, high-aspect-

Figure 55. PepA (PDB ID 3KL9) structure: (A) PepA surface presentation, (B) PepA interior surface, (C) GFET device with PepAPtNP schematic, (D) PepA−PtNP biocapacitor schematic. Reprinted from ref 309. Copyright 2014 American Chemical Society.

the GO, GMGO, and AuGO preparation ﬂowcharts. GO was prepared by the Hummer method, and then 0.5 g of GO was dispersed in 50 mL of water by sonication for 2 h (solution 1). A 4 g mass of glycine was dissolved in 50 mL of water for 5 min by sonication (solution 2). Solution 2 was then added to solution 1 after solution 1 was heated to 98 °C and reﬂuxed for 4 h. The solution was poured into the tube after it cooled to room temperature. It was then centrifuged for 10 min at 9000 rpm and then washed with water. This process was repeated to clear the liquid phase. The obtained GMGO was dried at 40 °C for 16 h.308 The potential for use as a bionanohybrid capacitor of the protein-shelled inorganic NP charge transport behavior integrated with graphene was investigated.309 A ﬁeld eﬀect transistor (FET) and graphene-based FET (GFET) were employed to conduct the measurement of the conductivity of AK

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Figure 56. Schematics and SEM images of (a) a pristine AAO membrane, (b) method 1, AAO coated by DLC, (c) method 2, AAO seeded by ND and exposed to ultra-nanocrystalline CVD diamond growth conditions, and (d) method 3, AAO seeded by ND and exposed to nanocrystalline CVD diamond growth conditions. The inset images show the pore size distribution of the pores in the SEM images. Reprinted with permission from ref 317. Copyright 2014 Elsevier.

electrical and optical qualities.318,319 With the majority of its qualities identical to those of diamond, the amorphous carbon form DLC consists of a considerable portion of sp3-bonded carbon.320−323 However, nanopatterning still remains challenging, even with the numerous eﬀorts made to process synthetic DLC and ND and their preparation.318−329 The top-down fabrications for sculpting nanostructures in diamond are very limited. This is due to their extreme chemical stability and hardness of sp3 carbon.330−337 The standard optical, electronic, or mask template lithographic processes combined with oxygen plasma etching were employed by previous attempts at nanostructuring diamond, generating diamond nanostructures with pores of hundreds of nanometers in size and aspect ratios of around 10.330−337 As an alternative to the porous diamond and DLC nanostructure fabrication, a bottom-up approach has been used by researchers.334−343 Patterning in diamond ﬁlms with high resolution was achieved through diamond nucleation and development with spatial selectivity.335−337 Recent research in which organic compounds were subjected to plasma polymerization resulted in the creation of subnanometer-sized pores in free-standing DLC membranes with a thickness of 10−40 nm.338 Organic solvents rapidly permeated the sp3 carbon highly cross-linked networks through the membranes. However, so far no straightforward technique has been formulated for creating nanoporous sp3-bonded carbon nanostructures with diﬀerent pore sizes.317 High surface area, quasi-ordered nanopore structure, adjustable surface chemistry and electrical conductivity, and exceptional biological, chemical, and corrosion resistance are among the qualities possessed by the new nanoporous alumina materials coated with hybrid diamond and amorphous DLC which were developed in this study.317 Due to its ability to alter the surface and internal part of anodic alumina nanopores, plasma-induced carbonization was applied to prepare these materials, resulting in a DLC protecting layer displaying uniformity and minimal thickness that covered the membrane

the protein shell (PS) dodecameric bacterial aminopeptidase (PepA) and of the PepA-incorporated platinum NPs (PtNPs). In addition, it was demonstrated that by varying the size of the PtNPs the electrical properties of PepA−PtNPs were controlled. A bionanohybrid capacitor with adjustable features was assembled by employing two poly(methyl methacrylate) (PMMA)-coated graphene layers divided by PepA−PtNPs. The fabrication of bionanoelectronic devices displaying ﬂexibility and biocompatibility to be incorporated into bioelectrical circuits within biomedical applications is believed to beneﬁt from the integration of graphene with bioinorganic nanohybrids.309 The assembly of PepA into a tetrahedrally shaped channel at the subunit pair interfaces is shown in Figure 56A,B.310 By preparing NPs with PepA, the precise size control of NPs inside the PepA is an advantage. PepA−NPs have been used in diﬀerent ﬁelds such as a reactive oxygen species (ROS) quencher,311 multifunctional nanobiocatalysts,312 and an MRI contrasting agent.313 Due to their chemical stability and high work function (5.65 eV), PtNPs can be considered for use in electronic devices.314−316 Similarly, PepA−PtNPs could be applied for bionanocapacitor and bioelectronic devices.309 The FET device was fabricated on a SiO2/Si substrate, and gold electrodes were used for the drain and source (Figure 56C). FET and GFET could enable the measurement of PepA−PtNP electron transport properties. The results suggested that a bionanohybrid capacitor could be developed by combining PSencapsulated PtNPs with graphene and could allow electron entrapment and capacitance improvement by PepA−PtNPs. For this purpose, a symmetric multilayered bionanocapacitor (Figure 56D) could be produced by inserting diﬀerent sizes of PepA−PtNPs between the top and bottom poly(methyl methacrylate) (PMMA)-coated layers of graphene.309 3.2.4. Nanodiamond. Nanodiamond (ND) and diamondlike carbon (DLC) have exceptional properties which make them particularly useful for devices that need to withstand harsh environments.317 DLC is also appreciated for its unique AL

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Figure 57. H-ND functionalization schemes. Reprinted with permission from ref 349. Copyright 2011 Royal Society of Chemistry.

Figure 58. UNCD functionalization with RNA. Reprinted with permission from ref 352. Copyright 2005 Elsevier.

rough porous nanocrystalline diamond (NCD) ﬁlm with broad pore size distribution and a thickness of 50 nm (Figure 57b). Pores in the NCD were reduced signiﬁcantly compared to those in the AAO. The pore size distribution of the porous diamond ﬁlm dispersion and roughness has been improved by using the ultra-nanocrystalline (UNCD) diamond growth plasma in the second approach (Figure 57c). Porous nitrogen-incorporated UNCD (N-UNCD) ﬁlms possessing conductivity were obtained through the addition of nitrogen to UNCD growth.326 The distribution of the pore size of the diamond-coated AAO membranes was substantially broadened and reduced by both approaches. This was due to an “overlayer” eﬀect engendered by a Gaussian expansion of the pore size distribution due to the fact that the deposited diamond layer had a ﬁnite roughness.317 The maximum value documented for any system, even ferroelectrics, was associated with detonation-ND (DND) powder, which always adsorbs small amounts of water from air spontaneously, and at low frequencies, its dielectric permittivity (ε) increases from singledigit values to more than 1019.347 Furthermore, the physical qualities of water were signiﬁcantly inﬂuenced by DND traces, which not only augmented its ε from ∼80 to over 106 but also modiﬁed the sound velocity. The interaction between protondonating functional groups on the diamond surface and the adsorbed water monolayer was the cause of this phenomenon, which means that DND without hydrogen lacks the eﬀect.347 One study investigated how the ion sensitivity of Hterminated single-crystalline diamond surface conductive layers was aﬀected by surface charge.348 The inﬂuence of both monovalent and divalent salts was assessed at diﬀerent pH values. The ionic strength increased at pH above 3.5, decreasing the surface conductivity. The ﬁndings were explained with regard to Coulombic screening of surface potential electrolyte ions, which is a function of the surface charge dependent on the pH. The charge modulation by amphoteric hydroxyl surface groups and heterogeneous

external and internal surfaces completely. Meanwhile, it has been demonstrated that the development of the sp3-bonded carbon layer of minimal thickness in the nanopores depended directly on the interaction between internal and external carbon supplies. Apart from enhancing knowledge of the mechanisms underpinning DLC development in restricted nanospaces, the study also laid the ground for the production of hybrid carbon-coated nanoarchitectures with chemical resistance and biocompatibility on diﬀerent inorganic supports.317 Elements such as hydrogen, nitrogen, silicon, boron, ﬂuorine, phosphorus, and metals could be used to alter the surface energy and electrical conductivity.344 Nanoporous anodic aluminum oxide (AAO) could be used to produce hybrid diamond and amorphous carbon-coated alumina membranes via chemical CVD through three diﬀerent methods (Figure 57). The ﬁrst approach depicts the AAO templates being treated with H2/CH4 or Ar/CH4 plasmas in CVD to produce ultrathin DLC coating over the whole surface of nanoporous AAO. In the other two approaches, to promote diamond nucleation, the surface of the AAO templates must be treated by ND followed by development in CVD. This ND seeding step is essential for diamond growth. Due to this reason, the AAO sample was immersed in a colloidal dispersion of ND in water.345,346 ND adhesion to the alumina surface in water improved by the hydrogen termination of the ND surface in a furnace at 800 °C with a H2/Ar gas mixture (5% H2). Parts c and d of Figure 57 show SEM images after the CVD growth, which illustrate that the ND seeds homogeneously and covers the entire surface of the anodic alumina. While the internal surface of nanopores was coated by DLC, diamond ﬁlms have grown only on the top surface of the AAO substrates. CVD diamond growth was the only diﬀerence between the second and third approaches. The polycrystalline CVD diamond growth was achieved by using the H2/CH4 plasma in the third approach, which resulted in a relatively AM

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Figure 59. MCSN schematic illustration: (i) Li embedding, (ii) Li converting, (iii) Li dislodging. The top illustration shows the details of the Li embedding process at a low temperature (60 °C) under ultrasonication. Reprinted with permission from ref 369. Copyright 2013 Elsevier.

are prone to contaminations. Furthermore, the H termination can be either improved or replaced by OH or F termination by photochemical and plasma treatments. DNA binding on HUNCD and antifouling polyethylene glycol layer deposition on OH-UNCD ﬁlms were then explained. It was shown that atom transfer radical polymerization with α-bromoisobutyryl bromide as the catalyst enabled the direct grafting of a nonfouling polyethylene glycol layer on oxygen-terminated surfaces.351 An additional set of experiments revealed that, although unspeciﬁc interactions between UNCD surfaces and highly fouling proteins (e.g., bovine serum albumin [BSA]) were scarce, some form of contact still occurred. Nonetheless, surface termination permitted the adjustment of the adsorption level and ratio of BSA and ﬁbrinogen adsorption, on which surface hemocompatibility depends. Moreover, it was reported that, for various cell lines, continuous as-grown UNCD surfaces were bioinert and lacked cytotoxicity.352 A photochemical technique applied in some studies353−358 was applied to achieve the binding of molecules of doublestranded RNA to H-terminated a-C/UNCD surfaces.359 This technique involves photochemical adhesion of amine groups, reaction with a bifunctional cross-linker, and ﬁnally RNA molecule adhesion (Figure 59). The procedure that has been employed is as follows. The ﬁrst step consists of photochemical adhesion of 1-amino-3-cyclopentene hydrochloride (C5H10ClN) by exposure to UV light (244 nm) for 195 min followed by deprotection of the amino groups in 10% NH4OH. The next step is attachment of sulfosuccinimidyl 4-(Nmaleimidomethyl)cyclohexane-1-carboxylate (SSMCC), which serves as a linker molecule. This is followed by functionalization with a thiolated DNA oligonucleotide (5′GATCCCCGGTACCGAGCTCGAATTCGCCC-SH-3). Finally, double-stranded RNA with a length of 374 base pairs was bound with a single-stranded overhand consisting of 30 nucleotides at the 5′-end, enabling the formation of Watson− Crick base pairs alongside the thiolated DNA oligonucleotide.352 Hydrogen-free a-C coatings have been developed by cathodic vacuum arc evaporation (CVAE). Hard a-C coatings were deposited by direct-CAVE (DCVAE) and ﬁltered-CAVE (FCVAE) cathodic arc evaporation, including pulsed arc. Highest hardness was provided by hydrogen-free coatings (taC) that were monolithic tetrahedrally bonded, while in some applications various softer a-C coatings are useful.344 A report on how moderately boron-doped diamond behaved electrochemically was also initiated.360 The analysis focused on

hydroxide and hydronium ion adsorption were caused by the hydrophobic nature of the H-terminated diamond surface. The diamond aqueous interface controlled various mechanisms, including electron transfer to charged redox molecules, charged molecule and protein adsorption, and ion sensitivity.348 Particular functionalization routes are promoted by hydrogen terminations (C−H) through endowment of diamond layers with certain surface qualities such as negative electron aﬃnity and a superﬁcial conductive layer. Furthermore, diazonium salts or alkene moieties can be covalently linked on hydrogenated diamond thin ﬁlms, due to the electronic exchanges at the interface.349 UV hydroxylation was the initial reaction performed on H-NDs. After the hydrogen plasma was exposed to high-pressure and high-temperature (HPHT) NDs, water vapors and air were used to ﬁll the quartz pipe, which was then exposed to UV irradiation for 6 h (Figure 58).349 Due to therapeutic purposes, it would be helpful for dopamine levels to be precisely measured in situ. This prompted the formulation of a new approach employing carbon thin ﬁlm electrodes to selectively determine dopamine levels.350 Conventionally, boron atoms in various concentrations were used to dope diamond ﬁlms to endow them with conductivity. Unbalanced magnetron sputtering made it possible to obtain various carbon thin ﬁlm conductivities. It is possible to apply this method at ambient temperature followed by widening the appropriate substrate choice. In the case of the carbon thin ﬁlm with the highest resistance, the potential diﬀerence of carbon was 4.6 V. Moreover, conductivity had little eﬀect on the electrode sensitivity with regard to dopamine. Furthermore, the behaviors of the diﬀerent surfaces in terms of dopamine oxidation were approximately the same. Variation in conductivity and/or surface charges as well as diﬀerent surface chemical qualities were the probable reasons for the minor discrepancies that the thin ﬁlms did exhibit in their electrochemical behavior. Overall, it is clear that the amorphous carbon thin ﬁlm constitutes a promising candidate as a neural sensing material.350 The a-C/UNCD deposition by microwave plasma CVD with a 17% CH4/N2 mixture at 600 °C was investigated. The ﬁlms consist of diamond nanocrystallites of 3−5 nm embedded in an amorphous carbon matrix of 1−1.5 nm width. Films were subjected to various treatments (plasma processes, UV/O3 exposure) to obtain H-, O-, and F-terminated surfaces.351 First, it is reported that as-grown a-C/UNCD ﬁlms are H-terminated and are conductive and very stable, while O-terminated ones AN

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when sensing bacteria from 106 cfu/mL E. coli O157:H7. Comparable to the magnitude of preimpedance detection application of magnetic NP-based sample enhancement, there was a modiﬁcation in charge transfer resistance by ∼46% for 108 cfu/mL E. coli O157:H7. Therefore, ND seeding allows impedance biosensing in solutions with competitive sensitivity that are not very conductive.363

how as-deposited, annealed, and oxidized electrodes behaved in a 2 M sulfuric acid environment incorporating the Ce4+/ Ce3+ redox couple. The results indicated that these electrodes responded electrochemically in a manner similar to that of semiconductors. The study particularly highlighted the p+-type conductivity of the surface-hydrogenated layer included in asdeposited samples as well as the eﬀect on the charge transfer of surface bond termination of hydrogen or oxygen.360 Numerous materials are included under the umbrella term ND or NCD. The consensus is that material with a facet size of under 100 nm is denoted by NCD, while material with a grain size not exceeding 10 nm is denoted by UNCD. The development process is the source of such morphological distinctions. Faceted diamond with a grain size equivalent to the ﬁlm thickness and reduced sp2 content is the product of standard gas phases rich in hydrogen. These ﬁlms are classiﬁed as NCD if they have a minimal thickness and a grain size of under 100 nm. 361 Renucleation can be initiated by minimization in sp2 etching occurring when plasma is deprived of hydrogen. This can signiﬁcantly diminish the grain size on the order of 3−5 nm, and therefore, the material will be classiﬁed as UNCD. The two types of materials have distinct electronic qualities. NCD may be subjected to boron doping because it is a microcrystalline diamond of minimal thickness and inherent transparency, and the more it is doped, the higher its absorption capacity. As a result of its higher sp2 content, high absorption is demonstrated by UNCD as well, which also has a smaller band gap because of disorder. The density of states in the band gap can be enhanced through nitrogen addition to the gas phase, generating metallic conductivity, which is obtained from the n-type but not the doping.361 Krypton ﬂuoride (KrF) pulsed laser deposition is used to produce DLC-doped zinc nanocomposite thin ﬁlms. The laser system source used carbon containing 3.0, 5.0, and 10.0 atom % zinc. Doping zinc into DLC could lower the electrical sheet resistivity, which investigation by the four-point probe shows. According to microstructural analysis based on Raman spectroscopy and XPS, the higher the zinc quantity added, the more restricted the sp3 content and the higher the content of silicon carbide (SiC). Furthermore, attachment is made stronger by SiC enhancement. While the ﬁlm friction coeﬃcients do not change, its surface roughness increases.362 The sonication-assisted nanostructuring of biosensing electrodes with nanodiamonds (NDs) has been explored, due to the prohibitive cost of biosensor construction based on chemical vapor deposition of diamond ﬁlms.363 While it improves the detector sensitivity and stability, it also enables real-time continuous sensing by exploiting the fact that diamond biofunctionalization is hydrolytically stable. It was found that more bacteria were captured when the surface coverage was expansive, which can be achieved through the seeding time, ND concentration, and proper choice of solvent. By comparison to dimethyl sulfoxide diluted with ethanol, acetone, isopropyl alcohol, or water, a greater surface coverage (33.6 ± 3.4%) for the NDs with positive ζ potential was supplied by a mixture of dimethyl sulfoxide and methanol. Impedance spectroscopy of ND-seeded interdigitated electrodes (IDEs) indicated that the ND seeds functioned as islands of electrical conductivity separated by a few nanometers. It has also been reported that UV-alkene chemistry enabled decoration of seeded NDs with antibodies, while hydrogenation of the seeded NDs enhanced bacterial capture. The resistance to charge transfer at the IDEs decreased by ∼38.8%

3.3. Modiﬁed Polymers with Alloys

Titanium alloys have wide application in the biomedical ﬁeld due to their high corrosion resistance and good strength-toweight ratio.364 By varying the PEG concentration, the eﬀect of PEG on the stability and antibacterial properties of the polymeric coating PPy/PEG on TiAlZr was studied.365 In brief, PPy was synthesized on Ti6Al7Nb alloy in the precence of poly(sodium 4-styrenesulfonate) (NaPSS), (tertoctylphenoxy)polyethoxyethanol (Triton X-100), and Ndodecyl β-D-maltoside (DM) surfactants by potentiostatic polymerization. The results indicated an improvement in corrosion resistance, electrochemical stability, and surface wettability by adding the surfactants. Furthermore, the results indicted that the RAW264.7 macrophages cultured on PPy surfactant were dependent on the surfactant, suggesting that the immune response to biomaterial deposited with PPy may be controlled by the choice of surfactant molecules.366 Of note is a report on the substrate modiﬁcation of Nitinol (equiatomic Ni and Ti alloy (NiTi)) with a coating system formed by a self-assembled alkylsilane (propyltrichlorosilane (C3H7SiCl3) or octadecyltrichlorosilane (C18H37SiCl3)) and PPy ﬁlm doped with sodium bis(2-ethylhexyl)sulfosuccinate (Aerosol OT or AOT).367 The combination of an alkylsilane and a voluminous molecule such as AOT entrapped into PPy ﬁlms improved the substrate corrosion resistance. The longest alkylsilane chains demonstrated the best performance, where the PPy ﬁlm remained adhered to the underlying coating after a pitting corrosion test.367 Self-construction electrode position at various current densities was the method of preparation of highly ordered nanotube and nanowire arrays made of Ni−P alloy with a high aspect ratio within porous membranes of anodic AAO.368 The amorphous phase structure of these arrays was the same as that of crystalline Ni nanograin. The AAO membrane deposition time and pore diameter gave an outer diameter of 40 μm and length of 200 nm. The current densities, deposition time, and concentration of phosphorus acid in the electroplating bath were the major determinants of nanotube or nanowire development during electrodeposition. The arrays of nanotubes and nanowires were shown to possess anisotropy with easy magnetization along the array direction, based on the hysteresis curve obtained from the investigation of the magnetic properties of the nanostructure arrays. Furthermore, in terms of saturation magnetization, the magnetic performance of the nanotube array was higher than that of the nanowire array, despite both being soft magnetic materials.368 On the basis of a Li2CO3 molten salt strategy, the closely interconnected networks of mesopore-functional carbon sphere nanochains (MCSNs) with one-dimensional porosity were derived straight from colloidal carbon sphere nanochains (CCSNs).369 Here, 2.5 nm size PtRu alloy NPs were integrated into the mesopores of MCSNs to achieve PtRu/MCSNs.369 Furthermore, the synthesis of solid carbon sphere nanochain (SCSN)-supported PtRu NPs (PtRu/SCSN) and benchmark carbon (Vulcan XC-72)-supported PtRu (PtRu/C) was AO

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undertaken to provide points of comparison. It is illustrated that the PtRu/MCSN indicated superior catalytic properties toward methanol oxidation with desirable stability and enhanced catalytic activity. The forward peak current density of PtRu/MCSNs (437 mA mg−1) was much higher than those of PtRu/SCSNs (265 mA mg−1) and PtRu/C (310 mA mg−1). The onset potentials of PtRu/SCSNs (0.38 V) and PtRu/C (0.37 V) were later than that of PtRu/MCSNs (0.24 V). The functionalities of the mesoporous carbon support were the reason for the observed attractive eﬃciency, making nano-PtRu catalysts available in greater proportion by improving electron transfer and mass transport.370 The dependence of MCSNs on the singular Li2CO3 molten salt strategy is evidenced by their mesopore growth processes shown in Figure 59. Underpinned by the ultrasonic eﬀect, the integration of lithium acetate (Li source) into the swelled CCS matrix can be achieved without diﬃculty at 60 °C (Figure 59). Furthermore, esteriﬁcation between the CH3COO− and the OH groups led to the production of potential acetic ester and lithium hydroxide (see eq 1). (ROH)n + nCH3COOLi ⇒ nCH3COOR + n LiOH

The structured arrays of iron−palladium (Fe−Pd) binary alloy nanotubes are also of interest. An uncomplicated electrodeposition technique in conjunction with nanoporous AAO was used to prepare these arrays from a mixed metal− complex solution.373 This process was facilitated by the control of the electrodeposition Fe2+ and Pd2+ potentials by complex agents. Thus, the alloy nanotubes displayed variability in internal diameters and Fe−Pd composition ratios due to the alteration of the cathodic current density. Furthermore, annealing was applied to transform the metastable phase structure into an L12 superlattice structure, despite the inclusion of face centered cubic (fcc) crystal structures in the as-synthesized Fe−Pd nanotubes. On the basis of the ﬁndings, it was surmised that the preparation of other binary alloy nanotubes could also be undertaken through electrodeposition alongside the AAO template, in accordance with a suitable choice of complex agents.373 An electrochemical cell was employed to accomplish homogeneous growth of Fe−Pd nanotubes (Figure 60). There was clear distinction between

(1)

In situ transformation of the potential LiOH contained in the swelled CCS into nanoscale Li2CO3 could be achieved at 550 °C (see eq 2). LiOH + CH3COOR ⇒ Li 2CO3 + H 2O

(2)

At the latter high temperature (850 °C), the Li2 CO 3 component (618 °C melting point) was mostly melted and dislodged from the carbonized framework of CCSNs, resulting in mesoporous MCSN structures.369 The electrochemical behavior of three ZrTi alloys (Zr5Ti, Zr25Ti, and Zr45Ti) in Ringer’s solution was studied by Bolat et al.371 Polarization of the metal samples at 0.50 V enabled the use of scanning electrochemical microscopy to detect heightened reactivity. However, the character of the metallic material inﬂuenced how pronounced this feature became. Furthermore, localized corrosion appeared on the Zr5Ti alloy at 37 °C. Overpotentials of about 600 mV were necessary for occurrence of disintegration because of the negative spontaneous corrosion of the material, despite the relatively low potential of the Zr25Ti alloy. However, in the polarization curve, a more extensive passive range was illustrated by the Zr45Ti alloy, which also withstood localized corrosion.371 Biodegradable magnesium alloys may be integrated in bone implants. Microarc oxidation in conjunction with electrochemical deposition permitted the synthesis of a composite coating with high substrate attachment strength on Mg−Zn− Ca alloy with the purpose of making the latter more resistant to corrosion and aﬀording it greater surface bioactivity.372 Presenting a needle-like architecture, the composite coating contained MgO, Mg3(PO4)2, hydroxyapatite, and octacalcium phosphate and was around 12−15 μm thick. In the context of hydrogen evolution tests, the composite coating was indicated to have acceptable surface bioactivity on the basis of the Ca/P salt deposited on it. Furthermore, compatibility with the requirements of bone implant materials during the ﬁrst bone reunion phase was demonstrated by compression tests, in which the alloy modiﬁed with composite coating was introduced in simulated body ﬂuid for various periods of time. Therefore, magnesium and its alloy were considered promising candidates as degradable implant materials based on surface modiﬁcation of the composite coating.372

Figure 60. Electrochemical cell schematic illustration for Fe−Pd electrodeposition. Reprinted with permission from ref 373. Copyright 2009 Elsevier.

the vertical cell with a cylindrical form and the commonly applied electroplating bath with a horizontal metal growth direction. The disk-shaped electrodes (anode, Pt; cathode, Cufoil-covered cell bottom) displayed a parallel orientation in a vertical direction. The conductive-surface side in the middle of the cell bottom covered in copper foil was where the metalsputtered AAO template disk was aﬃxed, thus hindering AAO template crispation. It was anticipated that the electric ﬁeld gradient would be lowered by the cell and electrode shape and structure, resulting in homogeneous potential and current dispersal on the surface of the electrode. Moreover, nanochannel blockage due to gas bubbles from a hydrogenevolution reaction, in which electrode connection with electrolytes is maintained, could be prevented due to the upward openings of the AAO nanochannels. The homogeneous Fe−Pd nanotube growth was supported by such cell properties.373 A study was conducted on AE21 and AE42 magnesium alloy corrosion properties in the extruded state and following eight passes of equal channel angular pressing (ECAP) through AP

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Figure 61. Immunosensor schematic illustration. Reprinted with permission from ref 378. Copyright 2011 Elsevier.

route Bc by EIS in a 0.1 M solution of NaCl.374 The results showed that the corrosion process was aﬀected by Al-rich Al11RE3 dispersed particles, which also augmented resistance to corrosion. On the other hand, AE21 was made less resistant to corrosions by the ultraﬁne grained structure. Furthermore, in comparison to extruded material, corrosion resistance was improved by the AE42 microstructure following ECAP and enhanced matrix distribution of alloying elements.374 The Co67Cr29W4 alloy electrode surface could also support electrodeposition of PPy−PANi composite ﬁlms.375 Possibly regulated by electrolyte diﬀusion, the redox process mechanism was revealed to possess great complexity. In addition, the ﬁlm electrochemical activity of both PPy and PANi was substantially aﬀected by the cobalt-based alloy substrate, due to the polymeric ﬁlm presence, and anodization of these modiﬁed electrodes resulted in polymeric layers simultaneously and oxide complex ﬁlm formation. This was equivalent to a galvanic interaction among the polymer and the cobalt− chromium-based alloy substrate, with the outcome that cobalt, chromium, and tungsten were oxidized and the polymer was reduced.375 As passive materials with biocompatibility, CoCrMo alloys display eﬀective mechanical qualities and corrosion resistance, which is why they are regularly employed as joint replacements. Interesting results were obtained from an analysis of how CoCrMo alloys subjected to thermal treatment behaved electrochemically when their bulk alloy composition contained varying carbon amounts. The electrochemical qualities of biomedical alloys were inﬂuenced by the carbide amount in the CoCrMo alloys and the simulated body ﬂuid chemical composition, which therefore also aﬀected the passive dissolution rate.376 Surface homogenization was favored by reduced carbon content in the bulk alloy chemical composition as well as by thermal treatment, therefore increasing the availability of Cr to form an oxide ﬁlm and make the alloy more resistant to corrosion.376 The physiological relevance of two biomedical alloys AISI 316L and CoCrMo has also been investigated by noting their electrochemical behavior through simulations of body ﬂuids. Particular attention was paid to how passive behavior was inﬂuenced by the immersion time and the chemical composition of the solution.377 The alloy character determined the extent to which both biomaterials were aﬀected by the model protein employed, albumin. This protein was found to make AISI 316L less resistant to corrosion while making CoCrMo more resistant. Furthermore, passive layer properties modiﬁed the albumin eﬀect, despite its adsorption on both alloys. On the contrary, the maximum resistance values in the phosphate solutions associated with both alloys were elucidated by phosphate ion precipitation. The investigation depicted that, compared to AISI 316L, CoCrMo possessed passive ﬁlms of greater thickness and protection, as its electrochemical behavior indicated lower capacitance and higher transfer resistance.377 During gestation and gestational trophoblastic diseases, the placenta produces human chorionic gonadotrophin (hCG). Abnormal placental invasion and underdeveloped placenta are

associated with higher hCG production. Therefore, hCG is a crucial indicator in diagnosing not only pregnancy but also various disease conditions, including hydatidiform mole, choriocarcinoma, and orchic teratoma. A Pt−Au alloy nanotube array was developed via electrodeposition with a nanopore polycarbonate (PC) membrane at −0.35 V and was employed for hCG antibody immobilization to create a new amperometric immunosensor capable of detecting hCG. The Pt−Au alloy nanotube possessed vertical orientation and was classiﬁed as an electrode, meaning that similarity existed between every electrode and the nanoelectrode. The hCG antigen was inhibited by electrocatalytic reduction of H2O2 by Pt−Au alloys following immunoreaction-based attachment to the electrode surface, therefore enabling antigen detection. Under ideal circumstances, there was a direct correlation between the immunosensor current response and the hCG concentration in the range of 25−400 mIU/mL, with a 12 mIU/mL detection limit. In the serum samples, hCG was detected eﬀectively.378 Moreover, Pt−Au alloy development was validated by EDS analysis (Figure 61).

4. MODIFIED NATURAL POLYMERS FOR CONDUCTIVITY A large number of natural polymers have been modiﬁed mainly with conductive ﬁller in the development of conductive natural nanocomposites. The following are examples of the key polymer. 4.1. Chitosan

As potent inducers of chondrogenesis, glycosaminoglycans and GAG analogues can be employed as components in scaﬀolds for cartilaginous tissues.379 Chitosan, for instance, is a natural polysaccharide that can be puriﬁed from the exoskeleton of crustaceans. It is a linear, partially deacetylated chitin derivative consisting of D-glucosamine residues linked by β(1→ 4) glycosidic bonds, randomly interspersed with N-acetylglucosamine residues. It therefore somewhat resembles components of articular cartilage such as hyaluronic acid and certain GAGs, as illustrated in Figure 62.380 The average molecular weight of

Figure 62. Chitosan repeating unit molecular structures. Reprinted with permission from ref 380. Copyright 1990 Taylor & Francis Group.

chitosan ranges from 50000 to 1000000, depending on source isolation and the preparation methods. The degree of deacetylation varies from 50% to 90% and determines its crystalline properties. Chitin with 0% deacetylation and chitosan with 100% deacetylation give maximal crystallinity, while intermediate degrees of deacetylation give minimum crystallinity. The stable crystal structure means that chitosan is insoluble in alkaline solution. However, chitosan is soluble in AQ

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Figure 63. Scaﬀold preparation. The resulting scaﬀolds were washed with distilled water and lyophilized. Reprinted from ref 382. Copyright 2008 American Chemical Society.

incorporated into the multilayered composite ﬁlm to demonstrate the protein electron transfer ability of the ﬁlm. The movement of electrons from microperoxidase to the electrode suggests that CNTs could electrically wire the protein to the electrode. The electrocatalytic activity toward H2O2 and O2 was then evaluated. The results revealed an increase in the number of self-assembled layers in the composite ﬁlm and a positive shift in the reduction potentials of H2O2 and O2. The multilayer chitosan/CNT composite ﬁlm containing protein was thus a sensitive interface for electrocatalytic analysis.383 Moreover, a composite scaﬀold of polypyrrole (PPy; 2.5%) and chitosan (97.5%), which conferred conductivity and biodegradability respectively to the overall structure, has been evaluated. This scaﬀold was developed with the ultimate aim of electrically stimulating Schwann cells (SCs).115 It was found that the PPy/chitosan scaﬀold facilitated cell adhesion, spreading, and proliferation both with and without ES. However, application of ES to the scaﬀold signiﬁcantly increased the expression and secretion of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). This suggests that ES-induced neurotrophin secretion may be useful in supporting nerve regeneration in conductive scaﬀolds.115 Bioactive glass nanoparticles (BG-NPs), which were able to precipitate apatite when submerged in simulated body ﬂuid (SBF), were studied.384 Essentially, a poly(dimethylsiloxane) (PDMS) stamp was pressed against a dried membrane of BGNPs, and this BG-NP-inked stamp was pressed onto a freestanding chitosan membrane in a process known as microcontact printing. The pattern of BG-NPs formed could be visualized by scanning electron microscopy (SEM). These samples were then immersed in SBF for diﬀerent durations of up to 7 days to achieve mineralization of the bioactive glass patterns. In vitro analyses revealed that L929 cells preferentially attached to and proliferated on areas printed with BGNPs. This technique allows for microscale spatial regulation of biomaterial characteristics and thus has important implications in directing regeneration of tissue, in developing cell cocultures, and in producing constructs that can limit cells to speciﬁc locations and geometric dimensions within the substrate.384 Of relevance here is a novel electroactive polymer, synthesized by aniline pentamer (AP) cross-linking chitosan (CS) in acetic acid/DMSO/DMF solution.385 First, the two carboxyl groups from AP reacted with NHS in DMF. DMSO was then added to the 10 vol % acetic acid aqueous solution of CS, followed by slow addition of the DMF solution into the mixture. The composition of the AP cross-linking CS (AP-cCS) samples varied according to the diﬀerent feed weight

acidic solutions below pH 5 as the amino group then becomes protonated. The pH-dependent solubility is a useful characteristic that permits processing under mild conditions; viscous solutions can be gelled either in alkaline solutions or in baths of nonsolvents such as methanol. The strong gel ﬁbers can then be extracted and dried.381 MWCNTs were used as a doping material to build conductive, porous, and biocompatible 3D chitosan scaffolds.382 The porosity and interconnectedness of the structure were a direct result of the preparation technique, where 1 wt % chitosan acetic acid underwent thermally induced phase separation and subsequent freeze-drying. The MWCNTs were used as a ﬁller to enhance the conductivity of the chitosan scaﬀold, with the solubilizing hydrophobic and hydrophilic groups of chitosan facilitating production of a stable polymer/MWCNT solution with evenly distributed nanotubes throughout the ﬁnal composite matrix. Conductivity was evaluated as a function of the chitosan to MWCNT ratio, yielding a percolation theory threshold of approximately 2.5%. The powder resistivity of fully compressed scaﬀolds appeared similar (0.7−0.15 Ω cm) across the 0.8−5 wt % range of MWCNT concentrations used, and was approximately oneﬁfth of the 20 kΩ cm powder resistivity measured for pure chitosan scaﬀolds (Figure 63).382 Another highly conductive chitosan-based scaﬀold using carbon nanoﬁbers as a doping material has been developed.5 Chitosan-based scaﬀolds as well as chitosan/carbon composite scaﬀolds were produced by precipitation. The carbon nanoﬁbers were distributed uniformly throughout the chitosan matrix, and the composite scaﬀold demonstrated porosity and complete interconnectivity. The chitosan/carbon scaﬀolds had an elastic modulus of 28.1 ± 3.3 kPa, comparable to values measured for the rat myocardium. The scaﬀold also displayed good electrical characteristics, with conductivity measured at 0.25 ± 0.09 S m−1. Neonatal rat myocytes were seeded into the scaﬀold without electrical stimulation (ES), and after 2 weeks of culture, pores throughout the entire construct were populated with cells. The metabolic activity of myocytes in the chitosan/carbon composites was signiﬁcantly enhanced in comparison to that of cells in pure chitosan scaﬀolds. The use of carbon nanoﬁbers also resulted in enhanced expression of cardiac-speciﬁc genes that are implicated in muscle contraction and electrical coupling. This showed that incorporation of carbon nanoﬁbers into porous chitosan scaﬀolds could improve the properties of cardiac tissue constructs, likely by enhancing electrical transmission between adjacent myocytes.5 The electron transfer properties of stable ﬁlms of biopolymer chitosan and CNTs, which were formed by layered selfassembly, have been described.383 Microperoxidase-11 was AR

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percentages of AP used in the preparation procedure.385 The amphiphilic polymers self-assembled into micelles with a diameter of 200−300 nm when dialyzed against deionized water from the acetic acid buﬀer solution. Three samples with various AP weight percentages were used to investigate the correlation between the percentage composition of AP and the degree of diﬀerentiation of rat neuronal pheochromocytoma (PC-12) cells without external stimulation. The results indicated that the presence of AP was associated with enhanced PC-12 diﬀerentiation; PC-12 cells cultured on pure CS ﬁlms demonstrated few neurites on day 5, while cells on ﬁlms with AP were able to form intricate networks. The AP content inﬂuence was the most notable at 4.9 wt % and subsequently decreased with increasing percentage composition of AP. The process of synthesizing AP-c-CS is depicted in Figure 64.385

A novel electroactuating chitosan/PANi composite biomaterial has been produced by wet spinning a chitosan solution to obtain chitosan ﬁbers, followed by two separate steps of in situ chemical polymerization of aniline on the surface of the chitosan ﬁbers.387 The resultant chitosan ﬁbers had a double coating of PANi and exhibited improved chemical and electrochemical actuation subject to pH and electrical stimuli. The measured electrical conductivity of the ﬁbers was relatively good at 2.856 × 10−2 S cm−1. The strain ratio and response time during electrochemical actuation were signiﬁcantly inﬂuenced by the electrolyte pH. The microﬁbers displayed an isotonic swelling strain of 0.39% during electrochemical actuation in an aqueous HCl solution of pH 0, as well as a strain of 6.73% for pH actuation. The higher strain ratio at lower pH values could be attributed to a faster diﬀusion rate. While cyclic voltammetry conﬁrmed the electrochemical properties to be due to PANi, the exact actuation mechanism deviated from that observed in pure PANi.387 Signiﬁcantly, a conductive chitosan-g-polycaprolactone (CPC)/PPy biomaterial oﬀers some promise in the ﬁeld of nerve repair.388 Compared to chitosan/PPy conduits, CPC/ PPy conduits studied demonstrated higher tensile and lateral compressive strengths in the hydrated state, enhanced conductivity, and comparatively slower degradation after continuous exposure to PBS systems for up to 10 weeks. The rate of degradation was inﬂuenced by the CPC composition. The buﬀering eﬀect of chitosan eﬀectively minimized pH deviations in the media of certain CPC/PPy conduits. The chitosan/PPy conduits were implanted into rabbits for varying durations; it was subsequently found that the explanted conduits demonstrated markedly decreased compressive strength after a six-week degradation period, with most conduits showing drastically reduced conductivity and partial or total collapse after an eight-week or longer degradation. Nevertheless, some explanted conduits were still able to sustain adequate mechanical strength in the hydrated state, exhibiting suﬃcient conductivity even after a ten-week in vivo degradative process. These ﬁndings indicate that CPC/ PPy conduits with the correct percentage composition could have potential applications in nerve repair in vivo.388 Next, a hybrid O-butyryl chitosan (OBCS)−PPy material has been studied. The covalent bonding between OBCS and PPy was achieved by photo-cross-linking under UV light.389 It is known that azide compounds with −N3 groups release N2 molecules upon UV irradiation to give a highly reactive nitrene group. The nitrene group can then abstract the hydrogen atom from C−H bonds of substrates before combining with the carbon radicals hence formed. In this study, an O-butyryl chitosan derivative bearing azide groups (Az-OBCS) was ﬁrst prepared by reacting OBCS with p-azidobenzoic acid. This AzOBCS was next coated on a PPy ﬁlm and cross-linked with UV irradiation (Figure 65).389 The surface grafted with OBCS demonstrated signiﬁcantly reduced platelet and ﬁbrinogen adhesion compared to control surfaces. The superior blood compatibility and electrical conductivity of the hybrid ﬁlms support their potential use as a biomaterial for engineering electrically conducting blood vessels or for developing hemocompatible biosensors to be applied directly to whole blood.389 The possibility of producing enzymatic biosensors through biofunctionalization of monolithic and freestanding 3D graphene foam has also been investigated. This biofunction-

Figure 64. Aniline pentamer cross-linking chitosan (AP-c-CS) synthesis. Reprinted from ref 385. Copyright 2008 American Chemical Society.

A study on conductive PCL/chitosan/PPy composite membranes identiﬁed signiﬁcant interactions between PCL and chitosan components, with the composite membranes having partially miscible microstructures.386 Some composite membranes showed marked conductivity transitions at a PPy load of approximately 2 wt %. In addition, signiﬁcantly enhanced conductivity was accomplished in PCL/chitosan/ PPy composite membranes compared to membranes consisting of a single component (either chitosan or PCL) and PPy particles. It was also found that the tensile strength of composite membranes in the hydrated state was maintained if the weight ratios of PCL to chitosan were appropriately selected.386 AS

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also caused swelling of the surface layer of the PCL nanoﬁbers. There was possible entanglement of some chains in the aggregation unit entangled with the swelling surface of the PCL nanoﬁbers. These chains then started attaching evenly to the nanoﬁbers, since the aggregation units were generally uniformly distributed throughout the solution (Figure 67b). Continued evaporation caused the density of aggregation units to increase, with some units eventually fusing with units already attached to the nanoﬁber surface. The fused aggregation units then became large enough to occupy the entire cross section of the nanoﬁbers (Figure 67c). By the time the solvent completely evaporated, the PCL chains in the aggregation unit had folded together with the chains in the swelling surface layer of the PCL nanoﬁbers. Each aggregation unit eventually formed a crystal lamella, which appeared at regular intervals along the nanoﬁber axis (Figure 67d).391 The resulting structure mimicked that of natural collagen nanoﬁbrils in the ECM of human tissues, making it a good scaﬀold for tissue engineering. The results suggest that the geometric dimensions of the shish kebabs are closely associated with the original concentration of PCL solution. Cell assays with NIH 3T3 ECACC ﬁbroblasts indicate that the surface nanotopography of the SINSK crystals, which is comparable to that of native collagen ﬁbrils, was conducive for ﬁbroblast attachment and spreading.391 A collagen−SWCNT hybrid biomaterial embedded with human dermal ﬁbroblasts (HDFs)392 was obtained by polymerizing solubilized type I collagen in the presence of dispersed SWCNTs and HDFs; this is depicted in Figure 68. HDFs were mixed with a selected concentration of cold SWCNT solution, concentrated culture medium, 10% fetal bovine serum, and acid-solubilized bovine type I collagen. A 0.1 M concentration of sodium hydroxide was added to neutralize the mixture. A 3 mL volume of this cold suspension was then poured into each of the six wells in a standard culture plate. The temperature was raised to 37 °C to gel the collagen, producing a cell-seeded, disk-shaped construct with a diameter of 35 mm and a height of 3 mm. Initial HDF and collagen concentrations were 1.0 million cells mL−1 and 2.0 mg mL−1, respectively. Constructs were incubated under standard cell culture conditions for 3 or 7 days after embedding, with subsequent analysis via the undermentioned methods.392 HDF-driven gel compaction of the collagen−SWCNT hydrogel matrixes occurred over time in culture, but the rate and degree of this compaction were appreciably reduced by the presence of SWCNTs. HDFs maintained high viability with varying SWCNT concentrations, with cell morphology apparently unaﬀected by the presence of SWCNTs. However, the cell count at day 7 of culture decreased with increasing SWCNT concentration. The electrical conductivity of the constructs varied from 3 to 7 mS cm−1 according to the SWCNT concentration. The conductivity increased uniformly

Figure 65. Az-OBCS reaction scheme and OBCS on a PPy ﬁlm immobilization scheme. Reprinted with permission from ref 389. Copyright 2008 Elsevier.

alization was achieved via controllable chitosan (CS) electrodeposition technology,390 where a homogeneous threecomponent solution containing a ferrocene (Fc)-grafted CS hybrid (Fc−CS), GOD, and SWCNTs was deposited on the surface of 3D graphene foam in a single immobilization step, forming a homogeneous biocomposite ﬁlm of Fc−CS/GOD/ SWNTs. This electrodeposition procedure stably grafts the Fc−CS on the 3D graphene surface such that the Fc groups retain their initial electrochemistry (Figure 66). The SWCNTs doped into the Fc−CS matrix function as a nanowire to promote electron transfer and conductivity of the ﬁlm. Coupled with the large active surface area, high conductivity, and rapid mass transport properties of 3D graphene foam, this enzymatic biosensor was ultimately found to have a wide linear range (5.0 μM to 19.8 mM), a low detection threshold (1.2 μM), and a quick response (8 s to achieve the 95% steady-state response) for glucose sensing in a phosphate-buﬀered solution.390 4.2. Collagen

Collagen is a protein made up of amino acid residues, particularly glycine, proline, hydroxyproline, and arginine, which in turn are derived from carbon, oxygen, and hydrogen. In the recent decade, in vitro reconstituted three-dimensional collagen scaﬀolds have been extensively employed as biocompatible protein-based substrates in various biomedical applications, including cardiovascular implants, paracrine factor delivery, and tissue engineering. A self-induced nanohybrid shish kebab (SINSK) structure, which is essentially a 3D scaﬀold of PCL nanoﬁbers covered by regularly spaced PCL crystal lamellae, was formed by electrospinning and subsequent self-induced crystallization.391 The mechanism of this procedure is proposed and illustrated in Figure 67. After dropping the PCL solution onto the PCL nanoﬁbers, the solution was homogeneous (Figure 67a). Phase separation occurred with evaporation of the solvent, inducing aggregation of the PCL chains. At the same time, the solvent

Figure 66. 3D graphene-based reagentless enzymatic biosensor schematic illustration by chitosan electrodeposition. Reprinted from ref 390. Copyright 2014 American Chemical Society. AT

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Figure 67. PCL SINSK structure schematic. Reprinted from ref 391. Copyright 2013 American Chemical Society.

the scaﬀold revealed a gradual change in the Ca to P ratio across its width, with clear identiﬁcation of a Ca-rich side and a Ca-depleted side. The Ca-rich side was characterized by poor porosity and agglomerates of nano-HA crystallites. On the other hand, there was better integration of nano-HA crystallites with collagen in the Ca-depleted side, giving a more porous network.394 An electrode modiﬁed with 3D hemoglobin (Hb)−collagen microbelts was also fabricated.395 The collagen microbelts were generated by electrospinning, and Hb was immobilized onto their surfaces, promoting direct electron transfer. An apparent heterogeneous electron transfer rate constant (ks) of 270.6 s−1 was obtained. The modiﬁed electrode showed appreciable electrocatalytic activity in reducing H2O2. The amperometric response of the biosensor was linearly correlated with the H2O2 concentration, varying from 5 × 10−6 to 30 × 10−6 mol L−1, with a detection limit of 0.37 × 10−6 mol L−1. The apparent Michaelis−Menten constant (Kmapp) was calculated as 77.7 μ−1. The established biosensor thus demonstrated a rapid amperometric response, as well as high levels of sensitivity, reproducibility, and stability.395

Figure 68. Schematic illustration of collagen−SWCNT hybrid biomaterial embedded with human dermal ﬁbroblasts (HDFs). Reprinted with permission from ref 392. Copyright 2008 Elsevier.

with increasing percentage composition of SWCNTs and showed frequency dependence, indicating that the electrical percolation threshold had not yet been attained in these constructs. These results demonstrate that the incorporation of SWCNTs into cell-seeded collagen gels could enhance the electrical conductivity. Protein−SWCNT composites may hence potentially be used as scaﬀolds for artiﬁcial tissue, as substrates to investigate electrical stimulation of cells, or as biosensor transducers or leads.392 A biomimetic composite resembling bone, formed by selfassembly of collagen ﬁbrils and carbonate hydroxyapatite nanocrystals, was produced through electrochemical deposition on a titanium plate.393 A constant current was applied to a type I collagen suspension in diluted NH4H2PO4 and Ca(NO3)2NH4H2PO4 solution at room temperature for diﬀerent durations. Identical electrochemical conditions were used to obtain carbonate hydroxyapatite nanocrystals or reconstituted collagen ﬁbril coatings. Moreover, the roughness of the Ti plate seemed to exert an important inﬂuence on the nucleation pattern of the inorganic nanocrystals. Laser scanning confocal microscopy was used to determine the ﬁbronectin (FN) adsorption pattern on the synthetic biomimetic apatitic phase. Higher adsorption rates were observed when the apatite was intergrown with collagen ﬁbrils. These results could guide the development of compositecoated metallic implants resembling bone, with widespread applications in the ﬁeld of surgery.393 Collagen/nanohydroxyapatite (HA) scaﬀolds of variable composition have been fabricated.394 The procedure employed involved the diﬀusion of calcium and phosphate ions through a collagen scaﬀold. This was followed by in situ precipitation of needle-like, nonstoichiometric nano-HA crystals (∼2 × 2 × 20 nm) onto collagen ﬁbrils in the interior of the scaﬀold.394 Elucidation of the chemical composition and microstructure of

4.3. Fibroin

Fibroin is an insoluble protein found in the silk of spiders, silkworms, certain moth genera such as Antheraea and Gonometa, and various other insects. The raw form of silk consists primarily of two proteins, sericin and ﬁbroin, where a gluelike sericin layer coats two ﬁbroin ﬁlaments referred to as brins.396,397 The ﬁbroin consists of multiple layers of β sheets organized in an antiparallel orientation. The recurrent amino acid sequence (Gly-Ser-Gly-Ala-Gly-Ala)n constitutes its primary structure (Figure 69). The high glycine and, to a

Figure 69. Fibroin structure, (Gly-Ser-Gly-Ala-Gly-Ala)n.

smaller extent, alanine contenst facilitate compact packing of the sheets, conferring both rigidity and tensile strength to the overall structure of silk. This is an important structure− function relationship that makes ﬁbroin a promising material in the ﬁeld of bioengineering. SF was regenerated in aqueous solution using the three protocols for dissolution of raw SF ([LiBr] = 9.3 M, [CaCl2] = 50 wt %, and CaCl2:EtOH:H2O = 1:2:8 molar ratio).398 SDS− PAGE was used to assess the integrity of SF obtained this way, and it was noted that each protocol gave rise to a silk ﬁbroin AU

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SF ﬁbers have been modiﬁed with MO through in situ oxidation.173 It is thought that MO promotes the formation of a PANi shell layer over the SF ﬁber core. The density of this polyaniline coating could be controlled by varying the reaction time. Investigations with L929 cells reveal good cell attachment to and proliferation on the composite ﬁbers, along with appreciable biocompatibility. As with the generation of CPs, it seems that conjugated monomers are ﬁrst oxidized to produce cationic radicals that function as active seeds, stimulating elongation of the macromolecular chain. The nitrogen and oxygen atoms of the peptide bond (−CO−NH−) in pure SF ﬁbers bear only partial negative charges and thus interact with few active seeds due to weak electrostatic attractive forces. This results in a low content of conductive particles. However, surface modiﬁcation of the SF with MO increases the number of negative charges, making SF a good template for inducing conductive polymer nanostructures due to the presence of the SO3− functional group. A mechanism for generating the regular coaxial structure is depicted in Figure 71. At the initial stage of polymerization, aniline monomers are oxidized to cationic radicals that provide a focus of growth. The cationic radicals are adsorbed onto the surface of MO-modiﬁed SF through electrostatic attraction, a process which is augmented by the availability of −SO3− groups. Oxidative polymerization of aniline monomers thus occurs selectively on the ﬁber surface where there is a greater cation radical concentration compared to that in solution. Visual evidence of this can be observed in the initial few minutes of the reaction when the color of the ﬁber changes from yellow to deep green whereas the solution remains transparent. This preferential polymerization of aniline on the MO-modiﬁed SF surface eventually yields a composite ﬁber in which SF is completely and uniformly coated by a PANi shell.173

with a unique degradation proﬁle and aqueous solubility of the freeze-dried protein. Using solutions of SF 17 wt % in 1,1,1,1′,1′,1′-hexaﬂuoro-2-propanol (HFIP), mats were produced from the three diﬀerent SFs by electrospinning, yielding distinct properties in terms of ﬁber size, length, and strength.398 The e-gel formation kinetics could be ﬁnely regulated by altering the ﬁeld strength and assembly conditions. E-gel stiﬀness could be partly reversed by removing the applied electric ﬁeld. Transient adhesion testing revealed that the adhesive properties of e-gels were to some extent a result of the localized increase in proton concentration surrounding the positive electrode, which itself was because of the applied ﬁeld.399 One interesting study aimed to elucidate the material properties and exact mechanism of silk e-gel formation.400 With application of an electric ﬁeld, nanoparticles quickly assembled into larger nano- or microspheres, ranging from tens of nanometers to several micrometers in size. Repulsive forces from the negatively charged acidic groups of the protein were screened by the local increase in proton concentration in the solution around the positive electrode. Regulation of the formation and composition of SF nanoparticles even allowed egels to be produced from low concentrations of SF solutions (1%). E-gel formation could be reversed, with the aggregated nano- and microspheres dissolving in solution. This is an important ﬁnding with implications in processes such as the in vivo delivery of pharmaceuticals. In neutral aqueous solutions, the overall negative charge of the acidic groups prevents intermolecular association due to repulsive forces. However, application of an electric ﬁeld increases the proton concentration in the region of the positive electrode, eﬀectively shielding the charged acidic groups and permitting assembly of silk ﬁbroin.399 When silk ﬁbroin exists as a random coil, signiﬁcant time and energy are necessary for rearrangement of the hydrophobic and hydrophilic groups in the chains before intermolecular self-assembly and hence gelation can occur. As such, the brief application of the electric ﬁeld does not provide suﬃcient time for gelation to take place. However, once the hydrophobic and hydrophilic domains of the protein chains have reorganized into nanoparticles, the negative charge of the acidic groups hindering intermolecular self-assembly is masked. The nanoparticles then rapidly assembled into an e-gel under the applied electric ﬁeld (Figure 70). At the same time, the hydrophobic and hydrophilic groups were further reorganized to form more regular and tightly packed structures, eﬀectively decreasing the nanoparticle size from tens of nanometers to approximately 10 nm.400

4.4. Other Polymers with 3D Network Structure

An example of a 3D network structure polymer is hydrogels. They have 3D networks consisting of cross-linked hydrophilic polymer molecules. Hydrogels are soft, water-ﬁlled polymer networks; their mechanical properties could be ﬁne-tuned to diﬀerent tissues, and they are materials with FDA approval. Hydrogels have been used extensively in clinical medicine, including in plastic surgery as ﬁllers, and are considered a multimillion dollar market. They have huge potential in the ﬁeld of tissue engineering for a variety of reasons; they have a rubberlike consistency akin to soft tissue, are extremely biocompatible, and allow for convenient regulation of the concentrations of oxygen, nutrients, and other biological substances.401−404 Hydrogels also have been used in a 3D scaﬀold for repair and replacement of organs405 as well as stem cells406 and drug delivery. The conductive hydrogels represent a class of functional materials which combine the soft-wet feature of hydrogels with the electrical properties of CPs. Applications of conductive hydrogels in biomedicine are growing; these currently include chemical sensors/biosensors and medical devices such as conduits for nerve regeneration, cardiac patches, and deep brain stimulation devices. CP hydrogels have received intense interest in terms of research and development, due to their modiﬁable threedimensional (3D) matrix. They are promising candidates for bioelectronics and nanodevices for energy applications, due to their hybrid nature, harboring both a conductive nature and also structural integrity. To achieve their composite nature, cross-linkers are made up of diﬀerent functional groups to

Figure 70. Electrogelation mechanisms. Reprinted with permission from ref 400. Copyright 2011 Elsevier. AV

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Figure 71. Natural SF/PANi (core/shell) coaxial ﬁber schematic illustration. Reprinted with permission from ref 173. Copyright 2013 Elsevier.

Figure 72. Illustration of the water-retaining eﬀect (a) and interaction eﬀect (b) that inﬂuence the release of drugs. Reprinted with permission from ref 408. Copyright 2015 Wiley-VCH Verlag GmbH & Co.

Figure 73. Schematic, chemical formula, and microscopy images of polyaniline (PANi) hydrogel: (A) schematics of the nanoarchitecture, (B) photograph of PANi, (C) scanning electron microscopy (SEM) image of PANi, (D) SEM image at higher magniﬁcation, arrows depicting porous network, (E) transmission electron microscopy (TEM) image of PANi, arrows depicting nanoarchitecture porous network. Reprinted with permission from ref 409. Copyright 2012 National Academy of Sciences.

AW

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Figure 74. E2(SL)6E2GRGDS into nanoﬁber self-assembly: (a) E2(SL)6E2GRGDS chemical structure, (b) peptide dimer repeating unit assembly, a “hydrophobic sandwich”. Reprinted from ref 421. Copyright 2011 American Chemical Society.

high degree of hydration, and easy diﬀusivity to small molecules oﬀered by hydrogels. EHCs thus retain the original biologically advantageous characteristics of their constituent components.416−420 A multidomain peptide (MDP) which self-assembled into nanoﬁbers approximately 2 nm high, 8 nm wide, and micrometers in length when exposed to Mg2+ ions was designed.421 The MDP, E2(SL)6E2GRGDS (Gly-Arg-GlyAsp-Ser) (Figure 74), incorporates negatively charged glutamic acid (E) residues in the A block and utilizes six pairs of alternating serine (S) and leucine (L) to create the amphiphilic B block. It also contains the cell adhesion sequence RGD. While nanoﬁbers invariably form in water, gelation can be induced by various techniques that cause shielding of the negative charges on the glutamic acid residues421 A 1 wt % concentration of peptide facilitates formation of a large nanoﬁbrous network, which eventually yields a cross-linked viscoelastic hydrogel. The hydrogel undergoes shear thinning but rapidly recovers almost 100% of its elastic modulus upon release of the shearing force, making it a suitable injectable material. The nanoﬁbrous hydrogel behaves as a sponge when incubated with human embryonic stem cells (ESCs) by absorbing the diﬀerent growth factors and cytokines released by ESCs. The peptide hydrogel sponge can then be isolated from the ESCs and transferred to a new environment, where it can release these components. In an in vitro experimental model of diabetic nephropathy, the release of ESC secretome from hydrogels was observed to signiﬁcantly reduce protein permeability of glomerular epithelial cells treated with high glucose loads. Tracking experiments where hydrogels labeled with a Gd3+ MRI contrast agent were injected into the abdominal cavity of mice were then conducted to establish the outcome of the hydrogel in vivo. It was concluded that the hydrogel was rigid enough to remain localized and release the ESC secretome over 24 h instead of dissolving immediately in the abdominal cavity. In summary, the ability of nanoﬁbrous MDP hydrogels to recover from deformative stresses as revealed by rheometric assessment, coupled with their absorption and in vivo release of secretome, highlights their therapeutic potential as injectable delivery agents.421 Substantial interest has been seen in microfabrication techniques to create biomaterials that integrate electrode arrays and biofunctional enzyme molecules.422 Here, gold electrode arrays were interfaced with GOx and lactate oxidase (LOX) enzymes by PEG hydrogel photopatterning. In this process, PEG diacrylate (DA)-based prepolymer containing the enzymes and redox species (vinylferrocene) was spin-

bridge conductive polymer chains in the 3D matrix. These diﬀerent functional groups can also serve as dopants to increase the overall electrical conductivity of the resultant product. The chemical and structural attributes of CP hydrogels can be modiﬁed by tuning the manufacturing parameters, such as types of monomers, cross-linkers, solvents, and temperature. It is postulated that the resultant CP hydrogels have superior mechanical and electrical activity due to the synergistic eﬀects of the reactants. Electron ﬂow and ion diﬀusion can occur due to unimpeded pathways and matrix pores, respectively. The large surface area to volume ratio and their ability to function as solvents make CP hydrogels similar to natural gels, thus making them ideal candidates for a wide range of applications, including biosensors, bioelectronics, and wearable/implantable power-management devices.136,407 Ma et al.408 developed a controlled release drug delivery platform composed of polyethylenimine (PEI; which is hydrophilic) and poly(N-isopropylacrylamide) (PNIPAm). It was found that the diameter and the architecture of the pores of PNIPAm are aﬀected by PEI and that PEI also aﬀects the rate of release of water in the resultant product below the lower critical solution temperature (LCST) (Figure 72). This therefore makes a good controlled release platform for drugs at 37 °C (body temperature). Pan et al.409 described a facile technique to synthesize polyaniline (PANi) hydrogel that has hierarchical nanostructural components, and displayed excellent electrochemical attributes (Figure 73). These PANi hydrogels have a 3D porous nanoarchitechture and a high surface area to volume ratio, and showed high cycling stability, speciﬁc capacitance, and rate capability. Their ability to function as biosensors was also ascribed to the fact that they have a high sensitivity and response time to glucose oxidase. However, conductive hydrogels are mechanically weak and brittle, which severely hinders their practical applications for neurological diseases. The photopolymerization process permits ﬁne spatial and temporal regulation of hydrogel formation and can occur under ambient or physiological conditions. Photopolymerized hydrogels produced in this way are currently being used in drug delivery410,411 and cell transplantation.412,413 Electrically conducting hydrogels (ECHs) are a more recent development and are made up of polymeric blends or conetwork biomaterials.414,415 EHCs are particularly promising because they combine the unique optical switching and electrical and redox properties of inherently conducting polymers with the biocompatibility, AX

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evaluation of the possible role of PPy/DNA/CNT hybrid ﬁbers in future electrochemical capacitors and actuators found that the hybrid ﬁber redox response was enhanced by incorporating DNA into the PPy/CNT ﬁlm. The electrochemical capacitance was determined to be approximately 371 F g−1 in aqueous lithium bis[(triﬂuoromethyl)sulfonyl]imide (LiTFSI). The ﬁbers were stable during actuation, showing an expansion and contraction of around 4.41% under a lowvoltage electric ﬁeld (±1 V). The conﬁguration of the DNA/ CNT hydrogel yielded an extensive porous structure with a large actuation response. The use of DNA/CNT hydrogels as a scaﬀold also caused a uniform decrease in the size of PPy particles electrodeposited on the inner and outer surfaces of the hybrid ﬁbers; furthermore, it augmented the mechanical properties of the PPy hybrid ﬁbers, allowing more eﬃcient utilization of the actuation mechanism. The structure and charge transfer mechanism of DNA/PPy/CNT hybrid ﬁbers as the basis for an electrochemical actuator are illustrated schematically in Figure 76. The strong interaction between DNA/CNT and PPy ensures that the entangled hybrid network will form a highly porous ﬁbrous structure. It is thought that an increasing active CP content will further improve the actuation performance of the DNA/PPy/CNT hybrid ﬁbers. Immersion of DNA/PPy/CNTs into LiTFSI solution produces a layer of TFSI− ions and cations from the electrolyte solution on the reduced PPy. The result is an energetically favorable charge transfer complex, with this double layer appearing to make a notable contribution to the improved actuation strain. The comparatively high porosity of the DNA/CNT hydrogel also facilitates the quick electrolyte penetration into the PPy ﬁber surface. In this way, DNA/PPy/ CNT hybrid ﬁbers could form the basis of new materials to be used in the construction of bioengineered muscle.423 The physicochemical characteristics of soft electrode materials to be used at the abio−bio interface of newgeneration biosensors have been analyzed.424 These bioactive devices take the form of electroconductive hydrogels (ECHs), where interpenetrating networks of PPy form within poly(hydroxyethyl methacrylate)-based hydrogels. In this study, 1.5 mol % UV-cross-linked tetraethylene glycol diacrylate (TEGDA), poly(HEMA), and electropolymerized PPy conetworks were covalently linked by the bifunctional monomer (1.5 mol %) 2-(methacryloyloxy)ethyl 4-(3-pyrrolyl)butanate (MPB). The optical absorbance, extent of hydration, frequency-dependent electrical impedance, and elastic modulus were examined as a function of the electropolymerization charge density (ranging from 1 to 900 mC cm−2) used to obtain the linked conetworks. The absorption at 430 nm displayed a monotonic increase with electropolymerization charge density and was associated with an increased elastic modulus (from 56 ± 32 to 499 ± 293 kPa), decreased percentage hydration (from 68% to 0%), and decreased membrane electrical resistance. Polypyrrole was deposited initially at the gel−electrode interface to ﬁll gaps in the hydrogel before eventually encroaching onto the hydrogel surface. Proliferation of attachment-dependent rhabdomyosarcoma (RMS13) and PC-12 cells conformed to this pattern, increasing to a maximum value and subsequently decreasing at higher electropolymerization charge densities.424 Notable results were achieved by reinforcing PVA composite hydrogels with poly(vinylpyrrolidone) (PVP)-wrapped MWCNTs.425 The addition of PVP resulted in homogeneous distribution of the nanotubes and improved the interface

coated, registered, and UV-cross-linked on a gold electrode array. Circular hydrogel structures (600 μm in diameter) embedded with enzyme were thus formed on the surface of the gold electrodes (300 μm in diameter). The use of multiple masks in this photolithography process facilitated immobilization of GOX and LOX molecules on adjacent electrodes within the same electrode array. The response of the biosensor array was linear until a concentration of 20 mM for glucose and 10 mM for lactate, while its sensitivity was 0.9 μA cm−2 mM−1 for glucose and 1.1 μA cm−2 mM−1 for lactose. Furthermore, glucose and lactate could be detected simultaneously from the same electrode array. This integration of the biological and electrical aspects of biosensors allows spatial resolution and registration of diﬀerent biorecognition elements by separate electrodes in a particular array. Future applications of this technology include real-time measurement of changing metabolite concentrations around living cells.422 A degradable electrically conducting hydrogel (DECH)420 was synthesized by combining the photopolymerized macromer acrylated poly(D,L-lactide)−polyethylene glycol−poly(D,Llactide) (AC-PLA-PEG-PLA-AC), glycidyl methacrylate (GMA), ethylene glycol dimethacrylate (EGDMA), and aniline tetramer (AT) through a coupling reaction between AT and GMA (Figure 75). The electrical conductivity and

Figure 75. Electroactive hydrogel schematic synthesis. Reprinted from ref 420. Copyright 2011 American Chemical Society.

swelling behavior of the DECHs could be regulated by adjusting the hydrogel AT composition, extent of cross-linking, and environmental pH. The hydrogels display both degradability and electrical conductivity and are hence a distinct type of biomaterial with unique biomedical applications.420 Synchronized electrochemical linear actuation of CP/CNT hybrid ﬁbers in porous DNA hydrogels may achieve performance enhancement.423 Supramolecular interaction between PPy and DNA appeared to facilitate eﬃcient immobilization of PPy on the inner and outer surfaces of DNA-coated CNTs. An AY

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Figure 76. Idealized schematic illustration of ion diﬀusion in a DNA/PPy/CNT hybrid system during the actuation state: view of the outer surface of DNA/PPy/CNT hybrid ﬁbers and ion diﬀusion on the inner surface of the DNA/PPy/CNT hybrid ﬁbers. Reprinted with permission from ref 423. Copyright 2010 Elsevier.

radical initiation mechanism.427 OPF−PPy scaﬀolds were shown to contain up to 25 mol % polypyrrole, with a compressive modulus varying from 265 to 323 kPa and a sheet resistance varying from 6 to 30 × 103 Ω/sq. In vitro studies with PC-12 cells gave no evidence that OPF−PPy was cytotoxic, with the PC-12 cell population displaying enhanced cell attachment and a higher proportion of neurite-bearing cells on OPF−PPy composites compared to pure OPF. The average neurite length of PC-12 cells was appreciably increased in OPF−PPyNSA and OPF−PPyDBSA matrixes. These results hence indicate that electrically conductive OPF−PPy hydrogels might play an important role in future nerve regeneration attempts.426 A procedure to build a cross-linked hydrogel based on graphene−poly(N,N-dimethylacrylamide) (PDMAA) networks has been described.428 This unique structure displayed high conductivity and neural compatibility, along with prompt photothermal self-healing stimulated by electromagnetic radiation in the near-infrared region; these features could make graphene−PDMAA hydrogels useful as scaﬀolds for artiﬁcial tissue.428 Electrically conductive and soft graphene hydrogels were successfully fabricated by reducing composite hydrogels of GO and PAAm. The resultant hydrogels had a Young modulus of 50 kPa and a conductivity of 10−4 S/cm, and they are expected to be suitable for interfacing with many soft tissues, including muscle. In vitro studies with myoblasts revealed that r(GO/ PAAm) hydrogels could greatly improve myoblast growth and diﬀerentiation. More reduced substrates signiﬁcantly improved growth and diﬀerentiation, compared to less reduced substrates, suggesting that reduction promoted more interactions between myoblasts and the substrate compared to unreduced GO/PAAm. Application of electrical stimuli through the conductive graphene hydrogels revealed signiﬁcant increases in myogenic gene expression levels of myoblasts compared with those of unstimulated controls. Conductive graphene hydrogels can be synthesized by mild chemical reduction of graphene oxide/polyacrylamide (GO/ PAAm), which can be used for skeletal muscle tissue engineering.429 This can also serve as a multifunctional platform that can simultaneously deliver electrical and mechanical cues to biological systems. A spherical gelatin−MWCNT hybrid hydrogel was synthesized by emulsion polymerization in the presence of sodium methacrylate (NaMa) and N,N′-ethylenebis(acrylamide) (EBA).430 The use of gel-based hydrogels as drug delivery microspheres that can release diclofenac sodium salt when subjected to an electric ﬁeld was reported. Gel, NaMa, and

between the nanotubes and the matrix. The mechanical properties of the composite hydrogel improved markedly with the addition of less than 2 wt % PVP-treated MWCNTs, and were strongly inﬂuenced by the CNT concentration and distribution. The composite hydrogel friction coeﬃcient decreased primarily because of the lubricating eﬀect of PVP and was independent of the MWCNT concentration. In summary, it appears that the nonionic surfactant PVP may act synergistically with MWCNTs to facilitate the production and overall performance of PVA composite hydrogels.425 To further the search for materials that could support nerve regeneration, electrically conductive hydrogel composites of oligo(polyethylene glycol) fumarate (OPF) and PPy were manufactured.426 The OPF−PPy scaﬀolds were produced using three distinct anions: dioctyl sulfosuccinate sodium salt (DOSS), dodecylbenzenesulfonic acid sodium salt (DBSA), and naphthalene-2-sulfonic acid sodium salt (NSA). OPF hydrogels were synthesized by reacting fumaryl chloride with polyethylene glycol. The OPF chains (Figure 77) were then cross-linked by free radical polymerization of their fumarate groups. This water-insoluble cross-linked OPF hydrogel provided a scaﬀold for PPy to polymerize (Figure 77) via a

Figure 77. Chemical structures of oligo(polyethylene glycol) fumarate, polypyrrole, and anions dodecylbenzenesulfonic acid sodium salt (DBSA), naphthalene-2-sulfonic acid sodium salt (NSA), and dioctyl sulfosuccinate sodium salt (DOSS) used in the synthesis of OPF−PPy hydrogels. Reprinted from ref 426. Copyright 2010 American Chemical Society. AZ

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Figure 78. Hydrogel schematic: (a) gelatin solution in water, (b) MWNCT dispersion in gelatin solution, (c) GL-NT3 morphology. Initiator system: APS/TEMED. Reprinted with permission from ref 430. Copyright 2013 Elsevier.

nanoﬁbrous scaﬀolds produced by electrospinning have been vastly employed in tissue engineering. The three main components of the electrospinning unit are a high electric potential (5−30 kV), a syringe pump with a syringe attached to a blunt needle, and a collector (Figure 79). First, at applied

EBA were mixed in selected weight ratios to give the starting reaction feed. Evenly distributed MWCNTs in the feed are an essential criterion for attaining high-quality microspheres. As such, MWCNTs were ﬁrst dispersed in a gel aqueous solution by ultrasonication; 2 mL volumes of these solutions were then used as the dispersed aqueous phase in the emulsion polymerization step (Figure 78). Higher MWCNT amounts were disposed of due to water dispersion instability; in contrast, the tested dispersions remained stable over time, with no indication of sedimentation in the six months following preparation.430 In recent work, a novel conductive hydrogel has been used for the early diagnosis of cancer using sensor detecting neuronspeciﬁc enolase (NSE) in human serum samples. The conductive hydrogel used was obtained by a simple crosslinking coordination methodology using 1,3,5-benzenetricarboxylic acid as the ligand and Fe3+ as the gelatinizer and dopant. The as-prepared hydrogel was used as an electrochemical immunosensing substrate for detection of NSE. The proposed immunosensor showed good analytical performance, including acceptable repeatability, stability, and speciﬁcity for NSE.431

Figure 79. Electrospinning technology schematic. Reprinted with permission from ref 11. Copyright 2015 Elsevier.

5. FABRICATION OF THE 3D SCAFFOLD USING THE CONDUCTIVE POLYMER To date, scaﬀolds with bioactivity were constructed using various methods, including solvent casting and particulate leaching, gas foaming, freeze-drying, electrospinning, phase separation, and deposition.11 The development of scaﬀolds displaying conductivity is usually undertaken based on electrospinning and deposition.11

high potential across the needle and the collector with controlled rate, the polymer solution is pumped out of the spinneret. Then, through electromagnetic force, the polymer solution is starched by a high electric ﬁeld, followed by collection of the ﬁbers on a collector plate. The voltage, ﬂow rate, solution charge density, and viscosity are the major parameters during the preparation, which could aﬀect the process of electrospinning and ﬁber morphology. Thus, to obtain suitable ﬁbers, various conditions could be changed for speciﬁc applications. In contrast with natural and synthetic polymers, the fabrication of scaﬀolds using traditional CPs involves problems with solubility; CPs have to be well dispersed in a suitable solvent for electrospinning. 11 Furthermore, it is very diﬃcult to obtain ﬁbers by electrospinning CPs, due to the polymer backbone rigidity and their high charge density.433 Thus, diﬀerent biodegradable and

5.1. Electrospinning

Employed in tissue-associated scaﬀolds, electrospinning is an economical, fast, and simple approach for construction of ﬁbrous scaﬀolds.432 Cells are helped to proliferate, migrate, and diﬀerentiate by electrospun nanoﬁbers which are able to replicate the natural ECM architecture and are characterized by interlinked pores, high surface area-to-volume ratios, and nanoscaled ﬁber diameters. Due to the above reasons, the BA

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with tissues. CPs are being widely studied as suitable candidates for these biomedical devices because of both their electrical behavior and their biocompatibility. Among other applications, CPs have been used as biosensors,85 neural electrodes,454 bioactuators,455 drug delivery systems,456 or tissue scaﬀolds.457,458 For TE purposes, conducting scaﬀolds are intended to display similar features (chemical, mechanical, and topological) to the ECM in native tissues, thus behaving as an adequate substrate onto which cells are able to attach and communicate. Furthermore, their electrical properties can regulate cellular functions, including diﬀerentiation, adhesion, proliferation, and migration, via ES.459 However, CPs exhibit brittleness and poor mechanical properties when used individually. Therefore, the blending of CP with another polymer, generally insulating, results in ﬂexible conducting polymer-based scaﬀolds. Generally, the polymeric matrix embeds CP moieties, thus improving the mechanical stability and processability of the ﬁnal product. To obtain ﬂexible CPbased scaﬀolds that recapitulate the structure and function of the ECM, several approaches have been followed by using diﬀerent polymeric materials as the matrix (elastomers460 and hydrogels)415,461 and microfabrication technology for tailoring topographical and mechanical properties462 and functional nanomaterials, which include nanoﬁbers,463 nanotubes,456 or nanomembranes.464 Interestingly, research pertaining to robust ultrathin membranes made of two macroscopic dimensions and one nanodimension has recently gained attention.465 Although in the past decade several authors have reported selfsupported nanomembranes made of inorganic materials (e.g., silicon, metal, NPs, carbon nanotubes, and grapheme),466,467,427,468,469 the number of studies based on soft materials is still relatively scarce. Recently, a spin-coating method was used to fabricate robust and ﬂexible nanomembranes made of a variety of cross-linked synthetic materials (e.g., inorganic−soft material hybrids, thermosetting resins, and photopolymers).470−474 Nevertheless, the biocompatibility and elasticity of these nanomembranes were not comparable to those of basement membranes, which are amorphous sheetlike structures of ﬁbers that underlie the epithelium and play a critical role in cell proliferation, diﬀerentiation, and migration. Furthermore, free-standing nanomembranes have also been prepared using biopolymers (e.g., polysaccharides, silk, and biodegradable poly(lactic acid)).211,475−477

synthetic polymers, including poly(lactic acid-co-glycolic acid) (PLGA), PCL, poly(L-lactide) (PLLA), silk, and gelatin, are blended in polymer solutions during the process of electrospinning to promote biocompatibility.95,434−437 The overall conductivity of the resulting product is increased due to the small-diameter nanoﬁbers that are blended in the polymer solution during the electrospinning process.438 Coaxial electrospinning could be applied to encapsulate living cells in core−shell ﬁbers; in fact, one group found no detectable damage to the cells after post electrospun cell culturing for 9 days.439 Further improvement of the CP scaﬀold could be expected by coaxial electrospinning through CP encapsulation in the coaxial electrospun ﬁber core. For example, a biopolymer such as collagen could be used in the coaxial electrospun ﬁber core to improve the CP scaﬀold bioactivity. Furthermore, diﬀerent collector types could produce diﬀerent conductive ﬁber patterns. For instance, PPy nanoﬁbers could be aligned by collecting nanoﬁbers with a 2000 rpm rotating drum collector during the electrospinning process.11,440 5.2. Deposition

Diﬀerent conductive material depositions on ﬁber surfaces can be achieved through various approaches, such as in situ polymerization, CVD, sol−gel, and electroless plating.441 In one study, deposition of a thin PANi layer on an electrospun ultraﬁne PMMA ﬁber surface was performed via in situ polymerization with ammonium persulfate as the oxidant.442 A lengthier deposition time resulted in PANi particles aggregating around PMMA ﬁbers. In another study, in situ polymerization and chemical vapor deposition were used to produce PPy−cellulose conducting composite textiles.443 Vapor deposition involved immersion of viscose cellulose textile ﬁber in oxidant and dopant aqueous solution. Polymerization was initiated through exposure of the dried textiles to pyrrole vapor. Unlike fabrics synthesized via in situ polymerization, fabrics synthesized via vapor deposition displayed more homogeneous PPy coating of ﬁber surfaces. In a diﬀerent study, PEDOT, a conducting polymer with higher charge conductivity, was deposited on electrospun polyacrylonitrile nanoﬁbers based on vapor-phase polymerization.444 The process resulted in a highly conductive (close to 60 S cm−1) ultraﬁne nanoﬁbrous mat exhibiting excellent stability. In addition to this, hydrogen bonding among MWCNT carboxyl groups facilitated the deposition of MWCNTs with grafted carboxyl groups on electrospun polyamide 11 (PA11) nanoﬁbers. This indicated that, by melting the ﬁbers at 180 °C, the transmittance could be enhanced.11,445

6.1. Tissue Engineering and Regenerative Medicine

With an aging population, the burdens of fatal diseases such as cancer and organ failure are set to increase. The application of tissue-engineered organs and regenerative medicine such as stem cell and gene delivery to damaged organs are of huge interest to multidisciplinary researchers. The key to success is the development of a functional 3D scaﬀold, thereby highlighting the potential role of CPs due to their conductivity and surface energies. 6.1.1. Neural System. The capability to govern and manipulate engineered self-assembled substrates at the nanoor microscale confers macroscopic physicochemical characteristics otherwise not seen in the bulk material. The outcome of this is a degree of functional integration between the physiological systems and manipulated engineered substrates, which was previously not achievable. The ﬁeld of central nervous system (CNS) neuroprotection and regeneration will signiﬁcantly beneﬁt from progress in nanotechnology, in

6. BIOMEDICAL APPLICATIONS OF CONDUCTIVE POLYMERS CPs have been used in diﬀerent biomedical applications, including actuators,446 biosensors,447 neural prostheses,448,449 wound healing, and controlled release systems.450 Furthermore, CPs have been employed to regulate cell functions via applying ES for electrically excitable cells, including muscle and neuronal cells.89,451 Numerous investigations have shown that ES via a CP signiﬁcantly improves cell spreading and neurite outgrowth.115,451,452 The design of electrically conducting devices for biomedical and biotechnological applications has become a topic of growing interest.453 Fundamentally, these devices use electromagnetic ﬁelds that regulate biological processes to interact BB

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Figure 80. (a) AFM topography of nanodiamond (ND). (b) AFM topography of hydrogen-terminated ND. (c) AFM topography of oxygenterminated ND. (d) 2D ACF of AFM topography from (a). (e) 2D ACF of AFM topography from (b). (f) 2D ACF of AFM topography from (c). (g) 3D AFM topography of (a). (h) 3D AFM topography of (b). (i) 3D AFM topography of (c). Reprinted with permission from ref 647. Copyright 2016 University College London.

mechanical characteristics, nondegradability, and obstacles to processing them into complex 3D structures.99,452,490−493 PPy, one of the most widely investigated CPs for nerve conduit applications, lacks the required mechanical characteristics for sturdy biomaterial. This limitation has driven the search for a hybrid material which employs a host polymer that encompasses the desired physical material characteristics for the composition, while an electrically CP is the guest component that confers electrically conductive characteristics to the resulting product. Recently, various PPy composite materials have been manufactured, intended for nerve regeneration applications. For instance, in some of them, the bulk polymer consists of chitosan, PCL, poly(caprolactone fumarate), poly(lactic acid-co-glycolic acid), or poly(ethyl cyanoacrylate).115,486,494 Recent advances have been highlighted by Guiseppi-Elie in the conductive hydrogel composite materials.415 Another potential approach to incorporate electrical conductivity into the biomaterials includes carbon-based particles such as CNTs; however, it is reported that their in vivo toxicity is related to their functional group, size, and concentration.426,495−498 In addition, a type of stem cell known as a glial cell is based in the PNS, and is known to be crucial for nerve regeneration. It releases bioactive molecules and provides substrates for axonal migration, which regulate axonal outgrowth.499 Numerous investigations showed that seeding nerve conduits with glial cells considerably improved nerve regeneration in the CNS and PNS.500−502 Therefore, research into glial cells has become an integral part of tissue engineering CPs for neural constructs.115,500−503

parallel with advances in neurophysiology, neuropathology, and cell biology. The goal is to enhance the technologies, via multidisciplinary research, to help achieve the neuroprotection tissue integration and active signaling leading to axon growth. In some scenarios, there are requirements to introduce the substrates to the patients by a neurosurgeon. To lead bionanotechnology toward treatment of neurological disorders to its complete potential, it is critical for neurologists, neurosurgeons, and neuroscientists to engage and devote to the scientiﬁc procedure in addition to engineering scientists.478 Debilitating conditions associated with peripheral nervous system (PNS) and CNS damage have fueled a major eﬀort to regenerate injured nerves. The use of autografts is the gold standard therapy for segmental nerve loss, but it has major constraints, such as (1) the challenge of obtaining suﬃcient sizes and lengths of the necessary donor nerve and 2) the complex anatomical misalignment between the grafted and host nerves.479−481 The association of these constraints often precludes complete operative improvement from segmental nerve damage. However, by process engineering, the desired dimensions, mechanical characteristics, and degradation proﬁle of a synthetic scaﬀold could be fabricated. Methods of incorporating stimuli into the polymer-based scaﬀolds have increasingly become critical for nerve regeneration. These stimuli could be electrical or chemical,482,483 topological,484−486 and biological.487,488 Over the recent years, ES has gained interest for promoting axon and neurite extension in vitro451 and nerve regeneration in vivo.489 Moreover, there are constraints on CP-based biomaterials, due to poor BC

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physicochemical, and conductive characteristics, therefore mimicking the ECM architecturally and functionally.506 One of the major causes of heart failure is a myocardial infarction (MI), which leads to cardiac tissue impairment and loss of left ventricular function.507 During massive cardiomyocyte (CM) loss following an MI, the myocardial tissue lacks major intrinsic regenerative capability to replace the lost cells, mainly because of the nonproliferative nature of CMs; therefore, the heart wall muscle impairment becomes permanent.508 As a result, the injected heart pumps chaotically and irregularly, as the action potential impulses and electrical signals are unable to travel normally in the myocardium. Currently, the heart transplantation is the only choice for these patients; although there are a number of methodologies at the basic research level to restore the damaged myocardium, there are none at the clinical level. Existing constraints call for more feasible alternatives, including the application of cardiac constructs to promote recovery from cardiac muscle injury. Cardiac TE is an emerging approach designed to repair and regenerate damaged cardiac tissue by applying cellular transplantation and biomaterial 3D scaﬀolds.509 The major limitation of tissue-engineered myocardial patches for the repair of heart defects is that insulating the polymeric scaﬀold walls hinders the transfer of electrical signals between cardiomyocytes. To overcome this problem, numerous investigations have been conducted in vivo and in vitro, and promising outcomes have been achieved in this respect.506,510 The ideal choices of the 3D scaﬀold for cardiac muscle regeneration are conductive, biocompatible, and viscoelastic materials functionalized with bioactive molecules, genes, or stem cells.511 The recent development of conductive materials for cardiac muscle regeneration has been the use of CNTs or graphene oxide nanoparticles. Using CNTs as ﬁllers in a gelatin− chitosan hydrogel results in conductive materials and in 3D scaﬀolds which act as electrical nanobridges between cardiomyocytes, resulting in enhanced electrical coupling, synchronous beating, and cardiomyocyte function.512 6.1.3. Wound Healing with a Conductive Graphene Nanocomposite 3D Scaﬀold. Chronic nonhealing wounds represent a growing problem due to their high morbidity and cost. Despite recent advances in wound healing, several systemic and local factors can disrupt the weighed physiologic healing process. In this paper, we critically review and discuss the role of nanotechnology in promoting the wound healing process. Nanotechnology-based materials have physicochemical, optical, and biological properties unique from their bulk equivalent. These nanoparticles can be incorporated into scaﬀolds to create nanocomposite smart materials, which promote wound healing through their antimicrobial as well as selective anti- and pro-inﬂammatory and pro-angiogenic properties. Owing to their high surface area, nanoparticles have also been used for drug delivery as well as gene delivery vectors. In addition, nanoparticles aﬀect wound healing by inﬂuencing collagen deposition and realignment and provide approaches for skin regeneration and wound healing. Graphene-based nanoparticles, in particular, have been shown to promote wound healing through their antimicrobial properties.513,514 In addition to these properties, they can be combined with other materials to form nanocomposites, used for stem cell and/or growth factor delivery,515,516 to enhance the bioactivity of materials517 and to promote angiogenesis.518 The intracellular formation of reactive oxygen and nitrogen

Diamond is known for its hardness and chemical resistivity.318,319,327 Furthermore, to suit a speciﬁc device application and biocompatibility,324−326atomic doping can be applied to adjust its surface chemistry.328,329 Many nano- and biomedical applications could beneﬁt from the use of hybrid composite nanomaterials which, unlike any single material, can provide a range of integrated properties.317 In addition to biomedical applications, nanodiamond (ND) is also relevant for shedding light on the little known diamond surface conductivity and electrical spectroscopy of porous rocks due to its dielectric permittivity.347 We have shown504 increased cell viability of SC on functionalized ND coatings for nerve regeneration. We investigated the use of monolayered ND particles for Schwann cell culture, the results of which demonstrated that ND coatings have favorable biological eﬀects on SCs, both hydrogen- and oxygen-terminated ND coatings (Figure 80). Substrate surface characteristics are also reported to inﬂuence short-term Schwann cell adhesion, spreading and proliferation, functionalization, and viability (Figure 81). This ﬁnding can

Figure 81. DNA quantitation of SCs for diﬀerent surface treatments (see Figure 80 for diﬀerent surfaces) for 7 days in culture measured by Hoechst assay. Reprinted with permission from ref 647. Copyright 2016 University College London.

contribute not only to the development of artiﬁcial grafts to improve graft cell integration and nervous system regeneration, but also to the improvement of SC-based cell tissue engineering for neural tissue repair and regeneration. Comparing the surface properties of each surface to the viability of SCs shows that ND coatings, irrespective of functionalization, all support SC attachment and growth and are favorable in comparison to standard TCPS surfaces. Furthermore, oxygen-terminated ND coatings show increased proliferation and metabolism in subconﬂuent growth stages of SCs in comparison to hydrogen-terminated and untreated ND coatings. It is expected that the combination of Schwann cells and NDs will develop into an important tool in tissue engineering for the innovative treatment of nerve regeneration. 6.1.2. Cardiovascular Disorders. In industrialized countries, cardiovascular disease is one of the major causes of death, and it is becoming a main global threat in the 21st century.505 One of the most promising approaches to rehabilitate damaged heart tissue is cardiac TE; the main challenge here is to generate a bioactive substrate with suitable biological, BD

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Figure 82. Collagen−chitosan (COL−CHI) composite ﬁlm modiﬁed with grapheme oxide (GO) and 1-(3-(dimethylamino)propyl)-3ethylcarbodiimide hydrochloride (EDC), termed CC−G−E ﬁlm, was loaded with basic ﬁbroblast growth factor (bFGF) as the development of an eﬃcacious wound healing device. The ﬁlm was tested in an in vivo preclinical animal model. Reprinted with permission from ref 517. Copyright 2017 Elsevier.

interface degradation such that the electrodes are eventually unable to record over time.533,534 By applying interfacial contact between the electrode sites, this issue could potentially be resolved. On the basis of previous studies on the eﬀective lifetime increment of implants and modiﬁed electrode materials at the neural tissue−electrode interface, modiﬁcation with CP coatings has been suggested.51,535−539 Using CPs as a coating can increase the roughness and surface area of the electrode, and this could improve tissue−material contact. After application of the material to the body, the initiative process took place by protein adsorption.540,541 The initial adsorption of proteins may play an important role in directing subsequent interfacial reactions. Numerous studies have been done on protein interaction with artiﬁcial nonelectroactive surfaces at the solid−liquid interface.542 For example, BSA adsorption on polyethylene glycol-modiﬁed PANi was characterized.543,544 PANi is known as one of the promising CPs due to its unique characteristics, including environmental stability, ease of preparation, high synthesis yield, doping process simplicity, and impressive redox recyclability, which facilitate polymer coating fabrication.545 Therefore, it is a promising material for TE.174 6.2.2. DNA. Analysis after the hybridization process would allow DNA sequences to be recognized via biosensors. Applying a method to translate the biological occurrence to electrical signal permits the in situ observation of the hybridization kinetics.447 Over the recent years, the genetics ﬁeld has developed rapidly with the development of new methods, including the polymerase chain reaction (PCR). For instance, the identiﬁcation of DNA sequences that code for diseases is important in medical diagnoses. Therefore, electrochemical biosensors could be used for observation of DNA binding due to their high sensitivity. CPs integrated into these DNA electrochemical biosensors, known as genosensors, could lower the detection limit, decrease the overpotential, and simplify the binding orientation. Traditionally, genosensors are fabricated by covalent attachment of DNA to a GCE. The DNA sequence hybridization is detected by measuring adenine

species, as well as activation of phospho-eNOS and phosphoAkt, is believed to be the underlying mechanism for grapheneinduced angiogenesis and antimicrobial properties.519 The results of these studies conﬁrm the important role graphene NPs can play in wound healing. One group of researchers517 combine collagen−chitosan and graphene to develop a conductive composite ﬁlm (Figure 82). Chitosan is known for its clotting factor of blood with graphene antibacterial as well as angiogenic properties,519 making it an ideal scaﬀold for skin regeneration. The ﬁlm was loaded with basic ﬁbroblast growth factor (bFGF) as the development of an eﬃcacious wound-healing device. On the basis of their results, it was concluded that the ﬁlm operates as a novel drug delivery system and due to its performance in wound remodeling has potential to be developed as a wound dressing material. Our group has developed a new nanocomposite material520 based on functionalized graphene oxide. The composite also eludes nitric oxide to enhance the wound healing.521 The materials are fabricated to a 3D scaﬀold and are currently under investigation for wound healing. 6.2. Biosensors

CPs have been deployed in TE to assist the recovery of the tissues, which are responsive to ES, and biosensors to entrap biomolecules,522 due to their feasible synthesis,523 and superior conductivities and stabilities.11,85,506 For example, PEDOT ﬁlms are promising candidates for biosensing and bioengineering applications because they are negligibly cytotoxic and do not cause inﬂammatory reactions when they are implanted.49 6.2.1. Neural System. Injured nervous systems, healed by implanting biosensors, known as neural prostheses, are currently of intense interest in the research community.524,525 To attain the signal quality and activation of neural cells, there is intimate contact in neural interfaces. Diﬀerent electrically conductive material could be used to fabricate the electrode, such as glassy carbon, gold, 526,527 iridium oxide,528−530 and platinum.531,532 However, the above materials are normally fabricated with smooth surfaces, which do not exhibit strong contact to soft tissues; in addition, ion release from metal electrodes indicates BE

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or guanine oxidation, or by applying an electroactive intercalator, such as ethidium bromide. Intercalators stack between the double-stranded DNA (dsDNA) base pairs; hence, when probe DNA binds with target DNA on the sensor to form dsDNA, the redox signal could be detected where the intercalator is trapped near the electrode. Typically, ssDNA probes are randomly immobilized because the hydrophobic nitrogenous bases and phosphate backbone have multiple interactions with the surface of carbon.546 As the DNA orientation plays a signiﬁcant role in genosensor performance, the DNA immobilization process is of great interest. Probe DNA orientation binding could be facilitated by CP functionalization, which could increase the sensitivity and rate of the electron transfer.547 6.2.3. Retinal. Neuron regeneration in the mammalian CNS rarely occurs, and CNS neurons normally die soon after damage.548,549 On the other hand, the developing mammalian CNS and PNS can regenerate neurites after damage.550 In the adult CNS, numerous investigations have proposed diﬀerent solutions to the challenge of neural regeneration, such as oligodendrocyte myelin glycoprotein,551removing inhibitors in myelin, providing a permissive environment,552 changing the neuron’s intrinsic state,553−556 and myelin-associated glycoprotein. In early neural system development, EA was a key parameter,557 and an internal electric ﬁeld at the damaged sites stimulates and guides the nerve regeneration and heals the wound in vivo.558 Some methods were utilized to repair the environment where ES increases the neurite outgrowth. For instance, it has been illustrated that ES could aﬀect regeneration of neurite orientation,559,560 accelerate motor neuron regeneration,561 induce PC12 cell diﬀerentiation without NGF,562 and increase regeneration of peripheral axons and sensory neurons of the dorsal root ganglion.563,564 It has been shown that when stimulated with physiological ES, surviving retinal ganglion cells (RGCs) in the visual system will extend their axons.565 Also, applying square-shaped pulses to a transected rat optic nerve can considerably promote the RGC density.566 In addition, noninvasive transcorneal ES has been shown to signiﬁcantly increase the length of the regenerating crushed optic nerve as well as the RGC survival rate in axotomized rats in vivo.567,568 In human clinical trials, the visual function of patients with traumatic optic neuropathy or nonarteritic ischemic optic neuropathy has been ameliorated by transcorneal ES with seemingly few drawbacks.569 However, the positive eﬀects of EA on neural regeneration are not without caveats. For instance, by applying various EA patterns to DRG sensory neurons, it has been illustrated that the lamellipodia and ﬁlopodia of the growth cones are retracted after ES, and that the neurite growth rate is inﬂuenced by the frequency and ES pattern.570 It has also been shown that EA loss could be a pivotal signal that triggers axon outgrowth after a peripheral lesion.571 These outcomes indicated that the eﬀectiveness of ES on neural regeneration ultimately depends on a suitable pattern of EA being used.572−574 6.2.4. Metabolic Markers of Stress. Electrochemical biosensors are very convenient devices for monitoring medical diagnostics. The development of low-cost and versatile biosensors for the accurate, sensitive, and rapid detection of human metabolites could be of huge interest for both general practitioners (GPs) and specialized hospital doctors alike.575

Previous studies concentrated on various biomolecules that are electroactive and dependent on electrochemical detection. However, at practical redox potentials, many biomolecules are not electroactive and thus cannot be detected by traditional electrochemical methods. Redox enzymes are integrated into the sensor to detect these nonelectroactive molecules. Enzymes have a very high aﬃnity and speciﬁcity for substrates. Some enzyme sensors detect enzymatic electroactive byproduct reactions, while others detect electrons tunneled to the surface of the electrode. Carbon-based materials could be augmented to the enzyme sensors either for the electrocatalytic eﬀects of H2O2 or glucose detection or to more eﬃciently tunnel electrons to an enzyme. For instance, galactose, acetylcholine, ethanol, lactate, glucose, cholesterol, and glutamate are some of the common compounds which have been detected.547 6.2.4.1. Hematocrit. The percentage of whole blood volume occupied by red blood cells is called the hematocrit,576 which gives an indication of the oxygen-carrying capacity of whole blood.577,578 In relation to ischemic diseases to assess the delivery of oxygen, it is one the main properties of blood cells.579 To evaluate kidney, cardiovascular, and cerebral disease fatality risk, it has been considered as an oxygen carrying capacity marker of the blood associated with whole blood viscosity.580−583 Characterization of blood conductivity can be performed via electrochemical impedance spectroscopy (EIS).576,584−591 This is related to the red cell intracellular resistance, erythrocyte sedimentation, plasma resistance, and red cell membrane capacitance.576,591 There is, however, a degree of inaccuracy when using EIS for hematocrit measurement.576,584−586,588,591 Experiments have been done to study plasma resistance to minimize the electrolyte eﬀect by applying ac voltage within the range of ∼1 kHz to 1 GHz.576,591−594 This method improved the precision of the measurement for plasma resistance. Although the electrolyte concentration continued to aﬀect the plasma resistivity, this degree of inaccuracy was less than that of dc signal.576,594−596 6.2.4.2. Lactate. Lactic acid is deprotonated to form the lactate ion, which is a fermentation product created through pyruvate oxidation during anaerobic glucose metabolism. The blood lactate concentration is normally 1−2 mM; however, this could rise due to exercise or disease. The high lactate concentration could lessen the pH of the blood, which could harm the muscle tissue.597 In postoperative patients and patients with sepsis, monitoring the lactate is of great importance. The feasibility of a lactate-sensitive CNT electrode has been investigated with the use of PPy polymerization.598 The enzyme sensor contained lactate oxidase (LOx), which generates H2O2 and oxidizes lactate. The H2O2 could oxidize PPy and catalyze polymerization. LOx operates as a polymer nucleation site, the same as the CNTs, entrapping each in the polymer layer. The limit of detection (LOD) was 1 M, and indirect H2O2 detection was employed. Furthermore, via lactate dehydrogenase (LDH), NADH generated from the lactate oxidation has been detected at a CNT electrode. LDH coimmobilization and the mediator Meldola’s Blue on MWCNTs by gluteraldehyde cross-linking (LDH−MB− MWCNTs) were employed.599 The LDH−MB−MWCNTs were attached to a paste electrode with mineral oil and displayed properties comparable to those of the electrode. Alternatively, cross-linked chitosan lactate dehydrogenase and MWCNTs were immobilized on a glassy carbon electrode.600 BF

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also be oxidized. A more appropriate method might use amperometric enzyme sensors incorporating speciﬁc enzymes for the electrochemical detection of glucose, which provides real-time temporal selectivity and resolution. Carbon-based materials and CPs are often included in sensors to increase the sensitivity and electron transfer kinetics. The most common techniques for attaching CPs to sensor surfaces include deposition, covalent attachment, and adsorption in a polymer layer. Electrodes could be fabricated with conductive polymer that is intrinsically part of the electrode material and enzymes that are subsequently deposited on the surface. GOx, a common enzyme used on electrodes,547 catalyzes glucose oxidation on the basis of the following reaction:625

It was shown that the sensor had superior surface antifouling characteristics.547 6.2.4.3. Tissue Oxygenation. In biological systems, one of the major parameters measured in tissue oxygenation is the partial pressure of oxygen (pO2).601−605 To understand the underlying cellular events and to detect possible pathology, it is useful to measure the pO2.606,607 Various methods have been described to measure pO2.608−612 One of the most popular methods is the polarographic electrode technique, which is based on amperometry; however, another promising option based on photochemical quenching is the ﬁber-optic method.613 These methods are considered the least invasive; however, at the measurement time, the probe has to be inserted into the target location in the tissue. Reproducibility of the measurements is one of the main drawbacks for the electrode methods. In addition, during the process of measurement itself, the existence of the oxygen adjacent to the probe may vary the oxygen measurement. Since the desirable method for pO2 measurement is permanent implantable or noninvasive probes, various noninvasive methods based on principles of magnetic resonance, including electron paramagnetic resonance (EPR) oximetry, blood oxygen level dependent (BOLD) MRI, nuclear magnetic resonance imaging (MRI), Overhauser-enhanced MRI (OMRI), and EPR oxygen mapping (EPROM), have been investigated.610,614−617 For instance, in EPROM, the oxygen spatial distribution could be evaluated by the spectral-spatial EPR imaging method applying soluble oximetry probes.617 Furthermore, the soluble probes conﬁne their metabolic conversion to nonparamagnetic particles, or are cleared by excretion in in vivo systems. Therefore, they are not suitable for long-term pO2 tracking in tissues. In contrast, the solid probes appear superior to the soluble ones. The solid probes are characterized by tissue stability, minimal toxicity, and higher sensitivity for oximetry. More importantly, solid probes report pO2 from a small volume surrounding the probe, a phenomenon which enables spectroscopic characterization. In addition, the solid probe may remain in the implanted location for long periods of time, thus allowing repeated tissue pO2 characterization for several weeks after implantation. Three diﬀerent types of EPR oximetry probes have been identiﬁed, including crystalline materials,618 natural coal and its derivatives,619 and synthetic amorphous carbon-based materials.620,621 Examples of crystalline materials which have been well characterized include microcrystalline powders622,623and lithium phthalocyanine (LiPc) crystals.618 Although LiPc probes displayed desirable oximetery characteristics, due to power saturation of the radio frequency (rf) signal, their use in EPR oximetry is perhaps limited. For instance, the EPR absorption of LiPc crystalline particles saturated with a ∼0 dBm (1 mW) power level at 1.3 GHz therefore precluded the use of higher powers for signal enhancement.624 6.2.4.4. Glucose. Due to the redox enzyme availability and biological importance for detection, most research is concentrated upon enzyme electrodes. On the basis of an estimate by the Center for Disease Control and Prevention (CDC), the diabetes prevalence in the U.S. population has increased from 12 million in 2000 to 16.3 million in 2005 and to 20.8 million in 2010. Thus, fast, sensitive, and inexpensive glucose monitoring is required at about 3−8 mM physiological concentrations. Glucose direct amperometric detection is problematic, because of its prohibitively high oxidation potential, at which many other interfering molecules would

β‐D‐glucose + O2 → D‐glucose‐1,5‐lactone + H 2O2 + e−

The above reaction could be followed indirectly, by measuring H2O2 concentrations, or directly, by measuring electrons transferred to GOx. Glucose dehydrogenase (GDH) could be used for indirect biosensors. GDH catalyzes the reaction626 β‐D‐glucose + NAD+ → D‐glucose‐1,5‐lactone + NADH + e−

The obtained NADH could be detected electrochemically, which is related to the glucose concentration. Graphene has been used in enzyme immobilization and enzymatic biosensing applications because its layer count may have an impact on the conductivity. For example, one investigation focused on the electrochemical performance of graphene electrodes consisting of a diﬀerent number of layers which, to detect the model analyte glucose, immobilized the enzyme glucose oxidase.627 It was found that diﬀerent layered graphenes showed identical sensitivity and electrochemical performance toward the detection of glucose. Graphene electrodes with single or multiple layers immobilized a comparable glucose oxidase quantity. The ﬁndings revealed that enzyme conjugation and the electrochemical response during electroanalysis were largely unaﬀected by the layer count of the graphene structure.627 This application would not be possible if individual 2D graphene sheets were not incorporated into macroscopic structures.264,628,629 The high water content in conductive polymer hydrogels mimics the extracellular physiological system. Harnessing the power of hydrogels and organic conductors, conductive polymer hydrogels can function as biosensors with a high degree of ﬁdelity, acting as a bioelectrical platform for electrochemical reactions. For instance, they can function as a reaction platform for an artiﬁcial inorganic electrode and a biomaterial, an electronic platform for electron and ionic charge carriers, and an extrapolation of a two-dimensional (2D) surface to a three-dimensional (3D) electrical structure. Conductive polymer hydrogels have numerous applications, such as conferring biocompatibility to electrodes and controlling processes such as enzyme immobilization, electron transference, and diﬀusion630 (Figure 83). Li et al.631 utilized a platinum nanoparticle-based conductive polymer hydrogel to manufacture a biosensor. This biosensor has the ability to detect various metabolites with high sensitivity and low response times. These metabolites were detected in wide linear ranges and at low sensing limits, such as triglycerides (0.2−5 mM), cholesterol (0.3−9 mM), and uric acid (0.07−1 mM). BG

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CPs and help the ﬁeld move forward to the clinical stage. Therefore, one can reasonably expect to see more research on corona adsorption to CPs in the coming years. Due to their unique electrical properties, CPs may have a crucial role in overcoming several potentially problematic issues caused by the protein corona (e.g., the mistargeting eﬀect of corona). An example is the side eﬀect of the protein corona on the targeting eﬃcacy of nanoparticles. One of the main goals in nanomedicine is to engineer NPs capable of in vivo targeting for both imaging and delivery of therapeutic biomolecules in the human body. One way to produce a high targeting yield is to functionalize the NP surface with targeting ligands, such as antibodies or aptamers, which by receptormediated endocytosis enhance NP binding to receptors on the target cells to facilitate NP uptake. However, it was found that the protein corona can mask the targeting species at the surface of NPs and induce mistargeting, leading to the lower targeting yields and unfavorable distribution in the body.639,640 To overcome this critical issue, one possibility is to probe the feasibility of engineering NPs to direct protein corona composition for active targeting. For example, it was shown that precoating of the NPs with some speciﬁc proteins could recruit preferred proteins in a biological ﬂuid to facilitate targeting.637 By exploiting the unique electrical properties of CPs, one would be able to direct the formation of the corona structure by recruiting speciﬁc proteins in the corona composition.

Figure 83. Schematic diagram of conductive polymer hydrogels (CPHs) functioning as high-performance biosensors. Reprinted from ref 630. Copyright 2015 American Chemical Society.

A platinum nanoparticle polyaniline hydrogel conductive polymer was developed by Zhai et al.,632 which had the ability to detect glucose. Brieﬂy, platinum nanoparticles were incorporated into a 3D nanoarchitecture of polyaniline hydrogel matrix. This hybrid biosensor utilizes the attributes of the conducting ability of the hydrogel and the catalytic nature of the platinum nanoparticle to synergistically produce a favorable response. In essence, the enzyme was able to be immobilized, and water-soluble molecules could penetrate the conductive polymer hydrogel, serving as a catalyst for the oxidation of glucose. Furthermore, the conductive polymer hydrogel also served as a catalyst for hydrogen peroxide decomposition. The electrochemical signals from the reaction were thereby controlled by the conductive polymer hydrogel with a high degree of sensitivity (96.1 μA mM−1 cm−2), fast response time (3 s), low detection limit (0.7 μM), and linear range (0.01−8 mM).

7. CONCLUSION AND FUTURE PERSPECTIVE A comprehensive overview of various CPs and their advantages and associated challenges, from synthesis to applications, were fully discussed. To bring CPs into clinical practice, there are some major limitations, which should be properly addressed, including their processability, cytotoxicity, considerable gap between in vitro and in vivo outcomes, and suboptimal mechanical and magnetic properties. Thanks to new technologies (e.g., nanotechnology and the 3D printing technique), some of the predetermined limitations (e.g., magnetic and mechanical properties) are being resolved. However, the major obstacle, which is the huge gap between in vitro and in vivo results, needs to be addressed in the future. There is a lack of knowledge with regard to the interactions of CPs with proteins (the protein corona decoration on CPs); such knowledge can help researchers in the ﬁeld not only to better predict the biological fate of CPs, but also to diminish the gap between in vitro and in vivo outcomes. Taking advantage of the unique properties of CPs, one may expect to direct the corona decoration in vivo, thus facilitating new exciting biomedical applications for these polymers. Fine-tuning the mechanical properties and biocompatibility of CPs is a major challenge in surgical implant applications such as coating electrodes for deep brain stimulation or medical devices for insertion inside biological tissues and organs. This problem has been partially solved with nontoxic chemical functionalization of conductive nanoparticles to enhance their integration into biological tissues. There are some nonbiodegradable CPs functionalized with graphene oxide which seem promising. However, when it comes to bioabsorbable CPs, diﬀerent limitations are seen due to the inherent inability of CPs to degrade naturally. Attempts have been made to circumvent these problems by blending degradable materials such as polycaprolactone, polylactide, and polyglycolide and their copolymers or ester link-

6.3. Protein Corona

When nanomaterials are exposed to a biological ﬂuid/ environment, their surfaces will be covered by a layer comprising a variety of proteins, called a “protein corona”.633−636 The protein corona confers a new identity to the nanomaterials, which could be substantially diﬀerent from their pristine state.633,634,636 Therefore, when cells come into contact with the resulting nanoparticles, it is their coronacoated mask that interacts with the cells. In essence, there are two diﬀerent types of coronas: soft and hard coronas. The soft corona is formed within a few seconds after the interaction of nanoparticles with the protein environment. It is reversibly and loosely attached proteins. This layer will be replaced by a hard corona, which is irreversibly, and more tightly, attached proteins. The composition of the protein corona in terms of amount, type, and conformation of the proteins at the particle surface can essentially dictate the particle biodistribution and macrophage uptake.637 For example, if complement proteins and opsonin-based proteins are associated in corona composition, the particles would be removed by the immune system and end up in the liver or spleen. If carrier proteins, such as albumin, have rich contributions in the corona structure, then one could expect them to have a long blood circulation time. If other speciﬁc proteins such as ApoE come into the corona composition, the particles then can penetrate the blood−brain barrier and reach the brain tissue.638 Although much of the published literature focuses on the protein corona on the surface of various materials, published reports on the corona decoration at the surface of CPs are few and far between. Such corona knowledge can substantially enhance our prediction capability of the in vivo behavior of the BH

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ages.504,641,642 Seifalian et al. proposed an alternative to create a CP using a conductive nanoparticle nanostructure holding the scaﬀold while the backbone of the bulk CP was degraded,504,643 allowing a controllable degradation rate. Nevertheless, more in-depth in vivo studies on the degradation kinetics of bioabsorbable CPs and their nanotoxicology status must be robustly evaluated before embarking on more ambitious undertakings such as clinical trials in humans. Evidently, the application of CPs for use in human biological tissue is still in its nascent stages, although the rate and volume of publications pertaining to their use in biomedicine appear promising. Conventional biosensors face limitations, including slow response, low selectivity, and high detection limit, which opens the possibilities of using nanobiosensors based on CP nanomaterials. Overall application of CPs in biomedicine, especially with surgical implants and tissue engineering, remains challenging, and progress has been slow due to multidisciplinary science lagging behind research and development. Currently, there are large numbers of multidisciplinary centers growing at universities as well as in industries, working toward same goals to overcome the above-mentioned challenges. Another ﬁeld that may see substantial improvement in the near future is the application of CPs in tissue engineering using 3D printing. This approach may promote the emergence of a new type of “smart” artiﬁcial tissue with proper processability, mechanical properties, biocompatibility, and excellent tissue function. The unique electrical conductivity of polymers can signiﬁcantly enhance the possibility of cell engraftment to the artiﬁcial tissue and also trigger cell proliferation, which is a key determinant of success in our quest for the development of novel CPs for biomedical applications. Graphene plays huge role in the generation of CPs.520 The superior properties of graphene nanomaterial and its derivatives lead to some interesting biomedical applications, and dramatic progress has been made in this direction in recent times. The potential applications of graphene oxidebased conductive materials include drugs.

poly[3,4-(ethylenedioxy)thiophene] (PEDOT) that is highly conductive (4100 S/cm) and stretchable (at 100% strain). This was achieved by combining electrical conductivity enhancers and ionic additives. Recently, researchers have manufactured highly stretchable semiconductor polymers by utilization of the nanoconﬁnement eﬀect.138 Brieﬂy, they developed a technique called conjugated polymer/elastomer phase separation-induced elasticity (COPHINE), which enables the creation of nanoscale conjugated polymers with low crystallinity and high chain dynamics in the matrix to facilitate mobility during stretching. These stretchable CPs have the potential for many applications, including bioprosthetic skin.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Phone: +44 2076 911 122 or +44 7985 380 797. ORCID

Alexander M. Seifalian: 0000-0002-8334-9376 Notes

The authors declare no competing ﬁnancial interest. Biographies Toktam Nezakati is currently working for Google Inc. Before joining Google, she was a postdoctoral research assistant at the Department of Radiology at Stanford University. She obtained her B.Eng. in electronic engineering from the University of Surrey in England, M.Sc. in nanotechnology from San Francisco State University, and Ph.D. in nanotechnology and conductive biomaterials at University College London (UCL) in England. Her research interests are in carbonbased nanocomposites and conductive polymers for biomedical applications. Aaron Tan has completed his i.B.Sc., medical degree, and Ph.D. at the University College London (UCL) with a clinician-scientist training program. His Ph.D. research was in nanotechnology and bioengineering at UCL supervised by Professor Seifalian with Industrial Link Pharmidex Ltd., London. He is also concurrently a visiting scholar at the Biomaterials & Advanced Drug Delivery Laboratory (BioADD) at Stanford University. His research interests are in the ﬁeld of nanoscience for neuroengineering and neurosurgery.

7.1. Ongoing Development of Conductive Polymers

The concept of bioprosthetic skin that utilizes stretchable CPs is currently an exciting topic that has gained signiﬁcant traction in academic research. The hurdle in creating bioprosthetic skin with a high degree of ﬁdelity and similarity to real human skin is multifactorial. For instance, the technology involving siliconbased electronics has advanced to such a stage that it can be highly stretchable with a high degree of density and conditioned output; however, integrated signal processing has not quite kept up in terms of advancement.644,645 Organic and carbon-based ﬂexible electronics are seen as potential candidates for bioprosthetic skin. Current topics that are being researched include complementary metal-oxide semiconductors (CMOSs), complementary circuits, and short channels for intelligent power-eﬃcient devices. Techniques such as optogenetics, nanoengineering, and single-cell neuronal contact are being explored as potential avenues for making artiﬁcial skin more humanlike. These techniques are considered superior in transmitting signals to neurons from high-density arrays.644,645 CPs that are highly stretchable with the ability to change morphology and behave as conductivity-enhancing dopants were recently described by Wang et al.646 They developed a

Alexander Seifalian, Professor of Nanotechnology and Regenerative Medicine, worked at the Royal Free Hospital and University College London for over 27 years. During this time, he spent a period of time at Harvard Medical School looking at the cause of cardiovascular diseases and a year at Johns Hopkins Medical School looking at treatments of the liver. He has published more than 647 peerreviewed research papers and registered 14 U.K. and international patents. He is currently CEO of NanoRegMed Ltd., working on the commercialization of his research. During his career, Prof. Seifalian has led and managed many large projects with successful outcomes in terms of commercialization and translation to patients. In 2007, he was awarded the top prize in the ﬁeld for the development of nanomaterials and technologies for cardiovascular implants by Medical Future Innovation, and in 2009, he received a Business Innovation Award from UK Trade & Investment (UKTI). He was the European Life Science Awards’ winner of Most Innovative New Product 2012 for the “synthetic trachea”. Prof. Seifalian won the Nanosmat Prize in 2013, and in 2016, he received the Distinguished Research Award in recognition of his outstanding work in regenerative medicine from Heales Healthy Life Extension Society. BI

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His achievements include the development of the world’s ﬁrst synthetic trachea, lacrimal drainage conduit, and vascular bypass graft using nanocomposite materials, bioactive molecules, and stem cell technology. He has over 15000 media reports of his achievements, including BBC, ITV, WSJ, CNN, and many more. Currently, he is working on development and commercialization of human organs using graphene-based nanocomposite materials and stem cell technology. His current project is the development of conductive nanocomposite biomaterials for deep brain stimulation. Applications include treatment for Alzheimer’s and Parkinson’s diseases.

Self-Organization of Complex Systems. Chem. Rev. 2009, 109, 6275− 6540. (14) Yashima, E.; Maeda, K.; Iida, H.; Furusho, Y.; Nagai, K. Helical Polymers: Synthesis, Structures, and Functions. Chem. Rev. 2009, 109, 6102−6211. (15) Akagi, K. Helical Polyacetylene: Asymmetric Polymerization in a Chiral Liquid-Crystal Field. Chem. Rev. 2009, 109, 5354−5401. (16) Liu, J.; Lam, J. W. Y.; Tang, B. Z. Acetylenic Polymers: Syntheses, Structures, and Functions. Chem. Rev. 2009, 109, 5799− 5867. (17) Nagai, K.; Masuda, T.; Nakagawa, T.; Freeman, B. D.; Pinnau, I. Poly[1-(Trimethylsilyl)-1-Propyne] and Related Polymers: Synthesis, Properties and Functions. Prog. Polym. Sci. 2001, 26, 721−798. (18) Masuda, T.; Higashimura, T. Synthesis of High Polymers from Substituted Acetylenes: Exploitation of Molybdenum- and TungstenBased Catalysts. Acc. Chem. Res. 1984, 17, 51−56. (19) Mao, Y.; Xu, H. P.; Zhao, H.; Yuan, W. Z.; Qin, A.; Yu, Y.; Faisal, M.; Xiao A, Z.; Sun, J. Z.; Tang, B. Z. Composites of Quaternized Poly(pyridylacetylene) and Silver Nanoparticles: Nanocomposite Preparation, Conductivity and Photoinduced Patterning. J. Mater. Chem. 2011, 21, 13627−13633. (20) Shirakawa, H. Nobel Lecture: The Discovery of Polyacetylene Filmthe Dawning of an Era of Conducting Polymers. Rev. Mod. Phys. 2001, 73, 713−718. (21) Hu, X.; Wang, P.; Yang, J.; Zhang, B.; Li, J.; Luo, J.; Wu, K. Enhanced Electrochemical Detection of Erythromycin Based on Acetylene Black Nanoparticles. Colloids Surf., B 2010, 81, 27−31. (22) Li, M.; Qi, Y.; Ding, Y.; Zhao, Q.; Fei, J.; Zhou, J. Electrochemical Sensing Platform Based on the Quaternized Cellulose Nanoparticles/acetylene Black/enzymes Composite Film. Sens. Actuators, B 2012, 168, 329−335. (23) Tsou, T.; Lee, C.; Chiu, H. K and Au Bicatalyst Assisted Growth of Carbon Nanocoils from Acetylene: Effect of Deposition Parameters on Field Emission Properties. ACS Appl. Mater. Interfaces 2012, 4, 6505−6511. (24) Li, G.; Ji, Z.; Wu, K. Square Wave Anodic Stripping Voltammetric Determination of Pb2+ Using Acetylene Black Paste Electrode Based on the Inducing Adsorption Ability of I−. Anal. Chim. Acta 2006, 577, 178−182. (25) Jannakoudakis, A. D.; Jannakoudakis, P. D.; Pagalos, N.; Theodoridou, E.; Besenhard, J. O. Preparation And Behaviour of Acetylene Black Press-Electrodes As Adsorbents And Metal Catalysts Supports. Electrochim. Acta 1996, 41, 449−453. (26) Yang, X.; Wang, F.; Hu, S. High Sensitivity Voltammetric Determination of Sodium Nitroprusside at Acetylene Black Electrode in the Presence of CTAB. Colloids Surf., B 2007, 54, 60−66. (27) Yazhen, W.; Hongxin, Q.; Siqian, H.; Junhui, X. A Novel Methyl Parathion Electrochemical Sensor Based on Acetylene Black− chitosan Composite Film Modified Electrode. Sens. Actuators, B 2010, 147, 587−592. (28) Sun, D.; Zhang, H. Electrochemical Determination of 2Chlorophenol Using an Acetylene Black Film Modified Glassy Carbon Electrode. Water Res. 2006, 40, 3069−3074. (29) Zhang, H. Electrochemistry and Voltammetric Determination of Colchicine Using an Acetylene Black-Dihexadecyl Hydrogen Phosphate Composite Film Modified Glassy Carbon Electrode. Bioelectrochemistry 2006, 68, 197−201. (30) Aguiló-Aguayo, I.; Hossain, M. B.; Brunton, N.; Lyng, J.; Valverde, J.; Rai, D. K. Pulsed Electric Fields Pre-Treatment of Carrot Purees to Enhance Their Polyacetylene and Sugar Contents. Innovative Food Sci. Emerging Technol. 2014, 23, 79−86. (31) Lin, L.; Yang, J.; Lin, R.; Yu, L.; Gao, H.; Yang, S.; Li, X. In Vivo Study on the Monoamine Neurotransmitters and Their Metabolites Change in the Striatum of Parkinsonian Rats by Liquid Chromatography with an Acetylene Black Nanoparticles Modified Electrode. J. Pharm. Biomed. Anal. 2013, 72, 74−79. (32) Schopf, G.; Kossmehl, G. Polythiophenes - Electrically Conductive Polymers. Adv. Polym. Sci. 1997, 129. DOI: 10.1007/ BFb0111619

ACKNOWLEDGMENTS We acknowledge the contribution and comments from Dr. Morteza Mahmoudi, Department of Nanotechnology, Tehran University of Medical Sciences, Tehran, Iran, and Department of Medicine, Stanford University School of Medicine, California. REFERENCES (1) Hodgson, A. J.; Gilmore, K.; Small, C.; Wallace, G. G.; Mackenzie, I. L.; Aoki, T.; Ogata, N. Reactive Supramolecular Assemblies of Mucopolysaccharide, Polypyrrole and Protein as Controllable Biocomposites for a New Generation Of “intelligent biomaterials. Supramol. Sci. 1994, 1, 77−83. (2) Karagkiozaki, V.; Karagiannidis, P. G.; Gioti, M.; Kavatzikidou, P.; Georgiou, D.; Georgaraki, E.; Logothetidis, S. Bioelectronics Meets Nanomedicine for Cardiovascular Implants: PEDOT-Based Nanocoatings for Tissue Regeneration. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 4294−4304. (3) Povlich, L. K.; Cho, J. C.; Leach, M. K.; Corey, J. M.; Kim, J.; Martin, D. C. Synthesis, Copolymerization and Peptide-Modification of Carboxylic Acid-Functionalized 3,4-Ethylenedioxythiophene (EDOTacid) for Neural Electrode Interfaces. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 4288−4293. (4) Yang, B.; Yao, F.; Hao, T.; Fang, W.; Ye, L.; Zhang, Y.; Wang, Y.; Li, J.; Wang, C. Development of Electrically Conductive DoubleNetwork Hydrogels via One-Step Facile Strategy for Cardiac Tissue Engineering. Adv. Healthcare Mater. 2016, 5, 474−488. (5) Martins, A. M.; Eng, G.; Caridade, S. G.; Mano, J. F.; Reis, R. L.; Vunjak-Novakovic, G. Electrically Conductive Chitosan/Carbon Scaffolds for Cardiac Tissue Engineering. Biomacromolecules 2014, 15, 635−643. (6) Zhou, J.; Chen, J.; Sun, H.; Qiu, X.; Mou, Y.; Liu, Z.; Zhao, Y.; Li, X.; Han, Y.; Duan, C. Engineering the Heart: Evaluation of Conductive Nanomaterials for Improving Implant Integration and Cardiac Function. Sci. Rep. 2015, 4, 3733. (7) Lakshmanan, R.; Krishnan, U.; Sethuraman, S. Polymeric Scaffold Aided Stem Cell Therapeutics for Cardiac Muscle Repair and Regeneration. Macromol. Biosci. 2013, 13, 1119−1134. (8) Gerard, M.; Chaubey, A.; Malhotra, B. D. Application of Conducting Polymers to Biosensors. Biosens. Bioelectron. 2002, 17, 345−359. (9) Park, A. R.; Kim, J. S.; Kim, K. S.; Zhang, K.; Park, J.; Park, J. H.; Lee, J. K.; Yoo, P. J. Si-Mn/reduced graphene oxide nanocomposite anodes with enhanced capacity and stability for lithium-ion batteries. ACS Appl. Mater. Interfaces 2014, 6, 1702−8. (10) Green, R. A.; Baek, S.; Poole-Warren, L. A.; Martens, P. J. Conducting Polymer-Hydrogels for Medical Electrode Applications. Sci. Technol. Adv. Mater. 2010, 11, 014107. (11) Jin, G.; Li, K. The Electrically Conductive Scaffold as the Skeleton of Stem Cell Niche in Regenerative Medicine. Mater. Sci. Eng., C 2014, 45, 671−681. (12) Lam, J. W. Y.; Tang, B. Z. Functional Polyacetylenes. Acc. Chem. Res. 2005, 38, 745−754. (13) Rosen, B. M.; Wilson, C. J.; Wilson, D. A.; Peterca, M.; Imam, M. R.; Percec, V. Dendron-Mediated Self-Assembly, Disassembly, and BJ

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(33) Leclerc, M.; Faid, K. Electrical and Optical Properties of Processable Polythiophene Derivatives: Structure-Property Relationships. Adv. Mater. 1997, 9, 1087−1094. (34) Yamamoto, T.; Sanechika, K.; Yamamoto, A. Preparation of Thermostable and Electric-Conducting poly(2,5-Thienylene). J. Polym. Sci., Polym. Lett. Ed. 1980, 18, 9−12. (35) Feast, W. J.; Tsibouklis, J.; Pouwer, K. L.; Groenendaal, L.; Meijer, E. W. Synthesis, Processing and Material Properties of Conjugated Polymers. Polymer 1996, 37, 5017−5047. (36) Ten Hoeve, W.; Wynberg, H.; Havinga, E. E.; Meijer, E. W. Substituted 2,2’:5′,2’’:5′’,2’’’:5′’’,2’’’’:5′’’’,2’’’’’: 5′’’’’,2’’’’’’:5′’’’’’,2’’’’’’’:5′’’’’’’,2’’’’’’’’: 5′’’’’’’’,2’’’’’’’’’:5′’’’’’’’’,2’’’’’’’’’’ -undecithiophenes, the Longest Characterized Oligothiophenes. J. Am. Chem. Soc. 1991, 113, 5887−5889. (37) Garnier, F.; Deloffre, F.; Horowitz, G.; Hajlaoui, R. Structure Effect on Transport of Charge Carriers in Conjugated Oligomers. Synth. Met. 1993, 57, 4747−4754. (38) Yin, W.; Li, J.; Gu, T.; Wu, J. Design and Synthesis of Conducting Secondary Crosslinked Interpenetrating Polymer Network. J. Appl. Polym. Sci. 1997, 63, 13−16. (39) Glenis, S.; Benz, M.; LeGoff, E.; Kanatzidis, M. G.; DeGroot, D. C.; Schindler, J. L.; Kannewurf, C. R. Electrochemical Synthesis and Electronic Properties of poly(3,4-Dibutyl-α-Terthiophene). Synth. Met. 1995, 75, 213−221. (40) Zotti, G.; Salmaso, R.; Gallazzi, M. C.; Marin, R. A. In Situ Conductivity of a Polythiophene from a Branched Alkoxy-Substituted Tetrathiophene. Enhancement of Conductivity by Conjugated CrossLinking of Polymer Chains. Chem. Mater. 1997, 9, 791−795. (41) Laakso, J.; Ö sterholm, J.-E.; Nyholm, P. Conducting Polymer Blends. Synth. Met. 1989, 28, 467−471. (42) Isotalo, H.; Ahlskog, M.; Stubb, H.; Laakso, J.; Kärnä, T.; Jussila, M.; Ö sterholm, J.-E. Stability of Processed poly(3-Octylthiophene) and Its Blends. Synth. Met. 1993, 57, 3581−3586. (43) Meador, M. A. B.; Hardy-Green, D.; Auping, J. V.; Gaier, J. R.; Ferrara, L. A.; Papadopoulos, D. S.; Smith, J. W.; Keller, D. J. Optimization of Electrically Conductive Films: Poly(3-Methylthiophene) or Polypyrrole in Kapton. J. Appl. Polym. Sci. 1997, 63, 821− 834. (44) Kiesow, A.; Heilmann, A. Deposition and Properties of Plasma Polymer Films Made from Thiophenes. Thin Solid Films 1999, 343− 344, 338−341. (45) Choukourov, A.; Pleskunov, P.; Nikitin, D.; Titov, V.; Shelemin, A.; Vaidulych, M.; Kuzminova, A.; Solař, P.; Hanuš, J.; Kousal, J.; Kylián, O.; Slavínská, D.; Biederman, H. Advances And Challenges In The Field Of Plasma Polymer Nanoparticles. Beilstein J. Nanotechnol. 2017, 8, 2002−2014. (46) Groenewoud, L. M. H.; Engbers, G. H. M.; Terlingen, J. G. A.; Wormeester, H.; Feijen, J. Pulsed Plasma Polymerization of Thiophene. Langmuir 2000, 16, 6278−6286. (47) Cui, X.; Hetke, J. F.; Wiler, J. a.; Anderson, D. J.; Martin, D. C. Electrochemical Deposition and Characterization of Conducting Polymer polypyrrole/PSS on Multichannel Neural Probes. Sens. Actuators, A 2001, 93, 8−18. (48) Yang, J.; Martin, D. C. Impedance Spectroscopy and Nanoindentation of Conducting poly(3,4-Ethylenedioxythiophene) Coatings on Microfabricated Neural Prosthetic Devices. J. Mater. Res. 2006, 21, 1124−1132. (49) Luo, S.; Ali, E. M.; Tansil, N. C.; Yu, H.; Gao, S.; Kantchev, E. A. B.; Ying, J. Y. Poly(3,4-Ethylenedioxythiophene) (PEDOT) Nanobiointerfaces: Thin, Ultrasmooth, and Functionalized PEDOT Films with in Vitro and in Vivo Biocompatibility. Langmuir 2008, 24, 8071−8077. (50) Kim, D.-H.; Richardson-Burns, S. M.; Hendricks, J. L.; Sequera, C.; Martin, D. C. Effect of Immobilized Nerve Growth Factor on Conductive Polymers: Electrical Properties and Cellular Response. Adv. Funct. Mater. 2007, 17, 79−86. (51) Richardson-Burns, S. M.; Hendricks, J. L.; Foster, B.; Povlich, L. K.; Kim, D.-H.; Martin, D. C. Polymerization of the Conducting

Polymer poly(3,4-Ethylenedioxythiophene) (PEDOT) around Living Neural Cells. Biomaterials 2007, 28, 1539−1552. (52) Barisci, J. N.; Hughes, D.; Minett, A.; Wallace, G. G. Characterisation and Analytical Use of a Polypyrrole Electrode Containing Anti-Human Serum Albumin. Anal. Chim. Acta 1998, 371, 39−48. (53) Campbell, T. E.; Hodgson, A. J.; Wallace, G. G. Incorporation of Erythrocytes into Polypyrrole to Form the Basis of a Biosensor to Screen for Rhesus (D) Blood Groups and Rhesus (D) Antibodies. Electroanalysis 1999, 11, 215−222. (54) Gooding, J. J.; Wasiowych, C.; Barnett, D.; Hibbert, D. B.; Barisci, J. N.; Wallace, G. G. Electrochemical Modulation of AntigenAntibody Binding. Biosens. Bioelectron. 2004, 20, 260−268. (55) Richardson, R. T.; Thompson, B.; Moulton, S.; Newbold, C.; Lum, M. G.; Cameron, A.; Wallace, G.; Kapsa, R.; Clark, G.; O’Leary, S. The Effect of Polypyrrole with Incorporated Neurotrophin-3 on the Promotion of Neurite Outgrowth from Auditory Neurons. Biomaterials 2007, 28, 513−523. (56) Groenendaal, B. L.; Jonas, F.; Freitag, D.; Pielartzik, H.; Reynolds, J. R. Poly(3,4-Ethylenedioxythiophene) and Its Derivatives: Past, Present, and Future. Adv. Mater. 2000, 12, 481−494. (57) Dietrich, M.; Heinze, J.; Heywang, G.; Jonas, F. Electrochemical and Spectroscopic Characterization of Polyalkylenedioxythiophenes. J. Electroanal. Chem. 1994, 369, 87−92. (58) Pei, Q.; Zuccarello, G.; Ahlskog, M.; Inganas, O. Electrochromic and Highly Stable Poly (3,4-Ethylenedioxythiophene) Switches between Opaque Blue-Black and Transparent Sky Blue. Polymer 1994, 35, 1347−1351. (59) Winter, I.; Reese, C.; Hormes, J.; Heywang, G.; Jonas, F. The Thermal Ageing of poly(3,4-Ethylenedioxythiophene). An Investigation by X-Ray Absorption and X-Ray Photoelectron Spectroscopy. Chem. Phys. 1995, 194, 207−213. (60) Fabiano, S.; Tran-Minh, C.; Piro, B.; Dang, L. A.; Pham, M. C.; Vittori, O. Poly 3,4-Ethylenedioxythiophene as an Entrapment Support for Amperometric Enzyme Sensor. Mater. Sci. Eng., C 2002, 21, 61−67. (61) Kros, B. A.; van Hövell, S. W. F. M.; Sommerdijk, N. A. J. M.; Nolte, R. J. M. Poly(3,4-Ethylenedioxythiophene)-Based Glucose Biosensors. Adv. Mater. 2001, 13, 1555−1557. (62) Nien, P.-C.; Tung, T.-S.; Ho, K.-C. Amperometric Glucose Biosensor Based on Entrapment of Glucose Oxidase in a Poly(3,4Ethylenedioxythiophene) Film. Electroanalysis 2006, 18, 1408−1415. (63) Setti, L.; Fraleoni-Morgera, A.; Ballarin, B.; Filippini, A.; Frascaro, D.; Piana, C. An Amperometric Glucose Biosensor Prototype Fabricated by Thermal Inkjet Printing. Biosens. Bioelectron. 2005, 20, 2019−2026. (64) Piro, B.; Dang, L. A.; Pham, M. C.; Fabiano, S.; Tran-minh, C. A Glucose Biosensor Based on Modified-Enzyme Incorporated within Electropolymerised poly(3,4-Ethylenedioxythiophene) (PEDT) Films. J. Electroanal. Chem. 2001, 512, 101−109. (65) Zotti, G.; Zecchin, S.; Schiavon, G.; Louwet, F.; Groenendaal, L.; Crispin, X.; Osikowicz, W.; Salaneck, W.; Fahlman, M. Electrochemical and XPS Studies toward the Role of Monomeric and Polymeric Sulfonate Counterions in the Synthesis, Composition, and Properties of Poly (3, 4-Ethylenedioxythiophene). Macromolecules 2003, 36, 3337−3344. (66) Briggs, D.; Beamson, G. XPS Studies of the Oxygen Is and 2s Levels in a Wide Range of Functional Polymers. Anal. Chem. 1993, 65, 1517−1523. (67) Beamson, G.; Briggs, D. High Resolution XPS of Organic Polymers: The Scienta ESCA300 Database; John Wiley & Sons: New York, 1992. (68) Briggs, D. Surface Analysis of Polymers by XPS and Static SIMS; Cambridge University Press: Cambridge, U.K., 1998. (69) Spanninga, S. A.; Martin, D. C.; Chen, Z. X-Ray Photoelectron Spectroscopy Study of Counterion Incorporation in Poly(3,4Ethylenedioxythiophene). J. Phys. Chem. C 2010, 114, 14992−14997. (70) Zhao, H.; Zhu, B.; Luo, S.-C.; Lin, H.-A.; Nakao, A.; Yamashita, Y.; Yu, H. Controlled Protein Absorption and Cell Adhesion on BK

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

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Review

Polymer-Brush- Grafted Poly(3,4-Ethylenedioxythiophene) Films. ACS Appl. Mater. Interfaces 2013, 5, 4536−4543. (71) Xu, J.; Peng, R.; Ran, Q.; Xian, Y.; Tian, Y.; Jin, L. A Highly Soluble poly(3,4-Ethylenedioxythiophene)-Poly(styrene Sulfonic acid)/Au Nanocomposite for Horseradish Peroxidase Immobilization and Biosensing. Talanta 2010, 82, 1511−1515. (72) Zhao, H.; Zhu, B.; Sekine, J.; Luo, S.-C.; Yu, H.-H. Oligoethylene-Glycol-Functionalized Polyoxythiophenes for Cell Engineering: Syntheses, Characterizations, and Cell Compatibilities. ACS Appl. Mater. Interfaces 2012, 4, 680−686. (73) Li, D.-F.; Wang, H.-J.; Fu, J.-X.; Wang, W.; Jia, X.-S.; Wang, J.Y. Preparation of a Hydrophobic Polythiophene Film to Improve Protein Adsorption and Proliferation of PC 12 Cells. J. Phys. Chem. B 2008, 112, 16290−16299. (74) Shaytan, A. K.; Schillinger, E.-K.; Khalatur, P. G.; MenaOsteritz, E.; Hentschel, J.; Borner, H. G.; Bauerle, P.; Khokhlov, A. R. Self-Assembling Nanofibers from Thiophene-Peptide Diblock Oligomers: A Combined Experimental and Computer Simulations Study. ACS Nano 2011, 5, 6894−6909. (75) Zhang, L.; Duan, X.; Wen, Y.; Xu, J.; Yao, Y.; Lu, Y.; Lu, L.; Zhang, O. Electrochemical Behaviors of Roxithromycin at poly(3,4Ethylenedioxythiophene) Modified Gold Electrode and Its Electrochemical Determination. Electrochim. Acta 2012, 72, 179−185. (76) Markham, A.; Faulds, D. Roxithromycin An Update of Its Antimicrobial Activity, Pharmacokinetic Properties and Therapeutic Use. Drugs 1994, 48, 297−326. (77) Kirst, H. A. Recent Developments with Macrolide Antibiotics. Expert Opin. Ther. Pat. 1998, 8, 111−120. (78) Qi, M.; Wang, P.; Cong, R.; Yang, J. Simultaneous Determination of Roxithromycin and Ambroxol Hydrochloride in a New Tablet Formulation by Liquid Chromatography. J. Pharm. Biomed. Anal. 2004, 35, 1287−1291. (79) Guimard, N. K. E.; Sessler, J. L.; Schmidt, C. E. Toward a Biocompatible and Biodegradable Copolymer Incorporating Electroactive Oligothiophene Units. Macromolecules 2009, 42, 502−511. (80) Groenewoud, L. M. H.; Engbers, G. H. M.; Feijen, J. Plasma Polymerization of Thiophene Derivatives. Langmuir 2003, 19, 1368− 1374. (81) Malmstrom, J.; Nieuwoudt, M. K.; Strover, L. T.; Hackett, A.; Laita, O.; Brimble, M. A.; Williams, D. E.; Travas-Sejdic, J. Grafting from Poly(3,4-Ethylenedioxythiophene): A Simple Route to Versatile Electrically Addressable Surfaces. Macromolecules 2013, 46, 4955− 4965. (82) You, J.; Heo, J. S.; Kim, J.; Park, T.; Kim, B.; Kim, H.-S.; Choi, Y.; Kim, H. O.; Kim, E. Noninvasive Photodetachment of Stem Cells on Tunable Conductive Polymer Nano Thin Films: Selective Harvesting and Preserved Differentiation Capacity. ACS Nano 2013, 7, 4119−4128. (83) Li, X.-G.; Huang, M.-R.; Duan, W.; Yang, Y.-L. Novel Multifunctional Polymers from Aromatic Diamines by Oxidative Polymerizations. Chem. Rev. 2002, 102, 2925−3030. (84) Wang, L.-X.; Li, X.-G.; Yang, Y.-L. Preparation, Properties and Applications of Polypyrroles. React. Funct. Polym. 2001, 47, 125−139. (85) Guimard, N. K.; Gomez, N.; Schmidt, C. E. Conducting Polymers in Biomedical Engineering. Prog. Polym. Sci. 2007, 32, 876− 921. (86) Fonner, J. M.; Schmidt, C. E.; Ren, P. A Combined Molecular Dynamics and Experimental Study of Doped Polypyrrole. Polymer 2010, 51, 4985−4993. (87) Wong, J. Y.; Langer, R.; Ingber, D. E. Electrically Conducting Polymers Can Noninvasively Control the Shape and Growth of Mammalian Cells. Proc. Natl. Acad. Sci. U. S. A. 1994, 91, 3201−3204. (88) Li, X.; Kolega, J. Effects of Direct Current Electric Fields on Cell Migration and Actin Filament Distribution in Bovine Vascular Endothelial Cells. J. Vasc. Res. 2002, 39, 391−404. (89) Nishizawa, M.; Nozaki, H.; Kaji, H.; Kitazume, T.; Kobayashi, N.; Ishibashi, T.; Abe, T. Electrodeposition of Anchored Polypyrrole Film on Microelectrodes and Stimulation of Cultured Cardiac Myocytes. Biomaterials 2007, 28, 1480−1485.

(90) Gelmi, A.; Higgins, M. J.; Wallace, G. G. Quantifying Fibronectin Adhesion with Nanoscale Spatial Resolution on Glycosaminoglycan Doped Polypyrrole Using Atomic Force Microscopy. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 4305−4313. (91) Mîndroiu, M.; Ungureanu, C.; Ion, R.; Pîrvu, C. The Effect of Deposition Electrolyte on Polypyrrole Surface Interaction with Biological Environment. Appl. Surf. Sci. 2013, 276, 401−410. (92) Ramanavicius, A.; Finkelsteinas, A.; Cesiulis, H.; Ramanaviciene, A. Electrochemical Impedance Spectroscopy of Polypyrrole Based Electrochemical Immunosensor. Bioelectrochemistry 2010, 79, 11−16. (93) Zheng, L. Y.; Congdon, R. B.; Sadik, O. A.; Marques, C. N. H.; Davies, D. G.; Sammakia, B. G.; Lesperance, L. M.; Turner, J. N. Electrochemical Measurements of Biofilm Development Using Polypyrrole Enhanced Flexible Sensors. Sens. Actuators, B 2013, 182, 725−732. (94) Nita, I. I.; Abu-Rabeah, K.; Tencaliec, A. M.; Cosnier, S.; Marks, R. S. Amperometric Biosensor Based on the ElectroCopolymerization of a Conductive Biotinylated-Pyrrole and Alginate-Pyrrole. Synth. Met. 2009, 159, 1117−1122. (95) Aznar-Cervantes, S.; Roca, M. I.; Martinez, J. G.; MeseguerOlmo, L.; Cenis, J. L.; Moraleda, J. M.; Otero, T. F. Fabrication of Conductive Electrospun Silk Fibroin Scaffolds by Coating with Polypyrrole for Biomedical Applications. Bioelectrochemistry 2012, 85, 36−43. (96) Shamaeli, E.; Alizadeh, N. Nanostructured Biocompatible Thermal/electrical Stimuli-Responsive Biopolymer-Doped Polypyrrole for Controlled Release of Chlorpromazine: Kinetics Studies. Int. J. Pharm. 2014, 472, 327−338. (97) Mattioli-Belmonte, M.; Gabbanelli, F.; Marcaccio, M.; Giantomassi, F.; Tarsi, R.; Natali, D.; Callegari, a.; Paolucci, F.; Biagini, G. Bio-Characterisation of Tosylate-Doped Polypyrrole Films for Biomedical Applications. Mater. Sci. Eng., C 2005, 25, 43−49. (98) Shi, G.; Zhang, Z.; Rouabhia, M. The Regulation of Cell Functions Electrically Using Biodegradable Polypyrrole−polylactide Conductors. Biomaterials 2008, 29, 3792−3798. (99) Shi, G.; Rouabhia, M.; Wang, Z.; Dao, L. H.; Zhang, Z. A Novel Electrically Conductive and Biodegradable Composite Made of Polypyrrole Nanoparticles and Polylactide. Biomaterials 2004, 25, 2477−2488. (100) Li, Y.; Neoh, K. G.; Cen, L.; Kang, E. T. Porous and Electrically Conductive Polypyrrole-Poly(vinyl Alcohol) Composite and Its Applications as a Biomaterial. Langmuir 2005, 21, 10702− 10709. (101) An, K. H.; Jeong, S. Y.; Hwang, H. R.; Lee, Y. H. Enhanced Sensitivity of a Gas Sensor Incorporating Single-Walled Carbon Nanotube−Polypyrrole Nanocomposites. Adv. Mater. 2004, 16, 1005−1009. (102) Fan, L.-Z.; Maier, J. High-Performance Polypyrrole Electrode Materials for Redox Supercapacitors. Electrochem. Commun. 2006, 8, 937−940. (103) Pillai, R. G.; Zhao, J. H.; Freund, M. S.; Thomson, D. J. FieldInduced Carrier Generation in Conjugated Polymer Semiconductors for Dynamic, Asymmetric Junctions. Adv. Mater. 2008, 20, 49−53. (104) Pedrosa, V. A.; Luo, X.; Burdick, J.; Wang, J. Nanofingers” based on Binary Gold-Polypyrrole Nanowires. Small 2008, 4, 738− 741. (105) Jang, J.; Yoon, H. Formation Mechanism of Conducting Polypyrrole Nanotubes in Reverse Micelle Systems. Langmuir 2005, 21, 11484−11489. (106) Jang, J.; Yoon, H. Multigram-Scale Fabrication of Monodisperse Conducting Polymer and Magnetic Carbon Nanoparticles. Small 2005, 1, 1195−1199. (107) Li, X.-G.; Wei, F.; Huang, M.-R.; Xie, Y.-B. Facile Synthesis and Intrinsic Conductivity of Novel Pyrrole Copolymer Nanoparticles with Inherent Self-Stability. J. Phys. Chem. B 2007, 111, 5829−5836. (108) Li, X.-G.; Hou, Z.-Z.; Huang, M.-R.; Moloney, M. G. Efficient Synthesis of Intrinsically Conducting Polypyrrole Nanoparticles BL

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

Containing Hydroxy Sulfoaniline as Key Self-Stabilized Units. J. Phys. Chem. C 2009, 113, 21586−21595. (109) Kim, J. W.; Cho, C. H.; Liu, F.; Choi, H. J.; Joo, J. Physical Characteristics of Aniline/pyrrole Copolymer. Synth. Met. 2003, 135− 136, 17−18. (110) Tran, H. D.; Shin, K.; Hong, W. G.; D’Arcy, J. M.; Kojima, R. W.; Weiller, B. H.; Kaner, R. B. A Template-Free Route to Polypyrrole Nanofiber. Macromol. Rapid Commun. 2007, 28, 2289− 2293. (111) Li, X. G.; Huang, M. R.; Xie, Y. B. Synthesis, Properties and Application of Conducting PPY Nanoparticles. In NanoScience in Biomedicine; Shi, D., Ed.; Springer Press: Berlin, 2009; Chapter 22; pp 568−587. (112) Li, X.-G.; Li, A.; Huang, M.-R.; Liao, Y.; Lu, Y.-G. Efficient and Scalable Synthesis of Pure Polypyrrole Nanoparticles Applicable for Advanced Nanocomposites and Carbon Nanoparticles. J. Phys. Chem. C 2010, 114, 19244−19255. (113) Jerome, C.; Jerome, R. Electrochemical Synthesis of Polypyrrole Nanowires. Angew. Chem., Int. Ed. 1998, 37, 2488−2490. (114) Schmidt, C. E.; Shastri, V. R.; Vacanti, J. P.; Langer, R. Stimulation of Neurite Outgrowth Using an Electrically Conducting Polymer. Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 8948−8953. (115) Huang, J.; Hu, X.; Lu, L.; Ye, Z.; Zhang, Q.; Luo, Z. Electrical Regulation of Schwann Cells Using Conductive Polypyrrole/chitosan Polymers. J. Biomed. Mater. Res., Part A 2010, 93, 164−174. (116) Bax, D. V.; Tipa, R. S.; Kondyurin, A.; Higgins, M. J.; Tsoutas, K.; Gelmi, A.; Wallace, G. G.; Mckenzie, D. R.; Weiss, A. S.; Bilek, M. M. Cell Patterning via Linker-Free Protein Functionalization of an Organic Conducting Polymer (Polypyrrole) Electrode. Acta Biomater. 2012, 8, 2538−2548. (117) Cruz-Silva, R.; Amaro, E.; Escamilla, A.; Nicho, M. E.; Sepulveda-Guzman, S.; Arizmendi, L.; Romero-Garcia, J.; CastillonBarraza, F. F.; Farias, M. H. Biocatalytic Synthesis of Polypyrrole Powder, Colloids, and Films Using Horseradish Peroxidase. J. Colloid Interface Sci. 2008, 328, 263−269. (118) Tang, H.; Chen, L.; Xing, C.; Guo, Y. G.; Wang, S. DNATemplated Synthesis of Cationic Poly (3, 4-ethylenedioxythiophene) Derivative for Supercapacitor Electrodes. Macromol. Rapid Commun. 2010, 31, 1892−1896. (119) Chen, W.; Schuster, G. B. Precise Sequence Control in Linear and Cyclic Copolymers of 2, 5-Bis (2-Thienyl) Pyrrole and Aniline by DNA-Programmed Assembly. J. Am. Chem. Soc. 2013, 135, 4438− 4449. (120) Wang, G.; Tanaka, H.; Hong, L.; Matsuo, Y.; Niikura, K.; Abe, M.; Matsumoto, K.; Ogawa, T.; Ijiro, K. Novel Charge Transport in DNA-Templated Nanowires. J. Mater. Chem. 2012, 22, 13691−13697. (121) Pearson, A. C.; Liu, J.; Pound, E.; Uprety, B.; Woolley, A. T.; Davis, R. C.; Harb, J. N. DNA Origami Metallized Site Specifically to Form Electrically Conductive Nanowires. J. Phys. Chem. B 2012, 116, 10551−10560. (122) Ghanbari, K.; Bathaie, S. Z.; Mousavi, M. F. Electrochemically Fabricated Polypyrrole Nanofiber-Modified Electrode as a Newelectrochemical DNA Biosensor. Biosens. Bioelectron. 2008, 23, 1825− 1831. (123) Lei, Y.; Qian, X.; Shen, J.; An, X. Integrated Reductive/ Adsorptive Detoxification of Cr(VI)- Contaminated Water by Polypyrrole/Cellulose Fiber Composite. Ind. Eng. Chem. Res. 2012, 51, 10408−10415. (124) Pelto, J. M.; Haimi, S. P.; Siljander, A. S.; Miettinen, S. S.; Tappura, K. M.; Higgins, M. J.; Wallace, G. G. Surface Properties and Interaction Forces of Biopolymer-Doped Conductive Polypyrrole Surfaces by Atomic Force Microscopy. Langmuir 2013, 29, 6099− 6108. (125) Pickholz, M.; Oliveira, O. N., Jr.; Skaf, M. S. Interactions of Chlorpromazine with Phospholipid Monolayers: Effects of the Ionization State of the Drug. Biophys. Chem. 2007, 125, 425−434. (126) Ramanavičius, A.; Kaušaitė, A.; Ramanavičienė, A. Polypyrrole-Coated Glucose Oxidase Nanoparticles for Biosensor Design. Sens. Actuators, B 2005, 111−112, 532−539.

(127) Mermilliod, N.; Tanguy, J.; Petiot, F. A Study of Chemically Synthesized Polypyrrole as Electrode Material for Battery Applications. J. Electrochem. Soc. 1986, 133, 1073−1079. (128) de Mel, A.; Oh, J. T.; Ramesh, B.; Seifalian, A. M. Biofunctionalized Quantum Dots For Live Monitoring of Stem Cells: Applications in Regenerative Medicine. Regener. Med. 2012, 7, 335−47. (129) Oh, E. J.; Jang, K. S.; MacDiarmid, A. G. High Molecular Weight Soluble Polypyrrole. Synth. Met. 2001, 125, 267−272. (130) Ramanavicius, A.; Habermüller, K.; Csöregi, E.; Laurinavicius, V.; Schuhmann, W. Polypyrrole-Entrapped Quinohemoprotein Alcohol Dehydrogenase. Evidence for Direct Electron Transfer via Conducting-Polymer Chains. Anal. Chem. 1999, 71, 3581−3586. (131) Habermü ller, K.; Ramanavicius, A.; Laurinavicius, V.; Schuhmann, W. An Oxygen-Insensitive Reagentless Glucose Biosensor Based on Osmium-Complex Modified Polypyrrole. Electroanalysis 2000, 12, 1383−1389. (132) Hu, W.-W.; Hsu, Y.-T.; Cheng, Y.-C.; Li, C.; Ruaan, R.-C.; Chien, C.-C.; Chung, C.-A.; Tsao, C.-W. Electrical Stimulation to Promote Osteogenesis Using Conductive Polypyrrole Films. Mater. Sci. Eng., C 2014, 37, 28−36. (133) Forciniti, L.; Ybarra, J.; Zaman, M. H.; Schmidt, C. E. Schwann Cell Response on Polypyrrole Substrates upon Electrical Stimulation. Acta Biomater. 2014, 10, 2423−2433. (134) Pan, L.; Chortos, A.; Yu, G.; Wang, Y.; Isaacson, S.; Allen, R.; Shi, Y.; Dauskardt, R.; Bao, Z. An Ultra-Sensitive Resistive Pressure Sensor Based on Hollow-Sphere Microstructure Induced Elasticity in Conducting Polymer Film. Nat. Commun. 2014, 5, 3002. (135) Wang, Y.; Shi, Y.; Pan, L.; Ding, Y.; Zhao, Y.; Li, Y.; Shi, Y.; Yu, G. Dopant-Enabled Supramolecular Approach for Controlled Synthesis of Nanostructured Conductive Polymer Hydrogels. Nano Lett. 2015, 15, 7736−7741. (136) Zhao, F.; Shi, Y.; Pan, L.; Yu, G. Multifunctional Nanostructured Conductive Polymer Gels: Synthesis, Properties, and Applications. Acc. Chem. Res. 2017, 50, 1734−1743. (137) Shi, Y.; Ma, C.; Peng, L.; Yu, G. Conductive “smart” hybrid Hydrogels with PNIPAM and Nanostructured Conductive Polymers. Adv. Funct. Mater. 2015, 25, 1219−1225. (138) Xu, J.; Wang, S.; Wang, G. J. N.; Zhu, C.; Luo, S.; Jin, L.; Gu, X.; Chen, S.; Feig, V. R.; To, J. W. F.; et al. Highly Stretchable Polymer Semiconductor Films through the Nanoconfinement Effect. Science 2017, 355, 59−64. (139) Díez-Pascual, A. M.; Díez-Vicente, A. L. High-Performance Aminated Poly(phenylene sulfide)/ZnO Nanocomposites. ACS Appl. Mater. Interfaces 2014, 6, 10132−10145. (140) Lan, Y.-F.; Hsieh, B.-Z.; Lin, H.-C.; Su, Y.-A.; Chan, Y.-N.; Lin, J.-J. Poly(N-Isopropylacrylamide)-Tethered Silicate Platelets for Colloidal Dispersion of Conjugated Polymers with Thermoresponsive and Photoluminescence Properties. Langmuir 2010, 26, 10572− 10577. (141) Lovera, D.; Ruckdäschel, H.; Göldel, A.; Behrendt, N.; Frese, T.; Sandler, J. K. W.; Altstädt, V.; Giesa, R.; Schmidt, H.-W. Tailored Polymer Electrets Based on poly(2,6-Dimethyl- 1,4-Phenylene Ether) and Its Blends with Polystyrene. Eur. Polym. J. 2007, 43, 1195−1201. (142) Mihov, G.; Grebel-Koehler, D.; Lubbert, A.; Vandermeulen, G. W. M.; Herrmann, A.; Klok, H.-A.; Mullen, K. Polyphenylene Dendrimers as Scaffolds for Shape-Persistent Multiple Peptide Conjugates. Bioconjugate Chem. 2005, 16, 283−293. (143) Mondeshki, M.; Mihov, G.; Graf, R.; Spiess, H. W.; Mullen, K.; Papadopoulos, P.; Gitsas, A.; Floudas, G. Self-Assembly and Molecular Dynamics of Peptide-Functionalized Polyphenylene Dendrimers. Macromolecules 2006, 39, 9605−9613. (144) You, J.; Heo, J. S.; Lee, J.; Kim, H.-S.; Kim, H. O.; Kim, E. A Fluorescent Polymer for Patterning of Mesenchymal Stem Cells. Macromolecules 2009, 42, 3326−3332. (145) He, Q.; Wang, Y.; Alfeazi, I.; Sadeghi, S. Electrochemical Nucleophilic Synthesis of Di-Tert-Butyl-(4-[18F]fluoro-1,2-Phenylene)-Dicarbonat. Appl. Radiat. Isot. 2014, 92, 52−57. BM

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(146) Hasani-Sadrabadi, M. M.; Emami, S. H.; Moaddel, H. Preparation and Characterization of Nanocomposite Membranes Made of poly(2,6-Dimethyl-1,4-Phenylene Oxide) and Montmorillonite for Direct Methanol Fuel Cells. J. Power Sources 2008, 183, 551−556. (147) Weil, T.; Wiesler, U. M.; Herrmann, A.; Bauer, R.; Hofkens, J.; De Schryver, F. C.; Mullen, K. Polyphenylene Dendrimers with Different Fluorescent Chromophores Asymmetrically Distributed at the Periphery. J. Am. Chem. Soc. 2001, 123, 8101−8108. (148) Mihov, G.; Scheppelmann, I.; Mullen, K. Toward Nanoamphiphiles: Efficient Synthesis of Desymmetrized Polyphenylene Dendrimers. J. Org. Chem. 2004, 69, 8029−8037. (149) Bernhardt, S.; Baumgarten, M.; Mullen, K. Dendritic Encapsulation − “Postsynthetic” Functionalizations of a Single Benzophenone Shielded by Shape-Persistent Polyphenylene Dendrons. Eur. J. Org. Chem. 2006, 2006, 2523−2529. (150) Patel, N. G.; Sreeram, A.; Venkatanarayanan, R. I.; Krishnan, S.; Yuya, P. A. Elevated Temperature Nanoindentation Characterization of Poly(para-Phenylene Vinylene) Conjugated Polymer Films. Polym. Test. 2015, 41, 17−25. (151) Yoo, J.; Kwon, T.; Sarwade, B. D.; Kim, Y.; Kim, E. Multistate Fluorescence Switching of S-Triazine-Bridged P-Phenylene Vinylene Polymers. Appl. Phys. Lett. 2007, 91, 241107−241109. (152) Cho, H.; Kim, E. Highly Fluorescent and Photochromic Diarylethene Oligomer Bridged by P-Phenylenevinylene. Macromolecules 2002, 35, 8684−8687. (153) Pankov, R.; Yamada, K. M. Fibronectin at a Glance. J. Cell Sci. 2002, 115, 3861−3863. (154) Groth, T.; Altankov, G.; Klosz, K. Adhesion of Human Peripheral Blood Lymphocytes Is Dependent on Surface Wettability and Protein Preadsorption. Biomaterials 1994, 15, 423−428. (155) Rich, A.; Crick, F. H. C. The Structure of Collagen. Nature 1955, 176, 915−916. (156) He, W.; Ma, Z.; Yong, T.; Teo, W. E.; Ramakrishna, S. Fabrication of Collagen-Coated Biodegradable Polymer Nanofiber Mesh and Its Potential for Endothelial Cells Growth. Biomaterials 2005, 26, 7606−7615. (157) Grzesik, W. J.; Robey, P. G. Bone Matrix RGD Glycoproteins : Immunolocalization and Interaction with Human Primary Osteoblastic Bone Cells In Vitro. J. Bone Miner. Res. 1994, 9, 487−496. (158) Kargirwar, S. R.; Thakare, S. R.; Choudhary, M. D.; Kondawar, S. B.; Dhakate, S. R. Morphology and Electrical Conductivity of Self-doping Polyanilines Synthesized via Selfassembly Process. Adv. Mater. Lett. 2011, 2, 397−401. (159) Tiwari, A.; Kumar, R.; Prabaharan, M.; Pandey, R. R.; Kumari, P.; Chaturvedi, A.; Mishra, A. K. Nanofibrous Polyaniline Thin Film Prepared by Plasma-Induced Polymerization Technique for Detection of NO2 Gas. Polym. Adv. Technol. 2010, 21, 615−620. (160) Long, Y.; Chen, Z.; Wang, N.; Li, J.; Wan, M. Electronic Transport in PANI-CSA/PANI-DBSA Polyblends. Phys. B 2004, 344, 82−87. (161) Lee, I. S.; Lee, J. Y.; Sung, J. H.; Choi, H. J. Synthesis and Electrorheological Characteristics of Polyaniline-Titanium Dioxide Hybrid Suspension. Synth. Met. 2005, 152, 173−176. (162) Bedre, M. D.; Basavaraja, S.; Deshpande, R.; Balaji, D. S.; Venkataraman, A. Preparation and Characterization of Polypyrrole Silver Nanocomposites via Interfacial Polymerization. Int. J. Polym. Mater. 2010, 59, 531−543. (163) Godovski, D. Y. Electron Behavior and Magnetic Properties of Polymer Nanocomposites. Adv. Polym. Sci. 1995, 119, 79−122. (164) Mallikarjuna, N. N.; Manohar, S. K.; Kulkarni, P. V.; Venkataraman, A.; Aminabhavi, T. M. Novel High Dielectric Constant Nanocomposites of Polyaniline Dispersed with γ-Fe2O3 Nanoparticles. J. Appl. Polym. Sci. 2005, 97, 1868−1874. (165) Gilman, J. W. Flammability and Thermal Stability Studies of Polymer Layered-Silicate Clay Nanocomposites. Appl. Clay Sci. 1999, 15, 31−49. (166) Porter, D.; Metcalfe, E.; Thomas, M. J. K. Nanocomposite Fire Retardants-A Review. Fire Mater. 2000, 24, 45−52.

(167) Kant, S.; Kalia, S.; Kumar, A. A Novel Nanocomposite of Polyaniline and Fe0.01Ni0.01Zn0.98O: Photocatalytic, Electrical and Antibacterial Properties. J. Alloys Compd. 2013, 578, 249−256. (168) Tallury, S. S.; Smyth, M. B.; Cakmak, E.; Pasquinelli, M. A. Molecular Dynamics Simulations of Interactions between Polyanilines in Their Inclusion Complexes with β-Cyclodextrins. J. Phys. Chem. B 2012, 116, 2023−2030. (169) Xue, T.; Wang, X.; Kwak, S. K.; Lee, J.-M. Synthesis of Mesoporous Polyaniline (PANI)-Se0.5Te0.5 Dual-Layer Film from Lyotropic Liquid Crystalline Template. Ind. Eng. Chem. Res. 2013, 52, 5072−5078. (170) Di, L.; Wang, L.-P.; Lu, Y.-N.; He, L.; Lin, Z.-X.; Wu, K.-J.; Ren, Q.-S.; Wang, J.-Y. Protein Adsorption and Peroxidation of Rat Retinas under Stimulation of a Neural Probe Coated with Polyaniline. Acta Biomater. 2011, 7, 3738−3745. (171) Kumar, P. A.; Chakraborty, S. Fixed-Bed Column Study for Hexavalent Chromium Removal and Recovery by Short-Chain Polyaniline Synthesized on Jute Fiber. J. Hazard. Mater. 2009, 162, 1086−1098. (172) Guo, Y.; Li, M.; Mylonakis, A.; Han, J.; Macdiarmid, A. G.; Chen, X.; Lelkes, P. I.; Wei, Y. Biomacromolecules 2007, 8, 3025− 3034. (173) Xia, Y.; Lu, X.; Zhu, H. Natural Silk Fibroin/polyaniline (Core/shell) Coaxial Fiber: Fabrication and Application for Cell Proliferation. Compos. Sci. Technol. 2013, 77, 37−41. (174) Wang, L.-P.; Wang, W.; Di, L.; Lu, Y.-N.; Wang, J.-Y. Protein Adsorption under Electrical Stimulation of Neural Probe Coated with Polyaniline. Colloids Surf., B 2010, 80, 72−78. (175) Kumar, P. A.; Chakraborty, S.; Ray, M. Removal and Recovery of Chromium from Wastewater Using Short Chain Polyaniline Synthesized on Jute Fiber. Chem. Eng. J. 2008, 141, 130−140. (176) Chen, J. P.; Yoon, J.-T.; Yiacoumi, S. Effects of Chemical and Physical Properties of Influent on Copper Sorption onto Activated Carbon Fixed-Bed Columns. Carbon 2003, 41, 1635−1644. (177) Cui, H.; Li, Q.; Qian, Y.; Tang, R.; An, H.; Zhai, J. Defluoridation of Water via Electrically Controlled Anion Exchange by Polyaniline Modified Electrode Reactor. Water Res. 2011, 45, 5736−5744. (178) Lin, Y.; Cui, X.; Bontha, J. Electrically Controlled Anion Exchange Based on Polypyrrole and Carbon Nanotubes Nanocomposite for Perchlorate Removal. Environ. Sci. Technol. 2006, 40, 4004−4009. (179) Ma, Y.; Zhang, J.; Zhang, G.; He, H. Polyaniline Nanowires on Si Surfaces Fabricated with DNA Templates. J. Am. Chem. Soc. 2004, 126, 7097−7101. (180) Liu, W.; Kumar, J.; Tripathy, S.; Senecal, K. J.; Samuelson, L. Enzymatically Synthesized Conducting Polyaniline. J. Am. Chem. Soc. 1999, 121, 71−78. (181) Datta, B.; Schuster, G. B.; McCook, A.; Harvey, S. C.; Zakrzewska, K. DNA-Directed Assembly of Polyanilines: Modified Cytosine Nucleotides Transfer Sequence Programmability to a Conjoined Polymer. J. Am. Chem. Soc. 2006, 128, 14428−14429. (182) Gao, Z.; Rafea, S.; Lim, L. H. Detection of Nucleic Acids Using Enzyme-Catalyzed Template-Guided Deposition of Polyaniline. Adv. Mater. 2007, 19, 602−606. (183) Wang, Z. G.; Zhan, P.; Ding, B. Self-Assembled Catalytic DNA Nanostructures for Synthesis of Para-Directed Polyaniline. ACS Nano 2013, 7, 1591−1598. (184) Langer, R.; Cima, L. G.; Janet, A.; Wintermantel, E. Future Directions in Biomaterial. Biomaterials 1990, 11, 738−745. (185) Hutmacher, D. W. Scaffolds in Tissue Engineering Bone and Cartilage. Biomaterials 2000, 21, 2529−2543. (186) Nair, L. S.; Laurencin, C. T. Biodegradable Polymers as Biomaterials. Prog. Polym. Sci. 2007, 32, 762−798. (187) Emami, S. H.; Orang, F.; Mahmoudi, M.; Rafienia, M. A Study of Starch Addition on Burst Effect and Diameter of Polyurethane Microspheres Containing Theophylline. Polym. Adv. Technol. 2008, 19, 167−170. BN

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(188) Li, W.-J.; Danielson, K. G.; Alexander, P. G.; Tuan, R. S. Biological Response of Chondrocytes Cultured in Three-Dimensional Nanofibrous Poly(ϵ-Caprolactone) Scaffolds. J. Biomed. Mater. Res. 2003, 67, 1105−1114. (189) Madihally, S. V.; Matthew, H. W. Porous Chitosan Scaffolds for Tissue Engineering. Biomaterials 1999, 20, 1133−1142. (190) Nakamatsu, J.; Torres, F. G.; Troncoso, O. P.; Min-Lin, Y.; Boccaccini, A. R. Processing and Characterization of Porous Structures from Chitosan and Starch for Tissue Engineering Scaffolds. Biomacromolecules 2006, 7, 3345−3355. (191) Gentleman, E.; Lay, A. N.; Dickerson, D. A.; Nauman, E. A.; Livesay, G. A.; Dee, K. C. Mechanical Characterization of Collagen Fibers and Scaffolds for Tissue Engineering. Biomaterials 2003, 24, 3805−3813. (192) Gugala, Z.; Gogolewski, S. In Vitro Growth and Activity of Primary Chondrocytes on a Resorbable Polylactide Three-Dimensional Scaffold. J. Biomed. Mater. Res. 2000, 49, 183−191. (193) Schugens, C.; Maquet, V.; Grandfils, C.; Jerome, R.; Teyssie, P. Polylactide Macroporous Biodegradable Implants for Cell Transplantation. II. Preparation of Polylactide Foams by Liquid-Liquid Phase Separation. J. Biomed. Mater. Res. 1996, 30, 449−461. (194) Cai, Q.; Wan, Y.; Bei, J.; Wang, S. Synthesis and Characterization of Biodegradable Polylactide-Grafted Dextran and Its Application as Compatilizer. Biomaterials 2003, 24, 3555−3562. (195) Ma, L.; Gao, C.; Mao, Z.; Zhou, J.; Shen, J.; Hu, X.; Han, C. Collagen/chitosan Porous Scaffolds with Improved Biostability for Skin Tissue Engineering. Biomaterials 2003, 24, 4833−4841. (196) Zhao, J.; Yuan, X.; Cui, Y.; Ge, Q.; Yao, K. Preparation and Characterization of poly(L-Lactide)/ Poly(ϵ-Caprolactone) Fibrous Scaffolds for Cartilage Tissue Engineering. J. Appl. Polym. Sci. 2004, 91, 1676−1684. (197) Zhang, Y. Z.; Venugopal, J.; Huang, Z.-M.; Lim, C. T.; Ramakrishna, S. Characterization of the Surface Biocompatibility of the Electrospun PCL-Collagen Nanofibers Using Fibroblasts. Biomacromolecules 2005, 6, 2583−2589. (198) Lee, C.-T.; Huang, C.-P.; Lee, Y.-D. Biomimetic Porous Scaffolds Made from Poly(l-Lactide)-G-Chondroitin Sulfate Blend with Poly(l-Lactide) for Cartilage Tissue Engineering. Biomacromolecules 2006, 7, 2200−2209. (199) Willner, I.; Rubin, S. Control of the Structure and Functions of Biomaterials by Light. Angew. Chem., Int. Ed. Engl. 1996, 35, 367− 385. (200) George, P. M.; LaVan, D. A.; Burdick, J. A.; Chen, C.-Y.; Liang, E.; Langer, R. Electrically Controlled Drug Delivery from Biotin-Doped Conductive Polypyrrole. Adv. Mater. 2006, 18, 577− 581. (201) Kim, B.-S.; Qiu, J.-M.; Wang, J.-P.; Taton, T. A. Magnetomicelles: Composite Nanostructures from Magnetic Nanoparticles and Cross-Linked Amphiphilic Block Copolymers. Nano Lett. 2005, 5, 1987−1991. (202) Jones, M.-C.; Ranger, M.; Leroux, J.-C. pH-Sensitive Unimolecular Polymeric Micelles: Synthesis of a Novel Drug Carrier. Bioconjugate Chem. 2003, 14, 774−781. (203) Huang, L.; Zhuang, X.; Hu, J.; Lang, L.; Zhang, P.; Wang, Y.; Chen, X.; Wei, Y.; Jing, X. Synthesis of Biodegradable and Electroactive Multiblock Polylactide and Aniline Pentamer Copolymer for Tissue Engineering Applications. Biomacromolecules 2008, 9, 850−858. (204) Askim, J. R.; Mahmoudi, M.; Suslick, K. S. Optical Sensor Arrays for Chemical Sensing: The Optoelectronic Nose. Chem. Soc. Rev. 2013, 42, 8649−8682. (205) MacDiarmid, A. G. Synthetic Metals”: A Novel Role for Organic Polymers (Nobel Lecture). Angew. Chem., Int. Ed. 2001, 40, 2581−2590. (206) Ramanavičius, A.; Ramanavičienė, A.; Malinauskas, A. Electrochemical Sensors Based on Conducting Polymer Polypyrrole. Electrochim. Acta 2006, 51, 6025−6037.

(207) Blinova, N. V.; Stejskal, J.; Trchová, M.; Prokeš, J. Polyaniline Prepared in Solutions of Phosphoric Acid: Powders, Thin Films, and Colloidal Dispersions. Polymer 2006, 47, 42−48. (208) Karlsson, K. F.; Åsberg, P.; Nilsson, K. P. R.; Inganäs, O. Interactions between a Zwitterionic Polythiophene Derivative and Oligonucleotides As Resolved by Fluorescence Resonance Energy Transfer. Chem. Mater. 2005, 17, 4204−4211. (209) Kang, S. K.; Kim, J.-H.; An, J.; Lee, E. K.; Cha, J.; Lim, G.; Park, Y. S.; Chung, D. J. Synthesis of Polythiophene Derivatives and Their Application for Electrochemical DNA Sensor. Polym. J. 2004, 36, 937−942. (210) Zhang, L.; Peng, H.; Kilmartin, P. A.; Soeller, C.; TravasSejdic, J. Poly(3,4-Ethylenedioxythiophene) and Polyaniline Bilayer Nanostructures with High Conductivity and Electrocatalytic Activity. Macromolecules 2008, 41, 7671−7678. (211) Perez-Madrigal, M. M.; Giannotti, M. I.; Del Valle, L. J.; Franco, L.; Armelin, E.; Puiggali, J.; Sanz, F.; Aleman, C. Thermoplastic Polyurethane:Polythiophene Nanomembranes for Biomedical and Biotechnological Applications. ACS Appl. Mater. Interfaces 2014, 6, 9719−9732. (212) Khanduyeva, N.; Senkovskyy, V.; Beryozkina, T.; Horecha, M.; Stamm, M.; Uhrich, C.; Riede, M.; Leo, K.; Kiriy, A. Surface Engineering Using Kumada Catalyst-Transfer Polycondensation (KCTP): Preparation and Structuring of Poly(3-Hexylthiophene)Based Graft Copolymer Brushes. J. Am. Chem. Soc. 2009, 131, 153− 161. (213) Moreno, J. S.; Panero, S.; Scrosati, B. Electrochemical Polymerization of Polypyrrole−heparin Nanotubes: Kinetics and Morphological Properties. Electrochim. Acta 2008, 53, 2154−2160. (214) Moroder, P.; Runge, M. B.; Wang, H.; Ruesink, T.; Lu, L.; Spinner, R. J.; Windebank, A. J.; Yaszemski, M. J. Material Properties and Electrical Stimulation Regimens of Polycaprolactone Fumarate− polypyrrole Scaffolds as Potential Conductive Nerve Conduits. Acta Biomater. 2011, 7, 944−953. (215) Cucchi, I.; Boschi, A.; Arosio, C.; Bertini, F.; Freddi, G.; Catellani, M. Bio-Based Conductive Composites: Preparation and Properties of Polypyrrole (PPy)-Coated Silk Fabrics. Synth. Met. 2009, 159, 246−253. (216) Runge, M. B.; Dadsetan, M.; Baltrusaitis, J.; Knight, A. M.; Ruesink, T.; Lazcano, E. A.; Lu, L.; Windebank, A. J.; Yaszemski, M. J. The Development of Electrically Conductive Polycaprolactone Fumarateepolypyrrole Composite Materials for Nerve Regeneration. Biomaterials 2010, 31, 5916−5926. (217) Guo, B.; Finne-Wistrand, A.; Albertsson, A.-C. Enhanced Electrical Conductivity by Macromolecular Architecture: Hyperbranched Electroactive and Degradable Block Copolymers Based on Poly(ε-Caprolactone) and Aniline Pentamer. Macromolecules 2010, 43, 4472−4480. (218) Bayramoğ lu, G.; Metin, A. Ü .; Arıca, M. Y. Surface Modification of Polyacrylonitrile Film by Anchoring Conductive Polyaniline and Determination of Uricase Adsorption Capacity and Activity. Appl. Surf. Sci. 2010, 256, 6710−6716. (219) Bayramoğlu, G.; Karakışla, M.; Altıntaş, B.; Metin, A. U.; Saçak, M.; Arıca, M. Y. Polyaniline Grafted Polyacylonitrile Conductive Composite Fibers for Reversible Immobilization of Enzymes: Stability and Catalytic Properties of Invertase. Process Biochem. 2009, 44, 880−885. (220) Prabhakar, P. K.; Raj, S.; Anuradha, P. R.; Sawant, S. N.; Doble, M. Biointerfaces Biocompatibility Studies on Polyaniline and Polyaniline − Silver Nanoparticle Coated Polyurethane Composite. Colloids Surf., B 2011, 86, 146−153. (221) Gurunathan, T.; Rao, C. R. K.; Narayan, R.; Raju, K. V. S. N. Synthesis, Characterization and Corrosion Evaluation on New Cationomeric Polyurethane Water Dispersions and Their Polyaniline Composites. Prog. Org. Coat. 2013, 76, 639−647. (222) Bayramoğlu, G.; Metin, A. U.; Altintas, B.; Arica, M. Y. Reversible Immobilization of Glucose Oxidase on Polyaniline Grafted Polyacrylonitrile Conductive Composite Membrane. Bioresour. Technol. 2010, 101, 6881−6887. BO

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(223) Guo, B.; Finne-Wistrand, A.; Albertsson, A.-C. Electroactive Hydrophilic Polylactide Surface by Covalent Modification with Tetraaniline. Macromolecules 2012, 45, 652−659. (224) Piras, A. M.; Dessy, A.; Dinucci, D.; Chiellini, F. 2-Methoxy Aniline Grafted Poly(maleic Anhydride- Alt -Butyl Vinyl Ether) Hemiester: A New Biocompatible Polymeric Free Radical Scavenger. Macromolecules 2011, 44, 848−856. (225) Mao, H. Y.; Laurent, S.; Chen, W.; Akhavan, O.; Imani, M.; Ashkarran, A. A.; Mahmoudi, M. Graphene: Promises, Facts, Opportunities, and Challenges in Nanomedicine. Chem. Rev. 2013, 113, 3407−3424. (226) Li, X.; Liu, X.; Huang, J.; Fan, Y.; Cui, F.-Z. Biomedical Investigation of CNT Based Coatings. Surf. Coat. Technol. 2011, 206, 759−766. (227) Kumar, B.; Castro, M.; Feller, J. F. Poly(lactic Acid)−multiWall Carbon Nanotube Conductive Biopolymer Nanocomposite Vapour Sensors. Sens. Actuators, B 2012, 161, 621−628. (228) Lee, K. G.; Wi, R.; Imran, M.; Park, T. J.; Lee, J.; Lee, S. Y.; Kim, D. H. Functionalization Effects of Single- Walled Carbon Nanotubes as Templates for the Synthesis of Silica Nanorods and Study of Growing Mechanism of Silica. ACS Nano 2010, 4, 3933− 3942. (229) Weizmann, Y.; Chenoweth, D. M.; Swager, T. M. DNA-CNT Nanowire Networks for DNA Detection. J. Am. Chem. Soc. 2011, 133, 3238−3241. (230) Niemeyer, C. M.; Ceyhan, B. DNA-Directed Functionalization of Colloidal Gold with Proteins. Angew. Chem., Int. Ed. 2001, 40, 3685−3688. (231) Kim, B.-S.; Lee, S. W.; Yoon, H.; Strano, M. S.; Shao-Horn, Y.; Hammond, P. T. Pattern Transfer Printing of Multiwalled Carbon Nanotube Multilayers and Application in Biosensors. Chem. Mater. 2010, 22, 4791−4797. (232) Moreira, F. T.; Dutra, R. A.; Noronha, J. P.; Cunha, A. L.; Sales, M. G. Artificial Antibodies for Troponin T by Its Imprinting on the Surface of Multiwalled Carbon Nanotubes: Its Use as Sensory Surfaces. Biosens. Bioelectron. 2011, 28, 243−250. (233) Bello, A.; Laredo, E.; Marval, R.; Grimau, M.; Arnal, M. L.; Muller, A. J.; Ruelle, B.; Dubois, P. Universality and Percolation in Biodegradable Poly(ε-Caprolactone)/ Multiwalled Carbon Nanotube Nanocomposites from Broad Band Alternating and Direct Current Conductivity at Various Temperatures. Macromolecules 2011, 44, 2819−2828. (234) Baravik, I.; Tel-Vered, R.; Ovits, O.; Willner, I. Electrical Contacting of Redox Enzymes by Means of Oligoaniline-CrossLinked Enzyme/Carbon Nanotube Composites. Langmuir 2009, 25, 13978−13983. (235) Murugan, E.; Gopi, V. Amphiphilic Multiwalled Carbon Nanotube Polymer Hybrid with Improved Conductivity and Dispersibility Produced by Functionalization with Poly(vinylbenzyl)triethylammonium Chloride. J. Phys. Chem. C 2011, 115, 19897− 19909. (236) Razdan, S.; Patra, P. K.; Kar, S.; Ci, L.; Vajtai, R.; Kukovecz, A.; Kónya, Z.; Kiricsi, I.; Ajayan, P. M. Ionically Self-Assembled Polyelectrolyte-Based Carbon Nanotube Fibers. Chem. Mater. 2009, 21, 3062−3071. (237) Yuan, W.; Che, J.; Chan-Park, M. B. A Novel Polyimide Dispersing Matrix for Highly Electrically Conductive Solution-Cast Carbon Nanotube-Based Composite. Chem. Mater. 2011, 23, 4149− 4157. (238) Gu, H.; Swager, T. M. Fabrication of Free-Standing, Conductive, and Transparent Carbon Nanotube Films. Adv. Mater. 2008, 20, 4433−4437. (239) Baskaran, D.; Mays, J. W.; Bratcher, M. S. Noncovalent and Nonspecific Molecular Interactions of Polymers with Multiwalled Carbon Nanotubes. Chem. Mater. 2005, 17, 3389−3397. (240) Delozier, D. M.; Watson, K. A.; Smith, J. G.; Clancy, T. C.; Connell, J. W. Investigation of Aromatic/Aliphatic Polyimides as Dispersants for Single Wall Carbon Nanotubes. Macromolecules 2006, 39, 1731−1739.

(241) Zou, J.; Liu, L.; Chen, H.; Khondaker, S. I.; McCullough, R. D.; Huo, Q.; Zhai, L. Dispersion of Pristine Carbon Nanotubes Using Conjugated Block Copolymers. Adv. Mater. 2008, 20, 2055−2060. (242) Chen, J.; Liu, H.; Weimer, W. A.; Halls, M. D.; Waldeck, D. H.; Walker, G. C. Noncovalent Engineering of Carbon Nanotube Surfaces by Rigid, Functional Conjugated Polymers. J. Am. Chem. Soc. 2002, 124, 9034−9035. (243) Saini, V.; Li, Z.; Bourdo, S.; Dervishi, E.; Xu, Y.; Ma, X.; Kunets, V. P.; Salamo, G. J.; Viswanathan, T.; Biris, A. R.; et al. Electrical, Optical, and Morphological Properties of P3HT-MWNT Nanocomposites Prepared by in Situ Polymerization. J. Phys. Chem. C 2009, 113, 8023−8029. (244) Naffakh, M.; Díez-Pascual, A. M. Nanocomposite Biomaterials Based on Poly(ether- Ether-Ketone) (PEEK) and WS2 Inorganic Nanotubes. J. Mater. Chem. B 2014, 2, 4509−4520. (245) Badhulika, S.; Tlili, C.; Mulchandani, A. Poly(3-Aminophenylboronic Acid)-Functionalized Carbon Nanotubes-Based Chemiresistive Sensors for Detection of Sugars. Analyst 2014, 139, 3077−3082. (246) Wang, D.; Li, H.; Li, M.; Jiang, H.; Xia, M.; Zhou, Z. Stretchable Conductive Polyurethane Elastomer in Situ Polymerized with Multi-Walled Carbon Nanotubes. J. Mater. Chem. C 2013, 1, 2744−2749. (247) Miyauchi, M.; Miao, J.; Simmons, T. J.; Lee, J.-W.; Doherty, T. V.; Dordick, J. S.; Linhardt, R. J. Conductive Cable Fibers with Insulating Surface Prepared by Coaxial Electrospinning of Multiwalled Nanotubes and Cellulose. Biomacromolecules 2010, 11, 2440−2445. (248) Kroto, H. W.; Heath, J. R.; O’Brien, S. C.; Curl, R. F.; Smalley, R. E. C60: Buckminsterfullerene. Nature 1985, 318, 162−163. (249) Kai, W.; Hua, L.; Dong, T.; Pan, P.; Zhu, B.; Inoue, Y. Polyhedral Oligomeric Silsesquioxane- and Fullerene-End-Capped Poly (ε-Caprolactone. Macromol. Chem. Phys. 2008, 209, 1191−1197. (250) Rajagopalan, M.; Oh, I. K. Fullerenol-Based Electroactive Artificial Muscles Utilizing Biocompatible Polyetherimide. ACS Nano 2011, 5, 2248−2256. (251) Levi, N.; Hantgan, R. R.; Lively, M. O.; Carroll, D. L.; Prasad, G. L. C60-Fullerenes: Detection of Intracellular Photoluminescence and Lack of Cytotoxic Effects. J. Nanobiotechnol. 2006, 4, 14. (252) Lebedev, B. V.; Markin, A. V.; Davydov, V. A.; Kashevarova, L. S.; Rakhmanina, A. V. Thermodynamics of Crystalline Dimer of Fullerene C 60 in the Range from T → 0 to 340 K at Standard Pressure. Thermochim. Acta 2003, 399, 99−108. (253) Liu, J.-H.; Cao, L.; Luo, P. G.; Yang, S.-T.; Lu, F.; Wang, H.; Meziani, M. J.; Haque, S. A.; Liu, Y.; Lacher, S.; et al. FullereneConjugated Doxorubicin in Cells. ACS Appl. Mater. Interfaces 2010, 2, 1384−1389. (254) Hinokuma, K.; Ata, M. Proton Conduction in Polyhydroxy Hydrogensulfated Fullerenes. J. Electrochem. Soc. 2003, 150, A112− A116. (255) Margadonna, S.; Prassides, K. Recent Advances in Fullerene Superconductivity. J. Solid State Chem. 2002, 168, 639−652. (256) Hamblin, M. R.; Mroz, P.; Tegos, G. P.; Gali, H.; Wharton, T.; Sarna, T.; Pawlak, A. Photodynamic therapy with fullerenes. In Fullerene Research Advances; Kramer, C. N., Ed.; Nova Science: New York, 2007; Chapter 1, pp 1−31. (257) Hinokuma, K.; Ata, M. Fullerene Proton Conductors. Chem. Phys. Lett. 2001, 341, 442−446. (258) Li, Y. M.; Hinokuma, K. Proton Conductivity of Phosphoric Acid Derivative of Fullerene. Solid State Ionics 2002, 150, 309−315. (259) Maruyama, R. Electrochemical Mass-Flow Control of Hydrogen Using a Fullerene-Based Proton Conductor. Electrochim. Acta 2002, 48, 85−89. (260) Giacalone, F.; Martın, N. Fullerene Polymers: Synthesis and Properties. Chem. Rev. 2006, 106, 5136−5190. (261) Wang, C.; Guo, Z.-X.; Fu, S.; Wu, W.; Zhu, D. Polymers Containing Fullerene or Carbon Nanotube Structures. Prog. Polym. Sci. 2004, 29, 1079−1141. BP

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

Chemical Vapor Deposition: Wrinkle Formation. Adv. Mater. 2009, 21, 2328−2333. (282) Kim, H.; Macosko, C. W. Processing-Property Relationships of Polycarbonate/graphene Composites. Polymer 2009, 50, 3797− 3809. (283) Ahadian, S.; Ramón-Azcón, J.; Chang, H.; Liang, X.; Kaji, H.; Shiku, H.; Nakajima, K.; Ramalingam, M.; Wu, H.; Matsue, T.; et al. Electrically Regulated Differentiation of Skeletal Muscle Cells on Ultrathin Graphene-Based Films. RSC Adv. 2014, 4, 9534−9541. (284) Akhavan, O.; Ghaderi, E. The Use of Graphene in the SelfOrganized Differentiation of Human Neural Stem Cells into Neurons under Pulsed Laser Stimulation. J. Mater. Chem. B 2014, 2, 5602− 5611. (285) Dong, X.; Wang, X.; Wang, L.; Song, H.; Zhang, H.; Huang, W.; Chen, P. 3D Graphene Foam as a Monolithic and Macroporous Carbon Electrode for Electrochemical Sensing. ACS Appl. Mater. Interfaces 2012, 4, 3129−3133. (286) Hasan, S. A.; Tsekoura, E. K.; Sternhagen, V.; Strømme, M. Evolution of the Composition and Suspension Performance of Nitrogen-Doped Graphene. J. Phys. Chem. C 2012, 116, 6530−6536. (287) Huang, P.; Zhu, H.; Jing, L.; Zhao, Y.; Gao, X. Graphene Covalently Binding Aryl Groups: Conductivity Increases Rather than Decreases. ACS Nano 2011, 5, 7945−7949. (288) Kempaiah, R.; Chung, A.; Maheshwari, V. Graphene as Cellular Interface: Electromechanical Coupling with Cells. ACS Nano 2011, 5, 6025−6031. (289) Li, S.; Shu, K.; Zhao, C.; Wang, C.; Guo, Z.; Wallace, G.; Liu, H. K. One-Step Synthesis of Graphene/Polypyrrole Nanofiber Composites as Cathode Material for a Biocompatible Zinc/Polymer Battery. ACS Appl. Mater. Interfaces 2014, 6, 16679−16686. (290) Lee, J.-S.; Kim, S. T.; Cao, R.; Choi, N.-S.; Liu, M.; Lee, K. T.; Cho, J. Metal-Air Batteries with High Energy Density: Li-Air versus Zn-Air. Adv. Energy Mater. 2011, 1, 34−50. (291) Winther-Jensen, B.; Gaadingwe, M.; Macfarlane, D. R.; Forsyth, M. Control of Magnesium Interfacial Reactions in Aqueous Electrolytes towards a Biocompatible Battery. Electrochim. Acta 2008, 53, 5881−5884. (292) Kong, Y.; Wang, C.; Yang, Y.; Too, C. O.; Wallace, G. G. A Battery Composed of a Polypyrrole Cathode and a Magnesium Alloy anodeToward a Bioelectric Battery. Synth. Met. 2012, 162, 584− 589. (293) Liang, B.; Fang, L.; Hu, Y.; Yang, G.; Zhu, Q.; Ye, X. Fabrication and Application of Flexible Graphene Silk Composite Film Electrodes Decorated with Spiky Pt Nanospheres. Nanoscale 2014, 6, 4264−4274. (294) Hu, K.; Gupta, M. K.; Kulkarni, D. D.; Tsukruk, V. V. UltraRobust Graphene Oxide-Silk Fibroin Nanocomposite Membranes. Adv. Mater. 2013, 25, 2301−2307. (295) Huang, L.; Li, C.; Yuan, W.; Shi, G. Strong Composite Films with Layered Structures Prepared by Casting Silk Fibroin−graphene Oxide Hydrogels. Nanoscale 2013, 5, 3780−3786. (296) Liras, M.; García, O.; Quijada-Garrido, I.; Ellis, G.; Salavagione, H. J. Homogenous Thin Layer Coated Graphene via One Pot Reaction with Multidentate Thiolated PMMAs. J. Mater. Chem. C 2014, 2, 1723−1729. (297) Liras, M.; Quijada-Garrido, I.; Palacios-Cuesta, M.; MuñozDurieux, S.; García, O. Acetyl Protected Thiol Methacrylic Polymers as Effective Ligands to Keep Quantum Dots in Luminescent Standby Mode. Polym. Chem. 2014, 5, 433−442. (298) Matyjaszewski, K.; Xia, J. Atom Transfer Radical Polymerization. Chem. Rev. 2001, 101, 2921−2990. (299) Smith, A. M.; Nie, S. Minimizing the Hydrodynamic Size of Quantum Dots with Multifunctional Multidentate Polymer Ligands. J. Am. Chem. Soc. 2008, 130, 11278−11279. (300) Liras, M.; García, O.; Guarrotxena, N.; Palacios-Cuesta, M.; Quijada-Garrido, I. Versatile Thiolated Thermosensitive Polymers Synthesized by ATRP of MEO2MA and AcSEMA, a New Methacrylic Monomer with a Protected Thiol Group. Polym. Chem. 2013, 4, 5751−5759.

(262) Jung, J.-H.; Vadahanambi, S.; Oh, I.-K. Electro-Active NanoComposite Actuator Based on Fullerene-Reinforced Nafion. Compos. Sci. Technol. 2010, 70, 584−592. (263) Sardenberg, R. B.; Teixeira, C. E.; Pinheiro, M.; Figueiredo, J. M. A. Nonlinear Conductivity of Fullerenol Aqueous Solutions. ACS Nano 2011, 5, 2681−2686. (264) Geim, A. K.; Novoselov, K. S. The Rise of Graphene. Nat. Mater. 2007, 6, 183−191. (265) Zhu, Y.; Murali, S.; Cai, W.; Li, X.; Suk, J. W.; Potts, J. R.; Ruoff, R. S. Graphene and Graphene Oxide: Synthesis, Properties, and Applications. Adv. Mater. 2010, 22, 3906−3924. (266) Nezakati, T.; Cousins, B. G.; Seifalian, A. M. Toxicology of chemically modified graphene-based materials for medical application. Arch. Toxicol. 2014, 88, 1987−2012. (267) Wong, J. K. L.; Mohseni, R.; Hamidieh, A. A.; MacLaren, R. E.; Habib, N.; Seifalian, A. M. Will Nanotechnology Bring New Hope for Gene Delivery? Trends Biotechnol. 2017, 35, 434−451. (268) Mao, H.; Chen, W.; Laurent, S.; Thirifays, C.; Burtea, C.; Rezaee, F.; Mahmoudi, M. Hard Corona Composition and Cellular Toxicities of the Graphene Sheets. Colloids Surf., B 2013, 109, 212− 218. (269) Mbeh, D. A.; Akhavan, O.; Javanbakht, T.; Mahmoudi, M.; Yahia, L. H. Cytotoxicity of Protein Corona-Graphene Oxide Nanoribbons on Human Epithelial Cells. Appl. Surf. Sci. 2014, 320, 596−601. (270) Mahmoudi, M.; Akhavan, O.; Ghavami, M.; Rezaee, F.; Ghiasi, S. M. Graphene Oxide Strongly Inhibits Amyloid Beta Fibrillation. Nanoscale 2012, 4, 7322−7325. (271) Kim, H.; Namgung, R.; Singha, K.; Oh, I.-K.; Kim, W. J. Graphene Oxide−Polyethylenimine Nanoconstruct as a Gene Delivery Vector and Bioimaging Tool. Bioconjugate Chem. 2011, 22, 2558−1567. (272) Krol, S.; Macrez, R.; Docagne, F.; Defer, G.; Laurent, S.; Rahman, M.; Hajipour, M. J.; Kehoe, P. G.; Mahmoudi, M. Therapeutic Benefits from Nanoparticles: The Potential Significance of Nanoscience in Diseases with Compromise to the Blood Brain Barrier. Chem. Rev. 2013, 113, 1877−1903. (273) Tu, Q.; Pang, L.; Wang, L.; Zhang, Y.; Zhang, R.; Wang, J. Biomimetic Choline-like Graphene Oxide Composites for Neurite Sprouting and Outgrowth. ACS Appl. Mater. Interfaces 2013, 5, 13188−13197. (274) Peng, H.; Meng, L.; Niu, L.; Lu, Q. Simultaneous Reduction and Surface Functionalization of Graphene Oxide by Natural Cellulose with the Assistance of the Ionic Liquid. J. Phys. Chem. C 2012, 116, 16294−16299. (275) Chen, Z.; Ren, W.; Gao, L.; Liu, B.; Pei, S.; Cheng, H.-M. Three-Dimensional Flexible and Conductive Interconnected Graphene Networks Grown by Chemical Vapour Deposition. Nat. Mater. 2011, 10, 424−428. (276) Stankovich, S.; Dikin, D. A.; Dommett, G. H. B.; Kohlhaas, K. M.; Zimney, E. J.; Stach, E. A.; Piner, R. D.; Nguyen, S. T.; Ruoff, R. S. Graphene-Based Composite Materials. Nature 2006, 442, 282−286. (277) Rogers, J. A.; Someya, T.; Huang, Y. Materials and Mechanics for Stretchable Electronics. Science 2010, 327, 1603−1607. (278) Reina, A.; Jia, X.; Ho, J.; Nezich, D.; Son, H.; Bulovic, V.; Dresselhaus, M. S.; Kong, J. Large Area, Few-Layer Graphene Films on Arbitrary Substrates by Chemical Vapor Deposition. Nano Lett. 2009, 9, 30−35. (279) Yu, Q.; Lian, J.; Siriponglert, S.; Li, H.; Chen, Y. P.; Pei, S.-S. Graphene Segregated on Ni Surfaces and Transferred to Insulators. Appl. Phys. Lett. 2008, 93, 113103−113106. (280) Futaba, D. N.; Hata, K.; Yamada, T.; Hiraoka, T.; Hayamizu, Y.; Kakudate, Y.; Tanaike, O.; Hatori, H.; Yumura, M.; Iijima, S. Shape-Engineerable and Highly Densely Packed Single-Walled Carbon Nanotubes and Their Application as Super-Capacitor Electrodes. Nat. Mater. 2006, 5, 987−994. (281) Chae, S. J.; Güneş, F.; Kim, K. K.; Kim, E. S.; Han, G. H.; Kim, S. M.; Shin, H.-J.; Yoon, S.-M.; Choi, J.-Y.; Park, M. H.; et al. Synthesis of Large-Area Graphene Layers on Poly-Nickel Substrate by BQ

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(320) Robertson, J. Diamond-like Amorphous Carbon. Mater. Sci. Eng., R 2002, 37, 129−281. (321) Hauert, R.; Thorwarth, K.; Thorwarth, G. An Overview on Diamond-like Carbon Coatings in Medical Applications. Surf. Coat. Technol. 2013, 233, 119−130. (322) Tiainen, V.-M. Amorphous Carbon as a Bio-Mechanical Coating Mechanical Properties and Biological Applications. Diamond Relat. Mater. 2001, 10, 153−160. (323) Roy, R. K.; Lee, K. Biomedical Applications of Diamond-Like Carbon Coatings: A Review. J. Biomed. Mater. Res., Part B 2007, 83, 72−84. (324) Booth, L.; Catledge, S. A.; Nolen, D.; Thompson, R. G.; Vohra, Y. K. Synthesis and Characterization of Multilayered Diamond Coatings for Biomedical Implants. Materials 2011, 4, 857−868. (325) Fox, K.; Palamara, J.; Judge, R.; Greentree, A. D. Diamond as a Scaffold for Bone Growth. J. Mater. Sci.: Mater. Med. 2013, 24, 849− 861. (326) Garrett, D. J.; Ganesan, K.; Stacey, A.; Fox, K.; Meffin, H.; Prawer, S. Ultra-Nanocrystalline Diamond Electrodes: Optimization towards Neural Stimulation Applications. J. Neural Eng. 2012, 9, 016002. (327) Irifune, T.; Kurio, A.; Sakamoto, S.; Inoue, T.; Sumiya, H. Ultrahard Polycrystalline Diamond from Graphite. Nature 2003, 421, 599−600. (328) Krueger, A. The Structure and Reactivity of Nanoscale Diamond. J. Mater. Chem. 2008, 18, 1485−1492. (329) Szunerits, S.; Boukherroub, R. Different Strategies for Functionalization of Diamond Surfaces. J. Solid State Electrochem. 2008, 12, 1205−1218. (330) Aharonovich, I.; Lee, J. C.; Magyar, A. P.; Buckley, B. B.; Yale, C. G.; Awschalom, D. D.; Hu, E. L. Homoepitaxial Growth of Single Crystal Diamond Membranes for Quantum Information Processing. Adv. Mater. 2012, 24, OP54−OP59. (331) Burek, M. J.; de Leon, N. P.; Shields, B. J.; Hausmann, B. J. M.; Chu, Y.; Quan, Q.; Zibrov, A. S.; Park, H.; Lukin, M. D.; Loncar, M. Free-Standing Mechanical and Photonic Nanostructures in Single Crystal Diamond. Nano Lett. 2012, 12, 6084−6089. (332) Masuda, H.; Watanabe, M.; Yasui, K.; Tryk, D.; Rao, T.; Fujishima, A. Fabrication of a Nanostructured Diamond Honeycomb Film. Adv. Mater. 2000, 12, 444−447. (333) Mammana, V. P.; Salvadori, M. C.; Brown, I. G. Study of Porosity in Permeable Diamond Membranes. Thin Solid Films 1997, 308-309, 258−262. (334) Wang, X.; Ocola, L. E.; Divan, R. S.; Sumant, A. V. Nanopatterning of Ultrananocrystalline Diamond Nanowires. Nanotechnology 2012, 23, 075301. (335) Fox, N. A.; Youh, M. J.; Steeds, J. W.; Wang, W. N. Patterned Diamond Particle Films. J. Appl. Phys. 2000, 87, 8187−8191. (336) Ando, Y.; Kuwabara, J.; Suzuki, K.; Sawabe, A. Patterned Growth of Heteroepitaxial Diamond. Diamond Relat. Mater. 2004, 13, 1975−1979. (337) Kurdyukov, D. A.; Feoktistov, N. A.; Nashchekin, A. V.; Zadiranov, Y. M.; Aleksenskii, A. E.; Ya Vul, A.; Golubev, V. G. Ordered Porous Diamond Films Fabricated by Colloidal Crystal Templating. Nanotechnology 2012, 23, 015601. (338) Karan, S.; Samitsu, S.; Peng, X.; Kurashima, K.; Ichinose, I. Ultrafast Viscous Permeation of Organic Solvents Through DiamondLike Carbon Nanosheets. Science 2012, 335, 444−447. (339) Zakhidov, A. A.; Baughman, R. H.; Iqbal, Z.; Cui, C.; Khayrullin, I.; Dantas, S. O.; Marti, J.; Ralchenko, V. G. Carbon Structures with Three-Dimensional Periodicity at Optical Wavelengths. Science 1998, 282, 897−901. (340) Li, L.-Z.; Deng, H.-X.; Lou, W.-Z.; Sun, X.-Y.; Song, M.-W.; Tao, J.; Xiao, B.-X.; Guo, J.-M. Growth Inhibitory Effect of 4-Phenyl Butyric Acid on Human Gastric Cancer Cells Is Associated with Cell Cycle Arrest. World J. Gastroenterol 2012, 18, 79−83. (341) Masuda, H.; Yanagishita, T.; Yasui, K.; Nishio, K.; Yagi, I.; Rao, T. N.; Fujishima, A. Synthesis of Well-Aligned Diamond. Adv. Mater. 2001, 13, 247−249.

(301) Liras, M.; García, O.; Quijada-Garrido, I.; París, R. Transformation of the Bromine End Group into Thiol in (Meth)acrylic Polymers Synthesized by Atom Transfer Radical Polymerization. Macromolecules 2011, 44, 1335−1339. (302) Castelaín, M.; Martínez, G.; Ellis, G.; Salavagione, H. J. A Versatile Chemical Tool for the Preparation of Conductive GrapheneBased Polymer Nanocomposites. Chem. Commun. 2013, 49, 8967− 8969. (303) Hoyle, C. E.; Lowe, A. B.; Bowman, C. N. Thiol-Click Chemistry: A Multifaceted Toolbox for Small Molecule and Polymer Synthesis. Chem. Soc. Rev. 2010, 39, 1355−1387. (304) Lowe, A. B. Thiol-Ene “‘click’” Reactions and Recent Applications in Polymer and Materials Synthesis. Polym. Chem. 2010, 1, 17−36. (305) Liu, X.; Qin, Z.; Dou, Z.; Liu, N.; Chen, L.; Zhu, M. Fabricating Conductive Poly(ethylene Terephthalate) Nonwoven Fabrics Using an Aqueous Dispersion of Reduced Graphene Oxide as a Sheet Dyestuf. RSC Adv. 2014, 4, 23869−23875. (306) Luo, X.; Weaver, C. L.; Tan, S.; Cui, X. T. Pure Graphene Oxide Doped Conducting Polymer Nanocomposite for BioInterfacing. J. Mater. Chem. B 2013, 1, 1340−1348. (307) Rana, S.; Cho, J. W.; Tan, L. P. Graphene-Crosslinked Polyurethane Block Copolymer Nanocomposites with Enhanced Mechanical, Electrical, and Shape Memory Properties. RSC Adv. 2013, 3, 13796−13803. (308) Yu, Y.-H.; Chan, C.-C.; Lai, Y.-C.; Lin, Y.-Y.; Huang, Y.-C.; Chi, W.-F.; Kuo, C.-W.; Lin, H.-M.; Chen, P.-C. Biocompatible Electrospinning Poly(vinyl alcohol) Nanofibres Embedded with Graphene-Based Derivatives with Enhanced Conductivity, Mechanical Strength and Thermal Stability. RSC Adv. 2014, 4, 56373−56384. (309) San, B. H.; Kim, J. A.; Kulkarni, A.; Moh, S. H.; Dugasani, S. R.; Subramani, V. K.; Thorat, N. D.; Lee, H. H.; Park, S. H.; Kim, T.; Kim, K. K. Combining Protein-Shelled Platinum Nanoparticles with Graphene to Build a Bionanohybrid Capacitor. ACS Nano 2014, 8, 12120−12129. (310) Kim, D.; San, B. H.; Moh, S. H.; Park, H.; Kim, D. Y.; Lee, S.; Kim, K. K. Structural Basis for the Substrate Specificity of PepA from Streptococcus Pneumoniae, a Dodecameric Tetrahedral Protease. Biochem. Biophys. Res. Commun. 2010, 391, 431−436. (311) San, B. H.; Moh, S. H.; Kim, K. K. The Effect of Protein Shells on the Antioxidant Activity of Protein-Encapsulated Platinum Nanoparticles. J. Mater. Chem. 2012, 22, 1774−1780. (312) San, B. H.; Kim, S.; Moh, S. H.; Lee, H.; Jung, D.-Y.; Kim, K. K. Platinum Nanoparticles Encapsulated by Aminopeptidase: A Multifunctional Bioinorganic Nanohybrid Catalyst. Angew. Chem., Int. Ed. 2011, 50, 11924−11929. (313) San, B. H.; Lee, S.; Moh, S. H.; Park, J.-G.; Lee, J. H.; Hwang, H.-Y.; Kim, K. K. Size-Controlled Synthesis and Characterization of CoPt Nanoparticles Using Protein Shells. J. Mater. Chem. B 2013, 1, 1453−1460. (314) Moh, S. H.; San, B. H.; Kulkarni, A.; Kim, T.; Kim, K. K. Synthesis and Electric Characterization of Protein-Shelled CdSe Quantum Dots. J. Mater. Chem. C 2013, 1, 2412−2415. (315) Liu, Z.; Lee, C.; Narayanan, V.; Pei, G.; Kan, E. C. Metal Nanocrystal MemoriesPart II: Electrical Characteristics. IEEE Trans. Electron Devices 2002, 49, 1614−1622. (316) Park, B.; Cho, K.; Koo, Y.-S.; Kim, S. Memory Characteristics of Platinum Nanoparticle-Embedded MOS Capacitors. Curr. Appl. Phys. 2009, 9, 1334−1337. (317) Aramesh, M.; Fox, K.; Lau, D. W. M.; Fang, J.; Ostrikov, K.; Prawer, S.; Cervenka, J. Multifunctional Three-Dimensional Nanodiamond-Nanoporous Alumina Nanoarchitectures. Carbon 2014, 75, 452−464. (318) Koizumi, S.; Nebel, C.; Nesladek, M. Physics and Applications of CVD Diamond; Wiley-VCH: Morlenbach, Germany, 2008. (319) Gracio, J. J.; Fan, Q. H.; Madaleno, J. C. Diamond Growth by Chemical Vapour Deposition. J. Phys. D: Appl. Phys. 2010, 43, 374017. BR

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

Carbon Composite Coatings for Biomedical Applications. Diamond Relat. Mater. 2008, 17, 882−887. (360) Simon, N.; Girard, H.; Ballutaud, D.; Ghodbane, S.; Deneuville, A.; Herlem, M.; Etcheberry, A. Effect of H and O Termination on the Charge Transfer of Moderately Boron Doped Diamond Electrodes. Diamond Relat. Mater. 2005, 14, 1179−1182. (361) Williams, O. A.; Nesladek, M.; Daenen, M.; Michaelson, S.; Hoffman, A.; Osawa, E.; Haenen, K.; Jackman, R. B. Growth, Electronic Properties and Applications of Nanodiamond. Diamond Relat. Mater. 2008, 17, 1080−1088. (362) Wong, H.; Foong, Y. M.; Chua, D. H. C. Improving the Conductivity of Diamond-like Carbon Films with Zinc Doping and Its Material Properties. Appl. Surf. Sci. 2011, 257, 9616−9620. (363) Zhang, W.; Patel, K.; Schexnider, A.; Banu, S.; Radadia, A. D. Nanostructuring of Biosensing Electrodes with Nanodiamonds for Antibody Immobilization. ACS Nano 2014, 8, 1419−1428. (364) Amin, A. K. M. N.; Ismail, A. F.; Nor Khairusshima, M. K. N. Effectiveness of Uncoated WC−Co and PCD Inserts in End Milling of Titanium alloyTi−6Al−4V. J. Mater. Process. Technol. 2007, 192−193, 147−158. (365) Ungureanu, C.; Pirvu, C.; Mindroiu, M.; Demetrescu, I. Antibacterial Polymeric Coating Based on Polypyrrole and Polyethylene Glycol on a New Alloy TiAlZr. Prog. Org. Coat. 2012, 75, 349−355. (366) Mindroiu, M.; Ion, R.; Pirvu, C.; Cimpean, A. SurfactantDependent Macrophage Response to Polypyrrole-Based Coatings Electrodeposited on Ti6Al7Nb Alloy. Mater. Sci. Eng., C 2013, 33, 3353−3361. (367) Flamini, D. O.; Saidman, S. B. Corrosion Behaviour of Nitinol Alloy Coated with Alkylsilanes and Polypyrrole. Mater. Sci. Eng., C 2014, 44, 317−325. (368) Liu, J.; Wang, F.; Zhai, J.; Ji, J. Controllable Growth and Magnetic Characterization of Electrodeposited Nanocrystalline Ni−P Alloy Nanotube and Nanowire Arrays inside AAO Template. J. Electroanal. Chem. 2010, 642, 103−108. (369) Qi, P.; Siyuan, Y.; Chunyu, G.; Yingju, L.; Xiaotang, L.; Yueping, F.; Jianmin, Z.; Zesheng, L.; Liya, Z. Mesopore-Functional Carbon Sphere Nanochains and Their Integration with Alloy Nanoparticles for Enhanced Electrochemical Performances. Electrochim. Electrochim. Acta 2013, 114, 334−340. (370) Li, Z.; Li, B.; Liu, Z.; Liu, Z.; Li, D. Tungsten Carbide/Iron Sulfide/FePt Nanocomposite Supported on Nitrogen-doped Carbon as an Efficient Electrocatalyst for Oxygen Reduction Reaction. RSC Adv. 2015, 5, 106245−106251. (371) Bolat, G.; Izquierdo, J.; Santana, J. J.; Mareci, D.; Souto, R. M. Electrochemical Characterization of ZrTi Alloys for Biomedical Applications. Electrochim. Acta 2013, 88, 447−456. (372) Li, W.; Guan, S.; Chen, J.; Hu, J.; Chen, S.; Wang, L.; Zhu, S. Preparation and in Vitro Degradation of the Composite Coating with High Adhesion Strength on Biodegradable Mg−Zn−Ca Alloy. Mater. Charact. 2011, 62, 1158−1165. (373) Liu, H.; Wang, F.; Zhao, Y.; Liu, J.; Park, K. C.; Endo, M. Synthesis of Iron−palladium Binary Alloy Nanotubes by TemplateAssisted Electrodeposition from Metal-Complex Solution Hengjun. J. Electroanal. Chem. 2009, 633, 15−18. (374) Minárik, P.; Král, R.; Janeček, M. Effect of ECAP Processing on Corrosion Resistance of AE21 and AE42 Magnesium Alloys. Appl. Surf. Sci. 2013, 281, 44−48. (375) Branzoi, V.; Branzoi, F.; Pilan, L. Characterization of Electrodeposited Polymeric and Composite Modified Electrodes on Cobalt Based Alloy. Mater. Chem. Phys. 2009, 118, 197−202. (376) Valero-Vidal, C.; Casabán-Julián, L.; Herraiz-Cardona, I.; Igual-Muñoz, A. Influence of Carbides and Microstructure of CoCrMo Alloys on Theirmetallic Dissolution Resistance. Mater. Sci. Eng., C 2013, 33, 4667−4676. (377) Valero Vidal, C.; Igual Muñoz, A. Electrochemical Characterisation of Biomedical Alloys for Surgical Implants in Simulated Body Fluid. Corros. Sci. 2008, 50, 1954−1961.

(342) Ralchenko, V. G.; Sovyk, D. N.; Bolshakov, A. P.; Homich, A. A.; Vlasov, I. I.; Kurdyukov, D. A.; Golubev, V. G.; Zakhidov, A. A. Diamond Direct and Inverse Opal Matrices Produced by Chemical Vapor Deposition. Phys. Phys. Solid State 2011, 53, 1131−1134. (343) Sovyk, D. N.; Ralchenko, V. G.; Kurdyukov, D. A.; Grudinkin, S. A.; Golubev, V. G.; Khomich, A. A.; Konov, V. I. Photonic Crystals of Diamond Spheres with the Opal Structure. Phys. Solid State 2013, 55, 1120−1123. (344) Vetter, J. 60 Years of DLC Coatings: Historical Highlights and Technical Review of Cathodic Arc Processes to Synthesize Various DLC Types, and Their Evolution for Industrial Applications. Surf. Coat. Technol. 2014, 257, 213−240. (345) Cervenka, J.; Lau, D. W. M.; Dontschuk, N.; Shimoni, O.; Silvestri, L.; Ladouceur, F.; Duvall, S. G.; Prawer, S. Nucleation and Chemical Vapor Deposition Growth of Polycrystalline Diamond on Aluminum Nitride: Role of Surface Termination and Polarity. Cryst. Growth Des. 2013, 13, 3490−3497. (346) Hees, J.; Kriele, A.; Williams, O. A. Electrostatic Self-Assembly of Diamond Nanoparticles. Chem. Phys. Lett. 2011, 509, 12−15. (347) Batsanov, S. S.; Gavrilkin, S. M.; Batsanov, A. S.; Poyarkov, K. B.; Kulakova, I. I.; Johnson, D. W.; Mendis, B. G. Giant Dielectric Permittivity of Detonation-Produced Nanodiamond Is Caused by Water. J. Mater. Chem. 2012, 22, 11166−11172. (348) Hartl, A.; Garrido, J. A.; Nowy, S.; Zimmermann, R.; Werner, C.; Horinek, D.; Netz, R.; Stutzmann, M. The Ion Sensitivity of Surface Conductive Single Crystalline Diamond. J. Am. Chem. Soc. 2007, 129, 1287−1292. (349) Girard, H. A.; Petit, T.; Perruchas, S.; Gacoin, T.; Gesset, C.; Arnault, J. C.; Bergonzo, P. Surface Properties of Hydrogenated Nanodiamonds: A Chemical Investigation. Phys. Chem. Chem. Phys. 2011, 13, 11517−11523. (350) Kaivosoja, E.; Sainio, S.; Lyytinen, J.; Palomäki, T.; Laurila, T.; Kim, S. I.; Han, J. G.; Koskinen, J. Carbon Thin Films as Electrodematerial in Neural Sensing. Surf. Coat. Technol. 2014, 259, 33−38. (351) Kulisch, W.; Popov, C.; Gilliland, D.; Ceccone, G.; Sirghi, L.; Ruiz, A.; Rossi, F. Surface Properties of Differently Prepared Ultrananocrystalline Diamond Surfaces. Diamond Relat. Mater. 2009, 18, 745−749. (352) Kulisch, W.; Popov, C.; Gilliland, D.; Ceccone, G.; Reithmaier, J. P.; Rossi, F. UNCD/a-C Nanocomposite Films for Biotechnological Applications. Surf. Coat. Technol. 2011, 206, 667− 675. (353) Hamers, R. J.; Butler, J. E.; Lasseter, T.; Nichols, B. M.; Russell, J. N.; Tse, K.-Y.; Yang, W. Molecular and Biomolecular Monolayers on Diamond as an Interface to Biology. Diamond Relat. Mater. 2005, 14, 661−668. (354) Christiaens, P.; Vermeeren, V.; Wenmackers, S.; Daenen, M.; Haenen, K.; Nesládek, M.; vandeVen, M.; Ameloot, M.; Michiels, L.; Wagner, P. EDC-Mediated DNA Attachment to Nanocrystalline CVD Diamond Films. Biosens. Bioelectron. 2006, 22, 170−177. (355) Knickerbocker, T.; Strother, T.; Schwartz, M. P.; Russell, J. N.; Butler, J.; Smith, L. M.; Hamers, R. J. DNA-Modified Diamond Surfaces. Langmuir 2003, 19, 1938−1942. (356) Wang, J.; Firestone, M. A.; Auciello, O.; Carlisle, J. A. Surface Functionalization of Ultrananocrystalline Diamond Films by Electrochemical Reduction of Aryldiazonium Salts. Langmuir 2004, 20, 11450−11456. (357) Strother, T.; Knickerbocker, T.; Russell, J. N.; Butler, J. E.; Smith, L. M.; Hamers, R. J. Photochemical Functionalization of Diamond Films. Langmuir 2002, 18, 968−971. (358) Härtl, A.; Schmich, E.; Garrido, J. a.; Hernando, J.; Catharino, S. C. R.; Walter, S.; Feulner, P.; Kromka, A.; Steinmüller, D.; Stutzmann, M. Protein-Modified Nanocrystalline Diamond Thin Films for Biosensor Applications. Nat. Mater. 2004, 3, 736−742. (359) Popov, C.; Bliznakov, S.; Boycheva, S.; Milinovik, N.; Apostolova, M. D.; Anspach, N.; Hammann, C.; Nellen, W.; Reithmaier, J. P.; Kulisch, W. Nanocrystalline Diamond/amorphous BS

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(378) Tao, M.; Li, X.; Wu, Z.; Wang, M.; Hua, M.; Yang, Y. The Preparation of Label-Free Electrochemical Immunosensor Based on the Pt−Au Alloy Nanotube Array for Detection of Human Chorionic Gonadotrophin. Clin. Chim. Acta 2011, 412, 550−555. (379) Kosher, R. A.; Lash, J. W.; Minor, R. R. Environmental Enhancement of in Vitro Chondrogenesis. IV. Stimulation of Somite Chondrogenesis By Exogenous Chondromucoprotein. Dev. Biol. 1973, 35, 210−20. (380) Chandy, T.; Sharma, C. P. Chitosan-as a Biomaterial. Biomater., Artif. Cells, Artif. Organs 1990, 18, 1−24. (381) Suh, J.-K. F.; Matthew, H. W. Application of Chitosan-Based Polysaccharide Biomaterials in Cartilage Tissue Engineering: A Review. Biomaterials 2000, 21, 2589−2598. (382) Lau, C.; Cooney, M. J.; Atanassov, P. Conductive Macroporous Composite Chitosan - Carbon Nanotube Scaffolds. Langmuir 2008, 24, 7004−7010. (383) Xu, Z.; Gao, N.; Chen, H.; Dong, S. Biopolymer and Carbon Nanotubes Interface Prepared by Self-Assembly for Studying the Electrochemistry of Microperoxidase-11. Langmuir 2005, 21, 10808− 10813. (384) Luz, G. M.; Boesel, L.; del Campo, A.; Mano, J. F. Micropatterning of Bioactive Glass Nanoparticles on Chitosan Membranes for Spatial Controlled Biomineralization. Langmuir 2012, 28, 6970−6977. (385) Hu, J.; Huang, L.; Zhuang, X.; Zhang, P.; Lang, L.; Chen, X.; Wei, Y.; Jing, X. Electroactive Aniline Pentamer Cross-Linking Chitosan for Stimulation Growth of Electrically Sensitive Cells. Biomacromolecules 2008, 9, 2637−2644. (386) Lu, X.; Qiu, Z.; Wan, Y.; Hu, Z.; Zhao, Y. Preparation and Characterization of Conducting Polycaprolactone/chitosan/ Polypyrrole Composites. Composites, Part A 2010, 41, 1516−1523. (387) Ismail, Y. A.; Shin, S. R.; Shin, K. M.; Yoon, S. G.; Shon, K.; Kim, S. I.; Kim, S. J. Electrochemical Actuation in Chitosan/ polyaniline Microfibers for Artificial Muscles Fabricated Using an in Situ Polymerization. Sens. Actuators, B 2008, 129, 834−840. (388) Wan, Y.; Gao, J.; Zhang, J.; Peng, W.; Qiu, G. Biodegradability of Conducting Chitosan-G-Polycaprolactone/polypyrrole Conduits. Polym. Degrad. Stab. 2010, 95, 1994−2002. (389) Mao, C.; Zhu, A.; Wu, Q.; Chen, X.; Kim, J.; Shen, J. Newbiocompatible Polypyrrole-Based Films with Good Blood Compatibility and High Electrical Conductivity. Colloids Surf., B 2008, 67, 41−45. (390) Liu, J.; Wang, X.; Wang, T.; Li, D.; Xi, F.; Wang, J.; Wang, E. Functionalization of Monolithic and Porous Three-Dimensional Graphene by One-Step Chitosan Electrodeposition for Enzymatic Biosensor. ACS Appl. Mater. Interfaces 2014, 6, 19997−20002. (391) Wang, X.; Salick, M. R.; Wang, X.; Cordie, T.; Han, W.; Peng, Y.; Li, Q.; Turng, L. Poly(ε-Caprolactone) Nanofibers with a SelfInduced Nanohybrid Shish-Kebab Structure Mimicking Collagen Fibrils. Biomacromolecules 2013, 14, 3557−3569. (392) Macdonald, R. A.; Voge, C. M.; Kariolis, M.; Stegemann, J. P. Carbon Nanotubes Increase the Electrical Conductivity of FibroblastSeeded Collagen Hydrogels. Acta Biomater. 2008, 4, 1583−1592. (393) Manara, S.; Paolucci, F.; Palazzo, B.; Marcaccio, M.; Foresti, E.; Tosi, G.; Sabbatini, S.; Sabatino, P.; Altankov, G.; Roveri, N. Electrochemically-Assisted Deposition of Biomimetic Hydroxyapatite−collagen Coatings on Titanium Plate. Inorg. Chim. Acta 2008, 361, 1634−1645. (394) Liu, C.; Han, Z.; Czernuszka, J. T. Gradient Collagen/ nanohydroxyapatite Composite Scaffold: Development and Characterization. Acta Biomater. 2009, 5, 661−669. (395) Guo, F.; Xu, X. X.; Sun, Z. Z.; Zhang, J. X.; Meng, Z. X.; Zheng, W.; Zhou, H. M.; Wang, B. L.; Zheng, Y. F. A Novel Amperometric Hydrogen Peroxide Biosensor Based on Electrospun Hb−collagen Composite. Colloids Surf., B 2011, 86, 140−145. (396) Hakimi, O.; Knight, D. P.; Vollrath, F.; Vadgama, P. Spider and Mulberry Silkworm Silks as Compatible Biomaterials. Composites, Part B 2007, 38, 324−337.

(397) Dyakonov, T.; Yang, C. H.; Bush, D.; Gosangari, S.; Majuru, S.; Fatmi, A. Design and Characterization of a Silk-Fibroin-Based Drug Delivery Platform Using Naproxen as a Model Drug. J. Drug Delivery 2012, 2012, 1−10. (398) Aznar-Cervantes, S. D.; Vicente-Cervantes, D.; MeseguerOlmo, L.; Cenis, J. L.; Lozano-Pérez, A. A. Influence of the Protocol Used for Fibroin Extraction on the Mechanical Properties and Fiber Sizes of Electrospun Silk Mats. Mater. Sci. Eng., C 2013, 33, 1945− 1950. (399) Yucel, T.; Kojic, N.; Leisk, G. G.; Lo, T. J.; Kaplan, D. L. NonEquilibrium Silk Fibroin Adhesives. J. Struct. Biol. 2010, 170, 406− 412. (400) Lu, Q.; Huang, Y.; Li, M.; Zuo, B.; Lu, S.; Wang, J.; Zhu, H.; Kaplan, D. L. Silk Fibroin Electrogelation Mechanisms. Acta Biomater. 2011, 7, 2394−2400. (401) Hou, Y.; Matthews, A. R.; Smitherman, A. M.; Bulick, A. S.; Hahn, M. S.; Hou, H.; Han, A.; Grunlan, M. A. Thermoresponsive Nanocomposite Hydrogels with Cell-Releasing Behavior. Biomaterials 2008, 29, 3175−3184. (402) Vermonden, T.; Fedorovich, N. E.; van Geemen, D.; Alblas, J.; van Nostrum, C. F.; Dhert, W. J. A.; Hennink, W. E. Photopolymerized Thermosensitive Hydrogels: Synthesis, Degradation, and Cytocompatibility. Biomacromolecules 2008, 9, 919−926. (403) Ryner, M.; Valdre, A.; Albertsson, A. C. Star-Shaped and Photocrosslinked poly(1,5-Dioxepan-2-One): Synthesis and Characterization. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 2049−2054. (404) Målberg, S.; Plikk, P.; Finne-Wistrand, A.; Albertsson, A.-C. Design of Elastomeric Homo- and Copolymer Networks of Functional Aliphatic Polyester for Use in Biomedical Applications. Chem. Mater. 2010, 22, 3009−3014. (405) Anker, S. D.; Coats, A. J. S.; Cristian, G.; Dragomir, D.; Pusineri, E.; Piredda, M.; Bettari, L.; Dowling, R.; Volterrani, M.; Kirwan, B. A.; et al. A Prospective Comparison of Alginate-Hydrogel with Standard Medical Therapy to Determine Impact on Functional Capacity and Clinical Outcomes in Patients with Advanced Heart Failure (AUGMENT-HF Trial). Eur. Heart J. 2015, 36, 2297−2309. (406) Bobba, S.; Chow, S.; Watson, S.; Di Girolamo, N. Clinical Outcomes of Xeno-Free Expansion and Transplantation of Autologous Ocular Surface Epithelial Stem Cells via Contact Lens Delivery: A Prospective Case Series. Stem Cell Res. Ther. 2015, 6, 23. (407) Zhao, Y.; Liu, B.; Pan, L.; Yu, G. 3D Nanostructured Conductive Polymer Hydrogels for High-Performance Electrochemical Devices. Energy Environ. Sci. 2013, 6, 2856−2870. (408) Ma, C.; Shi, Y.; Pena, D. A.; Peng, L.; Yu, G. Thermally Responsive Hydrogel Blends: A General Drug Carrier Model for Controlled Drug Release. Angew. Chem., Int. Ed. 2015, 54, 7376− 7380. (409) Pan, L.; Yu, G.; Zhai, D.; Lee, H. R.; Zhao, W.; Liu, N.; Wang, H.; Tee, B. C.-K.; Shi, Y.; Cui, Y.; et al. Hierarchical Nanostructured Conducting Polymer Hydrogel with High Electrochemical Activity. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 9287−9292. (410) Aimetti, A. A.; Machen, A. J.; Anseth, K. S. Poly(ethylene Glycol) Hydrogels Formed by Thiol-Ene Photopolymerization for Enzyme-Responsive Protein Delivery. Biomaterials 2009, 30, 6048− 6054. (411) Mellott, M. B.; Searcy, K.; Pishko, M. V. Release of Protein from Highly Cross-Linked Hydrogels of Poly(ethylene Glycol) Diacrylate Fabricated by UV Polymerization. Biomaterials 2001, 22, 929−941. (412) Hoshikawa, A.; Nakayama, Y.; Matsuda, T.; Oda, H.; Nakamura, K.; Mabuchi, K. Encapsulation of Chondrocytes in Photopolymerizable Styrenated Gelatin for Cartilage Tissue Engineering. Tissue Eng. 2006, 12, 2333−2341. (413) Underhill, G. H.; Chen, A. A.; Albrecht, D. R.; Bhatia, S. N. Assessment of Hepatocellular Function within PEG Hydrogels. Biomaterials 2007, 28, 256−270. (414) Small, C. J.; Too, C.; Wallace, G. G. Responsive Conducting Polymer-Hydrogel Composites. Polym. Polym. Gels Networks 1997, 5, 251−265. BT

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(415) Guiseppi-Elie, A. Electroconductive Hydrogels: Synthesis, Characterization and Biomedical Applications. Biomaterials 2010, 31, 2701−2716. (416) Brahim, S.; Narinesingh, D.; Guiseppi-Elie, A. PolypyrroleHydrogel Composites for the Construction of Clinically Important Biosensors. Biosens. Bioelectron. 2002, 17, 53−59. (417) Ferris, C. J.; in het Panhuis, M. Conducting Bio-Materials Based on Gellan Gum Hydrogels. Soft Matter 2009, 5, 3430. (418) Justin, G.; Guiseppi-Elie, A. Characterization of Electroconductive Blends of Poly(HEMA-Co-PEGMA-Co-HMMA-CoSPMA) and Poly(Py-Co-PyBA). Biomacromolecules 2009, 10, 2539−2549. (419) Brahim, S.; Guiseppi-Elie, A. Electroconductive Hydrogels: Electrical and Electrochemical Properties of Polypyrrole-poly(HEMA) Composites. Electroanalysis 2005, 17, 556−570. (420) Guo, B.; Finne-wistrand, A.; Albertsson, A. Degradable and Electroactive Hydrogels with Tunable Electrical Conductivity and Swelling Behavior. Chem. Mater. 2011, 23, 1254−1262. (421) Bakota, E. L.; Wang, Y.; Danesh, F. R.; Hartgerink, D. Injectable Multidomain Peptide Nanofiber Hydrogel as a Delivery Agent for Stem Cell Secretome. Biomacromolecules 2011, 12, 1651− 1657. (422) Yan, J.; Pedrosa, V. A.; Simonian, A. L.; Revzin, A. Immobilizing Enzymes onto Electrode Arrays by Hydrogel Photolithography to Fabricate Multi-Analyte Electrochemical Biosensors. ACS Appl. Mater. Interfaces 2010, 2, 748−755. (423) Lee, S. H.; Lee, C. K.; Shin, S. R.; Gu, B. K.; Kim, S. I.; Kang, T. M.; Kim, S. J. Enhanced Actuation of PPy/CNT Hybrid Fibers Using Porous Structured DNA Hydrogel. Sens. Actuators, B 2010, 145, 89−92. (424) Kotanen, C. N.; Wilson, A. N.; Dong, C.; Dinu, C.; Justin, G. A.; Guiseppi-Elie, A. The Effect of the Physicochemical Properties of Bioactive Electroconductive Hydrogels on the Growth and Proliferation of Attachment Dependent Cells. Biomaterials 2013, 34, 6318−6327. (425) Huang, Y.; Zheng, Y.; Song, W.; Ma, Y.; Wu, J.; Fan, L. Poly(vinyl Pyrrolidone) Wrapped Multi-Walled Carbon Nanotube/ poly(vinyl Alcohol) Composite Hydrogels. Composites, Part A 2011, 42, 1398−1405. (426) Runge, M. B.; Dadsetan, M.; Baltrusaitis, J.; Ruesink, T.; Lu, L.; Windebank, A. J.; Yaszemski, M. J. Development of Electrically Conductive Oligo(polyethylene Glycol) Fumarate-Polypyrrole Hydrogels for Nerve Regeneration. Biomacromolecules 2010, 11, 2845− 2853. (427) Mueggenburg, K. E.; Lin, X.-M.; Goldsmith, R. H.; Jaeger, H. M. Elastic Membranes of Close-Packed Nanoparticle Arrays. Nat. Mater. 2007, 6, 656−660. (428) Hou, C.; Duan, Y.; Zhang, Q.; Wang, H.; Li, Y. Bio-Applicable and Electroactive near-Infrared Laser-Triggered Self-Healing Hydrogels Based on Graphene Networks. J. Mater. Chem. 2012, 22, 14991− 14996. (429) Jo, H.; Sim, M.; Kim, S.; Yang, S.; Yoo, Y.; Park, J.-H.; Yoon, T. H.; Kim, M.-G.; Lee, J. Y. Electrically Conductive Graphene/ polyacrylamide Hydrogels Produced by Mild Chemical Reduction for Enhanced Myoblast Growth and Differentiation. Acta Biomater. 2017, 48, 100−109. (430) Spizzirri, U. G.; Hampel, S.; Cirillo, G.; Nicoletta, F. P.; Hassan, A.; Vittorio, O.; Picci, N.; Iemma, F. Spherical gelatin/CNTs Hybrid Microgels as Electro-Responsive Drug Delivery Systems. Int. J. Pharm. 2013, 448, 115−122. (431) Wang, H.; Han, H.; Ma, Z. Conductive Hydrogel Composed of 1,3,5-Benzenetricarboxylic Acid and Fe3 + used as Enhanced Electrochemical Immunosensing Substrate for Tumor Biomarker. Bioelectrochemistry 2017, 114, 48−53. (432) Huang, Z. M.; Zhang, Y. Z.; Kotaki, M.; Ramakrishna, S. A Review on Polymer Nanofibers by Electrospinning and Their Applications in Nanocomposites. Compos. Sci. Technol. 2003, 63, 2223−2253.

(433) Chronakis, I. S.; Grapenson, S.; Jakob, A. Conductive Polypyrrole Nanofibers via Electrospinning: Electrical and Morphological Properties. Polymer 2006, 47, 1597−1603. (434) Bhang, S. H.; Jeong, S. I.; Lee, T. J.; Jun, I.; Lee, Y. B.; Kim, B. S.; Shin, H. Electroactive Electrospun Polyaniline/Poly[(L-Lactide)Co-(ε-Caprolactone)] Fibers for Control of Neural Cell Function. Macromol. Biosci. 2012, 12, 402−411. (435) Hsiao, C. W.; Bai, M. Y.; Chang, Y.; Chung, M. F.; Lee, T. Y.; Wu, C. T.; Maiti, B.; Liao, Z. X.; Li, R. K.; Sung, H. W. Electrical Coupling of Isolated Cardiomyocyte Clusters Grown on Aligned Conductive Nanofibrous Meshes for Their Synchronized Beating. Biomaterials 2013, 34, 1063−1072. (436) Li, M.; Guo, Y.; Wei, Y.; MacDiarmid, A. G.; Lelkes, P. I. Electrospinning Polyaniline-Contained Gelatin Nanofibers for Tissue Engineering Applications. Biomaterials 2006, 27, 2705−2715. (437) Yu, Q. Z.; Dai, Z. W.; Lan, P. Fabrication of High Conductivity Dual Multi-Porous Poly (L-Lactic Acid)/polypyrrole Composite Micro/nanofiber Film. Mater. Sci. Eng., B 2011, 176, 913− 920. (438) Jin, G.; Prabhakaran, M. P.; Kai, D.; Kotaki, M.; Ramakrishna, S. Electrospun Photosensitive Nanofibers: Potential for Photocurrent Therapy in Skin Regeneration. Photochem. Photobiol. Sci. 2013, 12, 124−134. (439) Townsend-Nicholson, A.; Jayasinghe, S. N. Cell Electrospinning: A Unique Biotechnique for Encapsulating Living Organisms for Generating Active Biological Microthreads/Scaffolds. Biomacromolecules 2006, 7, 3364−3369. (440) Liu, X.; Chen, J.; Gilmore, K. J.; Higgins, M. J.; Liu, Y.; Wallace, G. G. Guidance of Neurite Outgrowth on Aligned Electrospun Polypyrrole/ Poly(styrene-β-Isobutylene-β-Styrene) Fiber Platforms. J. Biomed. Mater. Res., Part A 2010, 94, 1004−1011. (441) Dong, H.; Jones, W. E. Preparation of Submicron Polypyrrole/Poly(methyl Methacrylate) Coaxial Fibers and Conversion to Polypyrrole Tubes and Carbon Tubes. Langmuir 2006, 22, 11384−11387. (442) Dong, H.; Nyame, V.; Macdiarmid, A. G.; Jones, W. E. Polyaniline/Poly(methyl Methacrylate) Coaxial Fibers: The Fabrication and Effects of the Solution Properties on the Morphology of Electrospun Core Fibers. J. Polym. Sci., Part B: Polym. Phys. 2004, 42, 3934−3942. (443) Dall’Acqua, L.; Tonin, C.; Varesano, A.; Canetti, M.; Porzio, W.; Catellani, M. Vapour Phase Polymerisation of Pyrrole on Cellulose-Based Textile Substrates. Synth. Met. 2006, 156, 379−386. (444) Laforgue, A.; Robitaille, L. Production of Conductive PEDOT Nanofibers by the Combination of Electrospinning and Vapor-Phase Polymerization. Macromolecules 2010, 43, 4194−4200. (445) Havel, M.; Behler, K.; Korneva, G.; Gogotsi, Y. Transparent Thin Films of Multiwalled Carbon Nanotubes Self-Assembled on Polyamide 11 Nanofibers. Adv. Funct. Mater. 2008, 18, 2322−2327. (446) Ryu, J.; Park, J.; Kim, B.; Park, J.-O. Design and Fabrication of a Largely Deformable Sensorized Polymer Actuator. Biosens. Bioelectron. 2005, 21, 822−826. (447) Lassalle, N.; Vieil, E.; Correia, J. P.; Abrantes, L. M. Study of DNA Hybridization on Polypyrrole Grafted with Oligonucleotides by Photocurrent Spectroscopy. Biosens. Bioelectron. 2001, 16, 295−303. (448) Cui, X.; Wiler, J.; Dzaman, M.; Altschuler, R. A.; Martin, D. C. In Vivo Studies of Polypyrrole/peptide Coated Neural Probes. Biomaterials 2003, 24, 777−787. (449) George, P. M.; Lyckman, A. W.; LaVan, D. A.; Hegde, A.; Leung, Y.; Avasare, R.; Testa, C.; Alexander, P. M.; Langer, R.; Sur, M. Fabrication and Biocompatibility of Polypyrrole Implants Suitable for Neural Prosthetics. Biomaterials 2005, 26, 3511−3519. (450) Li, Y.; Neoh, K. G.; Kang, E. T. Controlled Release of Heparin from Polypyrrole-Poly(vinyl Alcohol) Assembly by Electrical Stimulation. J. Biomed. Mater. Res., Part A 2005, 73, 171−181. (451) Björninen, M.; Gilmore, K.; Pelto, J.; Seppänen-Kaijansinkko, R.; Kellomäki, M.; Miettinen, S.; Wallace, G.; Grijpma, D.; Haimi, S. Electrically Stimulated Adipose Stem Cells on Polypyrrole-Coated BU

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

Scaffolds for Smooth Muscle Tissue Engineering. Ann. Biomed. Eng. 2017, 45, 1015−1026. (452) Zhang, Z.; Rouabhia, M.; Wang, Z.; Roberge, C.; Shi, G.; Roche, P.; Li, J.; Dao, L. H. Electrically Conductive Biodegradable Polymer Composite for Nerve Regeneration: Electricity-Stimulated Neurite Outgrowth and Axon Regeneration. Artif. Organs 2007, 31, 13−22. (453) Wallace, G. G.; Higgins, M. J.; Moulton, S. E.; Wang, C. Nanobionics: The Impact of Nanotechnology on Implantable Medical Bionic Devices. Nanoscale 2012, 4, 4327−4347. (454) Kim, D.-H.; Wiler, J. A.; Anderson, D. J.; Kipke, D. R.; Martin, D. C. Conducting Polymers on Hydrogel-Coated Neural Electrode Provide Sensitive Neural Recordings in Auditory Cortex. Acta Biomater. 2010, 6, 57−62. (455) Svennersten, K.; Berggren, M.; Richter-Dahlfors, A.; Jager, E. W. H. Mechanical Stimulation of Epithelial Cells Using Polypyrrole Microactuators. Lab Chip 2011, 11, 3287−3293. (456) Abidian, M. R.; Kim, D.-H.; Martin, D. C. ConductingPolymer Nanotubes for Controlled Drug Release. Adv. Mater. 2006, 18, 405−409. (457) Bendrea, A.-D.; Cianga, L.; Cianga, I. Review Paper: Progress in the Field of Conducting Polymers for Tissue Engineering Applications. J. Biomater. Appl. 2011, 26, 3−84. (458) Hardy, J. G.; Lee, J. Y.; Schmidt, C. E. Biomimetic Conducting Polymer-Based Tissue Scaffolds. Curr. Opin. Biotechnol. 2013, 24, 847−854. (459) Jun, I.; Jeong, S.; Shin, H. The Stimulation of Myoblast Differentiation by Electrically Conductive Sub-Micron Fiber. Biomaterials 2009, 30, 2038−2047. (460) Kim, Y. D.; Kim, J. H. Synthesis of Polypyrrole− polycaprolactone Composites by Emulsion Polymerization and the Electrorheological Behavior of Their Suspensions. Colloid Polym. Sci. 2008, 286, 631−637. (461) Guo, B.; Finne-Wistrand, A.; Albertsson, A.-C. Facile Synthesis of Degradable and Electrically Conductive Polysaccharide Hydrogels. Biomacromolecules 2011, 12, 2601−2609. (462) Mire, C. A.; Agrawal, A.; Wallace, G. G.; Calvert, P.; in het Panhuis, M. Inkjet and Extrusion Printing of Conducting poly(3,4Ethylenedioxythiophene) Tracks on and Embedded in Biopolymer Materials. J. Mater. Chem. 2011, 21, 2671−2678. (463) Ku, S. H.; Lee, S. H.; Park, C. B. Synergic Effects of Nanofiber Alignment and Electroactivity on Myoblast Differentiation. Biomaterials 2012, 33, 6098−6104. (464) Greco, F.; Zucca, A.; Taccola, S.; Mazzolai, B.; Mattoli, V. Patterned free-standing conductive nanofilms for ultraconformable circuits and smart interfaces. ACS Appl. Mater. Interfaces 2013, 5, 9461−9. (465) Matovic, J.; Jaksic, Z. Bionic (Nano) Membranes. Biomimetics Mater. Struct. Process. 2011, 9−24. (466) Lee, C.; Wei, X.; Kysar, J. W.; Hone, J. Measurement of the Elastic Properties and Intrinsic Strength of Monolayer Graphene. Science 2008, 321, 385−388. (467) Kim, K. S.; Zhao, Y.; Jang, H.; Lee, S. Y.; Kim, J. M.; Kim, K. S.; Ahn, J.-H.; Kim, P.; Choi, J.-Y.; Hong, B. H. Large-Scale Pattern Growth of Graphene Films for Stretchable Transparent Electrodes. Nature 2009, 457, 706−710. (468) Rogers, J. A.; Lagally, M. G.; Nuzzo, R. G. Synthesis, Assembly and Applications of Semiconductor Nanomembranes. Nature 2011, 477, 45−53. (469) Striemer, C. C.; Gaborski, T. R.; McGrath, J. L.; Fauchet, P. M. Charge- and Size-Based Separation of Macromolecules Using Ultrathin Silicon Membranes. Nature 2007, 445, 749−753. (470) Vendamme, R.; Onoue, S.-Y.; Nakao, A.; Kunitake, T. Robust Free-Standing Nanomembranes of Organic/inorganic Interpenetrating Networks. Nat. Mater. 2006, 5, 494−501. (471) Watanabe, H.; Muto, E.; Ohzono, T.; Nakao, A.; Kunitake, T. Giant Nanomembrane of Covalently-Hybridized Epoxy Resin and Silica. J. Mater. Chem. 2009, 19, 2425−2431.

(472) Watanabe, H.; Ohzono, T.; Kunitake, T. Fabrication of Large, Robust Nanomembranes from Diverse, Cross-Linked Polymeric Materials. Macromolecules 2007, 40, 1369−1371. (473) Watanabe, H.; Kunitake, T. A Large, Freestanding, 20 Nm Thick Nanomembrane Based on an Epoxy Resin. Adv. Mater. 2007, 19, 909−912. (474) Watanabe, H.; Ohzono, T.; Kunitake, T. Fabrication of Large Nanomembranes by Radical Polymerization of Multifunctional Acrylate Monomers. Polym. J. 2008, 40, 379−382. (475) Fujie, T.; Matsutani, N.; Kinoshita, M.; Okamura, Y.; Saito, A.; Takeoka, H. Adhesive, Flexible, and Robust Polysaccharide Nanosheets Integrated for Tissue-Defect Repair. Adv. Funct. Mater. 2009, 19, 2560−2568. (476) Fujie, T.; Okamura, Y.; Takeoka, S. Ubiquitous Transference of a Free-Standing Polysaccharide Nanosheet with the Development of a Nano-Adhesive Plaster. Adv. Mater. 2007, 19, 3549−3553. (477) Okamura, Y.; Kabata, K.; Kinoshita, M.; Saitoh, D.; Takeoka, S. Free-Standing Biodegradable Poly(lactic Acid) Nanosheet for Sealing Operations in Surgery. Adv. Mater. 2009, 21, 4388−4392. (478) Silva, G. A. Nanotechnology Approaches for the Regeneration and Neuroprotection of the Central Nervous System. Surg. Neurol. 2005, 63, 301−306. (479) Dahlin, L.; Johansson, F.; Lindwall, C.; Kanje, M. Chapter 28: Future Perspective in Peripheral Nerve Reconstruction. Int. Rev. Neurobiol. 2009, 87, 507−530. (480) Siemionow, M.; Brzezicki, G. Chapter 8: Current Techniques and Concepts in Peripheral Nerve Repair. Int. Rev. Neurobiol. 2009, 87, 141−172. (481) Schmidt, C. E.; Leach, J. B. Neural Tissue Engineering: Strategies for Repair and Regeneration. Annu. Rev. Biomed. Eng. 2003, 5, 293−347. (482) Hamid, S.; Hayek, R. Role of Electrical Stimulation for Rehabilitation and Regeneration after Spinal Cord Injury: An Overview. Eur. Spine J. 2008, 17, 1256−1269. (483) Lu, M. C.; Ho, C. Y.; Hsu, S. F.; Lee, H. C.; Lin, J. H.; Yao, C. H.; Chen, Y. S. Effects of Electrical Stimulation at Different Frequencies on Regeneration of Transected Peripheral Nerve. Neurorehabil. Neural Repair 2008, 22, 367−373. (484) Cao, H.; Liu, T.; Chew, S. Y. The Application of Nanofibrous Scaffolds in Neural Tissue Engineering. Adv. Drug Delivery Rev. 2009, 61, 1055−1064. (485) Prabhakaran, M. P.; Venugopal, J. R.; Ramakrishna, S. Mesenchymal Stem Cell Differentiation to Neuronal Cells on Electrospun Nanofibrous Substrates for Nerve Tissue Engineering. Biomaterials 2009, 30, 4996−5003. (486) Lee, J. Y.; Bashur, C. A.; Goldstein, A. S.; Schmidt, C. E. Polypyrrole-Coated Electrospun PLGA Nanofibers for Neural Tissue Applications. Biomaterials 2009, 30, 4325−4335. (487) Arino, H.; Brandt, J.; Dahlin, L. B. Implantation of Schwann Cells in Rat Tendon Autografts as a Model for Peripheral Nerve Repair: Long Term Effects on Functional Recovery. Scand. J. Plast. Reconst. Surg. Hand Surg. 2008, 42, 281−285. (488) Kemp, S. W.; Walsh, S. K.; Midha, R. Growth Factor and Stem Cell Enhanced Conduits in Peripheral Nerve Regeneration and Repair. Neurol. Res. 2008, 30, 1030−1038. (489) Vivó, M.; Puigdemasa, A.; Casals, L.; Asensio, E.; Udina, E.; Navarro, X. Immediate Electrical Stimulation Enhances Regeneration and Reinnervation and Modulates Spinal Plastic Changes after Sciatic Nerve Injury and Repair. Exp. Neurol. 2008, 211, 180−193. (490) Wang, Z.; Roberge, C.; Dao, L. H.; Wan, Y.; Shi, G.; Rouabhia, M.; Guidoin, R.; Zhang, Z. In Vivo Evaluation of a Novel Electrically Conductive polypyrrole/poly(D,L-Lactide) Composite and Polypyrrole-Coated poly(D,L-Lactide-Co-Glycolide) Membranes. J. Biomed. Mater. Res. 2004, 70, 28−38. (491) Rivers, T. J.; Hudson, T. W.; Schmidt, C. E. Synthesis of a Novel, Biodegradable Electrically Conducting Polymer for Biomedical Applications. Adv. Funct. Mater. 2002, 12, 33−37. (492) Park, J. S.; Park, K.; Moon, H. T.; Woo, D. G.; Yang, H. N.; Park, K.-H. Electrical Pulsed Stimulation of Surfaces Homogeneously BV

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

Engineering for Cardiac Regeneration and Transplantation. Crit. Rev. Biotechnol. 2016, 36, 705−715. (512) Pok, S.; Vitale, F.; Eichmann, S. L.; Benavides, O. M.; Pasquali, M.; Jacot, J. G. Biocompatible Carbon Nanotube-Chitosan Scaffold Matching the Electrical Conductivity of the Heart. ACS Nano 2014, 8, 9822−9832. (513) Palmieri, V.; Papi, M.; Conti, C.; Ciasca, G.; Maulucci, G.; De Spirito, M. The Future Development of Bacteria Fighting Medical Devices: The Role of Graphene Oxide. Expert Rev. Med. Devices 2016, 13, 1013−1019. (514) Shams, E.; Yeganeh, H.; Naderi-Manesh, H.; Gharibi, R.; Mohammad Hassan, Z. Polyurethane/siloxane Membranes Containing Graphene Oxide Nanoplatelets as Antimicrobial Wound Dressings: In Vitro and in Vivo Evaluations. J. Mater. Sci.: Mater. Med. 2017, 28, 75. (515) Li, Z.; Wang, H.; Yang, B.; Sun, Y.; Huo, R. ThreeDimensional Graphene Foams Loaded with Bone Marrow Derived Mesenchymal Stem Cells Promote Skin Wound Healing with Reduced Scarring. Mater. Sci. Eng., C 2015, 57, 181−188. (516) Zhou, Y.; Chen, R.; He, T.; Xu, K.; Du, D.; Zhao, N.; Cheng, X.; Yang, J.; Shi, H.; Lin, Y. Biomedical Potential of Ultrafine Ag/ AgCl Nanoparticles Coated on Graphene with Special Reference to Antimicrobial Performances and Burn Wound Healing. ACS Appl. Mater. Interfaces 2016, 8, 15067−15075. (517) Liu, T.; Dan, W.; Dan, N.; Liu, X.; Liu, X.; Peng, X. A Novel Grapheme Oxide-Modified Collagen-Chitosan Bio-Film for Controlled Growth Factor Release in Wound Healing Applications. Mater. Sci. Eng., C 2017, 77, 202−211. (518) Fan, L.; Yi, J.; Tong, J.; Zhou, X.; Ge, H.; Zou, S.; Wen, H.; Nie, M. Preparation and Characterization of Oxidized Konjac Glucomannan/carboxymethyl Chitosan/graphene Oxide Hydrogel. Int. J. Biol. Macromol. 2016, 91, 358−367. (519) Mukherjee, S.; Sriram, P.; Barui, A. K.; Nethi, S. K.; Veeriah, V.; Chatterjee, S.; Suresh, K. I.; Patra, C. R. Graphene Oxides Show Angiogenic Properties. Adv. Healthcare Mater. 2015, 4, 1722−1732. (520) Seifalian, A. M.; Hancock, S. Composite Material and Its Method of Production. Patent Appl. P9337GB1, 2016. (521) Naderi, N.; Karponis, D.; Mosahebi, A.; Seifalian, A. M. Nanoparticles in Wound Healing; from Hope to Promise, from Promise to Routine. Front. Biosci., Landmark Ed. 2018, 23, 1038− 1059. (522) Cosnier, S. Biosensors Based on Electropolymerized Films: New Trends. Anal. Bioanal. Chem. 2003, 377, 507−520. (523) Hong, S. Y.; Marynick, D. S. Understanding the Conformational Stability and Electronic Structures of Modified Polymers Based on Polythiophene. Macromolecules 1992, 25, 4652−4657. (524) Chader, G. J.; Weiland, J.; Humayun, M. S. Artificial Vision: Needs, Functioning, and Testing of a Retinal Electronic Prosthesis. Prog. Brain Res. 2009, 175, 317−332. (525) Hochberg, L. R.; Serruya, M. D.; Friehs, G. M.; Mukand, J. A.; Saleh, M.; Caplan, A. H.; Branner, A. J.; Chen, D. K.; Penn, R. D.; Donoghue, J. P. Neuronal Ensemble Control of Prosthetic Devices by a Human with Tetraplegia. Nature 2006, 442, 164−171. (526) Zhou, J.; Woo, S. J.; Park, S. I.; Lee, S. W.; Chung, H.; Kim, S. J. A Neurostimulator Design for Long-Term Animal Experiments. Proceedings of the Frontiers in the Convergence of Bioscience and Information Technologies FBIT; IEEE: Piscataway, NJ, 2007; pp 453− 457. (527) Stauffer, W. R.; Cui, X. T. Polypyrrole Doped with 2 Peptide Sequences from Laminin. Biomaterials 2006, 27, 2405−2413. (528) Cogan, S. F.; Ehrlich, J.; Plante, T. D.; Smirnov, A.; Shire, D. B.; Gingerich, M.; Rizzo, J. F. Sputtered Iridium Oxide Films for Neural Stimulation Electrodes. J. Biomed. Mater. Res., Part B 2009, 89, 353−361. (529) Lu, Y.; Wang, T.; Cai, Z.; Cao, Y.; Yang, H.; Duan, Y. Y. Anodically Electrodeposited Iridium Oxide Films Microelectrodes for Neural Microstimulation and Recording. Sens. Actuators, B 2009, 137, 334−339.

Coated with Gold Nanoparticles to Induce Neurite Outgrowth of PC12 Cells. Langmuir 2009, 25, 451−457. (493) Olayo, R.; Ríos, C.; Salgado-Ceballos, H.; Cruz, G. J.; Morales, J.; Olayo, M. G.; Alcaraz-Zubeldia, M.; Alvarez, A. L.; Mondragon, R.; Morales, A.; Diaz-Ruiz, A. Tissue Spinal Cord Response in Rats after Implants of Polypyrrole and Polyethylene Glycol Obtained by Plasma. J. Mater. Sci.: Mater. Med. 2008, 19, 817−826. (494) Durgam, H.; Sapp, S.; Deister, C.; Khaing, Z.; Chang, E.; Luebben, S.; Schmidt, C. E. Novel Degradable Co-Polymers of Polypyrrole Support Cell Proliferation and Enhance Neurite outGrowth with Electrical Stimulation. J. Biomater. Sci., Polym. Ed. 2010, 21, 1265−1282. (495) Simon-Deckers, A.; Loo, S.; Mayne-L’hermite, M.; HerlinBoime, N.; Menguy, N.; Reynaud, C.; Gouget, B.; Carrière, M. Size-, Composition- and Shape-Dependent Toxicological Impact of Metal Oxide Nanoparticles and Carbon Nanotubes toward Bacteria. Environ. Sci. Technol. 2009, 43, 8423−8429. (496) Pietroiusti, A.; Iavicoli, I.; Bergamaschi, A.; Magrini, A. Toxic Effects of Single-Walled Carbon Nanotubes on the Cardiovascular System: State of Art. Int. J. Environ. Health 2009, 3, 264−274. (497) Simeonova, P. P. Update on Carbon Nanotube Toxicity. Nanomedicine 2009, 4, 373−375. (498) Belyanskaya, L.; Weigel, S.; Hirsch, C.; Tobler, U.; Krug, H. F.; Wick, P. Effects of Carbon Nanotubes on Primary Neurons and Glial Cells. NeuroToxicology 2009, 30, 702−711. (499) Terzis, J. K.; Sun, D. D.; Thanos, P. K. Historical and Basic Science Review: Past, Present, and Future of Nerve Repair. J. Reconstr. Microsurg. 1997, 13, 215−225. (500) Aszmann, O. C.; Korak, K. J.; Luegmair, M.; Frey, M. Bridging Critical Nerve Defects through an Acellular Homograft Seeded with Autologous Schwann Cells Obtained from a Regeneration Neuroma of the Proximal Stump. J. Reconstr. Microsurg. 2008, 24, 151−158. (501) Novikova, L. N.; Pettersson, J.; Brohlin, M.; Wiberg, M.; Novikov, L. N. Biodegradable Poly-Beta-Hydroxybutyrate Scaffold Seeded with Schwann Cells to Promote Spinal Cord Repair. Biomaterials 2008, 29, 1198−1206. (502) Kim, S. M.; Lee, S. K.; Lee, J. H. Peripheral Nerve Regeneration Using a Three Dimensionally Cultured Schwann Cell Conduit. J. Craniofac. Surg. 2007, 18, 475−488. (503) Haastert, K.; Mauritz, C.; Matthies, C.; Grothe, C. Autologous Adult Human Schwann Cells Genetically Modified to Provide Alternative Cellular Transplants in Peripheral Nerve Regeneration. J. Neurosurg. 2006, 104, 778−786. (504) Nezakati, T.; Tan, A.; Seifalian, A. M. Enhancing the Electrical Conductivity of a Hybrid POSS-PCL/graphene Nanocomposite Polymer. J. Colloid Interface Sci. 2014, 435, 145−155. (505) Zimmermann, W. H.; Eschenhagen, T. Cardiac Tissue Engineering for Replacement Therapy. Heart Failure Rev. 2003, 8, 259−269. (506) Kai, D.; Prabhakaran, M. P.; Jin, G.; Ramakrishna, S. Polypyrrole-Contained Electrospun Conductive Nanofibrous Membranes for Cardiac Tissue Engineering. J. Biomed. Mater. Res., Part A 2011, 99, 376−385. (507) Baig, M. K.; Mahon, N.; McKenna, W. J.; Caforio, A. L.; Bonow, R. O.; Francis, G. S.; Gheorghiade, M. The Pathophysiology of Advanced Heart Failure. Am. Heart J. 1998, 135, S216−S230. (508) Mukherjee, S.; Venugopal, J. R.; Ravichandran, R.; Ramakrishna, S.; Raghunath, M. Multimodal Biomaterial Strategies for Regeneration of Infarcted Myocardium. J. Mater. Chem. 2010, 20, 8819−8831. (509) Vunjak-Novakovic, G.; Tandon, N.; Godier, A.; Maidhof, R.; Marsano, A.; Martens, T. P.; Radisic, M. Challenges in Cardiac Tissue Engineering. Tissue Eng., Part B 2010, 16, 169−187. (510) Shin, M.; Ishii, O.; Sueda, T.; Vacanti, J. P. Contractile Cardiac Grafts Using a Novel Nanofibrous Mesh. Biomaterials 2004, 25, 3717−3723. (511) Zia, S.; Mozafari, M.; Natasha, G.; Tan, A.; Cui, Z.; Seifalian, A. M. Hearts Beating through Decellularized Scaffolds: Whole-Organ BW

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(530) Majidi, M. R.; Jouyban, A.; Abdollahi, H.; Asadpour-Zeynali, K. Simultaneous Voltammetric Determination of Cysteine, Tyrosine and Tryptophan by Using Principal Component-Artificial Neural Networks. Asian J. Chem. 2006, 18, 2445−2457. (531) Liu, X.; Demosthenous, A.; Donaldson, N. Platinum Electrode Noise in the ENG Spectrum. Med. Biol. Eng. Comput. 2008, 46, 997− 1003. (532) Jia, X.; Zhen, G.; Puttgen, A.; Zhang, J.; Chen, T. Improved Long-Term Recording of Nerve Signal by Modified Intrafascicular Electrodes in Rabbits. Microsurgery 2008, 28, 173−178. (533) Stieglitz, T. Considerations on Surface and Structural Biocompatibility as Prerequisite for Long-Term Stability of Neural Prostheses. J. Nanosci. Nanotechnol. 2004, 4, 496−503. (534) Niissalo, S.; Li, T.-F.; Santavirta, S.; Takagi, M.; Hietanen, J.; Konttinen, Y. T. Dense Innervation in Pseudocapsular Tissue Compared to Aneural Interface Tissue in Loose Totally Replaced Hips. J. Rheumatol. 2002, 29, 796−803. (535) Abidian, M. R.; Martin, D. C. Multifunctional Nanobiomaterials for Neural Interfaces. Adv. Funct. Mater. 2009, 19, 573−585. (536) Abidian, M. R.; Martin, D. C. Experimental and Theoretical Characterization of Implantable Neural Microelectrodes Modified with Conducting Polymer Nanotubes. Biomaterials 2008, 29, 1273− 1283. (537) Green, R. A.; Poole-Warren, L. A.; Lovell, N. H. Novel Neural Interface for Vision Prosthesis Electrodes: Improving Electrical and Mechanical Properties through Layering. Proceedings of the 3rd International IEEE EMBS Conference on Neural Engineering; IEEE: Piscataway, NJ, 2007; pp 97−100. (538) Widge, A. S.; Jeffries-El, M.; Cui, X.; Lagenaur, C. F.; Matsuoka, Y. Self-Assembled Monolayers of Polythiophene Conductive Polymers Improve Biocompatibility and Electrical Impedance of Neural Electrodes. Biosens. Bioelectron. 2007, 22, 1723−1732. (539) Yang, J.; Kim, D. H.; Hendricks, J. L.; Leach, M.; Northey, R.; Martin, D. C. Ordered Surfactant-Templated poly(3,4-Ethylenedioxythiophene) (PEDOT) Conducting Polymer on Microfabricated Neural Probes. Acta Biomater. 2005, 1, 125−136. (540) Andrade, J. D.; Hlady, V. Plasma Protein Adsorption: The Big Twelve. Ann. N. Y. Acad. Sci. 1987, 516, 158−172. (541) Wahlgren, M.; Arnebrant, T. Protein Adsorption to Solid Surfaces. Trends Biotechnol. 1991, 9, 201−208. (542) Norde, W. Adsorption of Proteins from Solution at the Solidliquid Interface. Adv. Colloid Interface Sci. 1986, 25, 267−340. (543) Chen, Y.; Kang, E. T.; Neoh, K. G.; Wang, P.; Tan, K. L. Surface Modification of Polyaniline Film by Grafting of Poly Ethylene Glycol for Reduction in Protein Adsorption and Platelet Adhesion. Synth. Met. 2000, 110, 47−55. (544) Zhang, F.; Kang, E. T.; Neoh, K. G.; Wang, P.; Tan, K. L. Reactive Coupling of Poly(ethylene Glycol) on Electroactive Polyaniline Films for Reduction in Protein Adsorption and Platelet Adhesion. Biomaterials 2002, 23, 787−795. (545) Skotheim, T. A.; Elsenbaumer, R. L.; Reynolds, J. R. Handbook of Conducting Polymers, 2nd ed.; Marcel Dekker: New York, 1998. (546) Lucarelli, F.; Tombelli, S.; Minunni, M.; Marrazza, G.; Mascini, M. Electrochemical and Piezoelectric DNA Biosensors for Hybridisation Detection. Anal. Chim. Acta 2008, 609, 139−159. (547) Jacobs, C. B.; Peairs, M. J.; Venton, B. J. Review: Carbon Nanotube Based Electrochemical Sensors for Biomolecules. Anal. Chim. Acta 2010, 662, 105−127. (548) Goldberg, J. L.; Barres, B. A. The Relationship between Neuronal Survival and Regeneration. Annu. Rev. Neurosci. 2000, 23, 579−612. (549) Liu, K.; Tedeschi, A.; Park, K. K.; He, Z. Neuronal Intrinsic Mechanisms of Axon Regeneration. Annu. Rev. Neurosci. 2011, 34, 131−152. (550) Chen, Z. L.; Yu, W. M.; Strickland, S. Peripheral Regeneration. Annu. Rev. Neurosci. 2007, 30, 209−233.

(551) Kim, J. E.; Li, S.; GrandPre, T.; Qiu, D.; Strittmatter, S. M. Axon Regeneration in Young Adult Mice Lacking Nogo-A/B. Neuron 2003, 38, 187−199. (552) David, S.; Aguayo, A. J. Axonal Elongation into Peripheral Nervous System “bridges” after Central Nervous System Injury in Adult Rats. Science 1981, 214, 931−933. (553) Cai, D.; Shen, Y.; De Bellard, M.; Tang, S.; Filbin, M. T. Prior Exposure to Neurotrophins Blocks Inhibition of Axonal Regeneration by MAG and Myelin via a cAMP-Dependent Mechanism. Neuron 1999, 22, 89−101. (554) Dergham, P.; Ellezam, B.; Essagian, C.; Avedissian, H.; Lubell, W. D.; McKerracher, L. Rho Signaling Pathway Targeted to Promote Spinal Cord Repair. J. Neurosci. 2002, 22, 6570−6577. (555) Qiu, J.; Cai, D.; Dai, H.; McAtee, M.; Hoffman, P. N.; Bregman, B. S.; Filbin, M. T. Spinal Axon Regeneration Induced by Elevation of Cyclic AMP. Neuron 2002, 34, 895−903. (556) Song, H.; Ming, G.; He, Z.; Lehmann, M.; McKerracher, L.; Tessier-Lavigne, M.; Poo, M. Conversion of Neuronal Growth Cone Responses from Repulsion to Attraction by Cyclic Nucleotides. Science 1998, 281, 1515−1518. (557) Spitzer, N. C. Electrical Activity in Early Neuronal Development. Nature 2006, 444, 707−712. (558) Song, B.; Zhao, M.; Forrester, J.; McCaig, C. Nerve Regeneration and Wound Healing Are Stimulated and Directed by an Endogenous Electrical Field in Vivo. J. Cell Sci. 2004, 117, 4681− 4690. (559) Patel, N.; Poo, M. M. Orientation of Neurite Growth by Extracellular Electric Fields. J. Neurosci. 1982, 2, 483−496. (560) Patel, N. B.; Poo, M. M. Perturbation of the Direction of Neurite Growth by Pulsed and Focal Electric Fields. J. Neurosci. 1984, 4, 2939−2947. (561) Al-Majed, A. A.; Neumann, C. M.; Brushart, T. M.; Gordon, T. Brief Electrical Stimulation Promotes the Speed and Accuracy of Motor Axonal Regeneration. J. Neurosci. 2000, 20, 2602−2608. (562) Kimura, K.; Yanagida, Y.; Haruyama, T.; Kobatake, E.; Aizawa, M. Gene Expression in the Electrically Stimulated Differentiation of PC12 Cells. J. Biotechnol. 1998, 63, 55−65. (563) Geremia, N. M.; Gordon, T.; Brushart, T. M.; Al-Majed, A. A.; Verge, V. M. Electrical Stimulation Promotes Sensory Neuron Regeneration and Growth-Associated Gene Expression. Exp. Neurol. 2007, 205, 347−359. (564) Udina, E.; Furey, M.; Busch, S.; Silver, J.; Gordon, T.; Fouad, K. Electrical Stimulation of Intact Peripheral Sensory Axons in Rats Promotes Outgrowth of Their Central Projections. Exp. Neurol. 2008, 210, 238−247. (565) Goldberg, J. L.; Espinosa, J. S.; Xu, Y.; Davidson, N.; Kovacs, G. T.; Barres, B. A. Retinal Ganglion Cells Do Not Extend Axons by Default: Promotion by Neurotrophic Signaling and Electrical Activity. Neuron 2002, 33, 689−702. (566) Okazaki, Y.; Morimoto, T.; Sawai, H. Parameters of Optic Nerve Electrical Stimulation Affecting Neuroprotection of Axotomized Retinal Ganglion Cells in Adult Rats. Neurosci. Res. 2008, 61, 129−135. (567) Miyake, K.; Yoshida, M.; Inoue, Y.; Hata, Y. Neuroprotective Effect of Transcorneal Electrical Stimulation on the Acute Phase of Optic Nerve Injury. Invest. Ophthalmol. Visual Sci. 2007, 48, 2356− 2361. (568) Tagami, Y.; Kurimoto, T.; Miyoshi, T.; Morimoto, T.; Sawai, H.; Mimura, O. Axonal Regeneration Induced by Repetitive Electrical Stimulation of Crushed Optic Nerve in Adult Rats. Jpn. J. Ophthalmol. 2009, 53, 257−266. (569) Fujikado, T.; Morimoto, T.; Matsushita, K.; Shimojo, H.; Okawa, Y.; Tano, Y. Effect of Transcorneal Electrical Stimulation in Patients with Nonarteritic Ischemic Optic Neuropathy or Traumatic Optic Neuropathy. Jpn. J. Ophthalmol. 2006, 50, 266−273. (570) Fields, R. D.; Neale, E. A.; Nelson, P. G. Effects of Patterned Electrical Activity on Neurite Outgrowth from Mouse Sensory Neurons. J. Neurosci. 1990, 10, 2950−2964. BX

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(571) Enes, J.; Langwieser, N.; Ruschel, J.; Carballosa-Gonzalez, M. M.; Klug, A.; Traut, M. H.; Ylera, B.; Tahirovic, S.; Hofmann, F.; et al. Electrical Activity Suppresses Axon Growth through Ca(v)1.2 Channels in Adult Primary Sensory Neurons. Curr. Biol. 2010, 20, 1154−1164. (572) Fields, R. D.; Eshete, F.; Stevens, B.; Itoh, K. Action PotentialDependent Regulation of Gene Expression: Temporal Specificity in Ca2+, cAMP-Responsive Element Binding Proteins, and MitogenActivated Protein Kinase Signaling. J. Neurosci. 1997, 17, 7252−7266. (573) Morimoto, T.; Miyoshi, T.; Sawai, H.; Fujikado, T. Optimal Parameters of Transcorneal Electrical Stimulation (TES) to Be Neuroprotective of Axotomized RGCs in Adult Rats. Exp. Eye Res. 2010, 90, 285−291. (574) Ou, Y.-T.; Lu, M. S.; Chiao, C.-C. The Effects of Electrical Stimulation on Neurite Outgrowth of Goldfish Retinal Explants. Brain Res. 2012, 1480, 22−29. (575) Lenik, J. Cyclodextrins Based Electrochemical Sensors for Biomedical and Pharmaceutical Analysis. Curr. Med. Chem. 2017, 24, 2359−2391. (576) Cha, K.; Faris, R. G.; Brown, E. F.; Wilmore, D. W. An Electronic Method for Rapid Measurement of Haematocrit in Blood Samples. Physiol. Meas. 1994, 15, 129−137. (577) Carallo, C.; Pujia, A.; Irace, C.; De Franceschi, M. S.; Motti, C.; Gnasso, A. Whole Blood Viscosity and Haematocrit Are Associated with Internal Carotid Atherosclerosis in Men. Coron. Artery Dis. 1998, 9, 113−117. (578) Rim, S.-J.; Leong-Poi, H.; Lindner, J. R.; Wei, K.; Fisher, N. G.; Kaul, S. Decrease in Coronary Blood Flow Reserve during Hyperlipidemia Is Secondary to an Increase in Blood Viscosity. Circulation 2001, 104, 2704−2709. (579) Oshima, S.; Sankai, Y. Improvement of the Accuracy in the Optical Hematocrit Measurement by Optimizing Mean Optical Path Length. Artif. Organs 2009, 33, 749−756. (580) Kenyeres, P.; Juricskay, I.; Tarsoly, P.; Kesmarky, G.; Muhl, D.; Toth, K.; Bogar, L. Low Hematocrit per Blood Viscosity Ratio as a Mortality Risk Factor in Coronary Heart Disease. Clin. Hemorheol. Microcirc. 2008, 38, 51−56. (581) Foley, R. N.; Parfrey, P. S.; Harnett, J. D.; Kent, G. M.; Murray, D. C.; Barre, P. E. The Impact of Anemia on Cardiomyopathy, Morbidity, and and Mortality in End-Stage Renal Disease. Am. J. Kidney Dis. 1996, 28, 53−61. (582) Ritz, E.; Zeier, M.; Schneider, P.; Jones, E. Cardiovascular Mortality of Patients with Polycystic Kidney Disease on Dialysis: Is There a Lesson to Learn? Nephron 2004, 66, 125−128. (583) Shirakura, T.; Kubota, K.; Tamura, K. Blood Viscosity and Cerebral Blood Flow in Aged. Nihon Ronen Igakkai Zasshi 1993, 30, 174−181. (584) Hirsch, F. G.; Tester, E. C.; Wood, L. A.; Ballard, W. C.; Horna, F. E.; Wright, I. S. The Electrical Conductivity of Blood. I: Relationship to Erythrocyte Concentration. Blood 1950, 5, 1017− 1035. (585) Gram, H. C. Cell Volume and Electeical Conductivity of Blood. J. Biol. Chem. 1924, 59, 33−40. (586) Velick, B. Y. S.; Gorin, M. The Electrical Conductance of Suspensions of Ellipsoids and Its Relation to the Study of Avian Erythrocytes. J. Gen. Physiol. 1940, 23, 753−771. (587) Pop, G.; Hop, W.; Moraru, L.; van der Jagt, M.; Quak, J.; Dekkers, D.; Chang, Z.; Gijsen, F.; Duncker, D.; Slager, C. Blood Electrical Impedance Closely Matches Whole Blood Viscosity as Parameter of Hemorheology and Inflammation. Appl. Rheol. 2003, 13, 205−213. (588) Steinfelder-Visscher, J.; Weerwind, P. W.; Teerenstra, S.; Pop, G. A.; Brouwer, R. M. Conductivity-Based Hematocrit Measurement during Cardiopulmonary Bypass. J. Clin. Monit. Comput. 2007, 21, 7− 12. (589) Bull, H. B.; Breese, K. Electrical Conductance of Protein Solutions. J. Colloid Interface Sci. 1969, 29, 492−495.

(590) Ohshima, H. Electrical Conductivity of a Concentrated Suspension of Soft Particles. J. Colloid Interface Sci. 2000, 229, 140− 147. (591) Zhao, T. X. Electrical Impedance and Haematocrit of Human Blood with Various Anticoagulants. Physiol. Meas. 1993, 14, 299−307. (592) Ludt, H.; Herrmann, H. In Vitro Measurement of Tissue Impedance over a Wide Frequency Range. Radiat. Environ. Biophys. 1973, 10, 337−345. (593) Jaspard, F.; Nadi, M. Dielectric Properties of Blood: an investigation of temperature dependence. Physiol. Meas. 2002, 23, 547−554. (594) Zhao, T. X.; Jacobson, B.; Ribbe, T. Triple-Frequency Method for Measuring Blood Impedance. Physiol. Meas. 1993, 14, 145−156. (595) Okada, R.; Schwan, H. An Electrical Method to Determine Hematocrits. IRE Trans. Med. Electron. 1960, ME-7, 188−192. (596) Jung, J. M.; Lee, D. H.; Kim, K. T.; Cho, Y. I. Determination of Hematocrit Using on-Line Conductance Cell. Int. J. Heat Mass Transfer 2012, 55, 1836−1843. (597) Lindinger, M. I.; Kowalchuk, J. M.; Heigenhauser, G. J. F. Applying Physicochemical Principles to Skeletal Muscle Acid-Base Status. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005, 289, R891− R894. (598) Cui, X.; Li, C. M.; Zang, J.; Zhou, Q.; Gan, Y.; Bao, H.; Guo, J.; Lee, V. S.; Moochhala, S. M. Biocatalytic Generation of PpyEnzyme-CNT Nanocomposite: From Network Assembly to Film Growth. J. Phys. Chem. C 2007, 111, 2025−2031. (599) Pereira, A. C.; Aguiar, M. R.; Kisner, A.; Macedo, D. V.; Kubota, L. T. Amperometric Biosensor for Lactate Based on Lactate Dehydrogenase and Meldola Blue Coimmobilized on Multi-Wall Carbon-Nanotube. Sens. Actuators, B 2007, 124, 269−276. (600) Tsai, Y.-C.; Chen, S.-Y.; Liaw, H.-W. Immobilization of Lactate Dehydrogenase within Multiwalled Carbon NanotubeChitosan Nanocomposite for Application to Lactate Biosensors. Sens. Actuators, B 2007, 125, 474−481. (601) Vallet, B.; Tavernier, B.; Lund, N. Assessment of Tissue Oxygenation in the Critically Ill. Eur. J. Anaesthesiol. 2000, 17, 221− 229. (602) Nathan, A. T.; Singer, M. The Oxygen Trail: Tissue Oxygenation. Br. Med. Bull. 1999, 55, 96−108. (603) Vallet, B. Vascular Reactivity and Tissue Oxygenation. Intensive Care Med. 1998, 24, 3−11. (604) Vaupel, P.; Kallinowski, F.; Okunieff, P. Blood Flow, Oxygen Consumption, and Tissue Oxygenation of Human Tumors. Adv. Exp. Med. Biol. 1990, 277, 895−905. (605) Whitney, J. D. Physiologic Effects of Tissue Oxygenation on Wound Healing. Heart Lung 1989, 18, 466−474. (606) Robertson, P. W.; Hart, B. B. Assessment of Tissue Oxygenation. Respir. Care Clin. N. Am. 1999, 5, 221−263. (607) Siegemund, M.; van Bommel, J.; Ince, C. Assessment of Regional Tissue Oxygenation. Intensive Care Med. 1999, 25, 1044− 1060. (608) Vinogradov, S. A.; Lo, L. W.; Jenkins, W. T.; Evans, S. M.; Koch, C.; Wilson, D. F. Noninvasive Imaging of the Distribution in Oxygen in Tissue in Vivo Using near-Infrared Phosphors. Biophys. J. 1996, 70, 1609−1617. (609) Swartz, H. M.; Clarkson, R. B. The Measurement of Oxygen in Vivo Using EPR Techniques. Phys. Med. Biol. 1998, 43, 1957− 1975. (610) Robinson, S. P.; Howe, F. A.; Rodrigues, L. M.; Stubbs, M.; Griffiths, J. R. Magnetic Resonance Imaging Techniques for Monitoring Changes in Tumor Oxygenation and Blood Flow. Semin. Radiat. Oncol. 1998, 8, 197−207. (611) Lo, L. W.; Koch, C. J.; Wilson, D. F. Calibration of OxygenDependent Quenching of the Phosphorescence of Pd-Meso-Tetra (4Carboxyphenyl) Porphine: A Phosphor with General Application for Measuring Oxygen Concentration in Biological Systems. Anal. Biochem. 1996, 236, 153−160. (612) Horsman, M. R. Measurement of Tumor Oxygenation. Int. J. Radiat. Oncol., Biol., Phys. 1998, 42, 701−704. BY

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

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Polyaniline Hydrogel Heterostructures. ACS Nano 2013, 7, 3540− 3546. (633) Mahmoudi, M.; Lynch, I.; Ejtehadi, M. R.; Monopoli, M. P.; Bombelli, F. B.; Laurent, S. Protein−Nanoparticle Interactions: Opportunities and Challenges. Chem. Rev. 2011, 111, 5610−5637. (634) Monopoli, M. P.; Åberg, C.; Salvati, A.; Dawson, K. A. Biomolecular Coronas Provide the Biological Identity of Nanosized Materials. Nat. Nanotechnol. 2012, 7, 779−786. (635) Mahmoudi, M.; Shokrgozar, M. A.; Sardari, S.; Moghadam, M. K.; Vali, H.; Laurent, S.; Stroeve, P. Irreversible Changes in Protein Conformation due to Interaction with Superparamagnetic Iron Oxide Nanoparticles. Nanoscale 2011, 3, 1127−1138. (636) Monopoli, M. P.; Walczyk, D.; Campbell, A.; Elia, G.; Lynch, I.; Bombelli, F. B.; Dawson, K. A. Physical−Chemical Aspects of Protein Corona: Relevance to in Vitro and in Vivo Biological Impacts of Nanoparticles. J. Am. Chem. Soc. 2011, 133, 2525−2534. (637) Mirshafiee, V.; Kim, R.; Park, S.; Mahmoudi, M.; Kraft, M. Impact of Protein Pre-Coating on the Protein Corona Composition and Nanoparticle Cellular Uptake. Biomaterials 2016, 75, 295−304. (638) Mahmoudi, M.; Sheibani, S.; Milani, A. S.; Rezaee, F.; Gauberti, M.; Dinarvand, R.; Vali, H. Crucial Role of the Protein Corona for the Specific Targeting of Nanoparticles. Nanomedicine (London, U. K.) 2015, 10, 215−226. (639) Mirshafiee, V.; Mahmoudi, M.; Lou, K.; Cheng, J.; Kraft, M. L. Protein Corona Significantly Reduces Active Targeting Yield. Chem. Commun. 2013, 49, 2557−2559. (640) Salvati, A.; Pitek, A. S.; Monopoli, M. P.; Prapainop, K.; Bombelli, F. B.; Hristov, D. R.; Kelly, P. M.; Åberg, C.; Mahon, E.; Dawson, K. A. Transferrin-Functionalized Nanoparticles Lose Their Targeting Capabilities When a Biomolecule Corona Adsorbs on the Surface. Nat. Nanotechnol. 2013, 8, 137−143. (641) Guo, B.; Ma, P. X. Conducting Polymers for Tissue Engineering. Biomacromolecules 2018, 19, 1764−1782. (642) Zelikin, A. N.; Lynn, D. M.; Farhadi, J.; Martin, I.; Shastri, V.; Langer, R. Erodible Conducting Polymers for Potential Biomedical Applications. Angew. Chem., Int. Ed. 2002, 41, 141−144. (643) Antoniadou, E. V.; Ahmad, R. K.; Jackman, R. B.; Seifalian, A. M. Next Generation Brain Implant Coatings and Nerve Regeneration via Novel Conductive Nanocomposite Development. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS; IEEE: Piscataway, NJ, 2011; pp 3253− 3257. (644) Someya, T.; Bao, Z.; Malliaras, G. G. The Rise of Plastic Bioelectronics. Nature 2016, 540, 379−385. (645) Chortos, A.; Liu, J.; Bao, Z. Pursuing Prosthetic Electronic Skin. Nat. Nat. Mater. 2016, 15, 937−950. (646) Wang, Y.; Zhu, C.; Pfattner, R.; Yan, H.; Jin, L.; Chen, S.; Molina-Lopez, F.; Lissel, F.; Liu, J.; Rabiah, N. I.; et al. A Highly Stretchable, Transparent, and Conductive Polymer. Sci. Adv. 2017, 3, No. e1602076. (647) Nezakati, T. Development of a Graphene-POSS-Nanocomposite Conductive Material for Biomedical Application. Ph.D. Thesis, University College London, 2016.

(613) Griffiths, J. R.; Robinson, S. P. The OxyLite: A Fibre-Optic Oxygen Sensor. Br. J. Radiol. 1999, 72, 627−630. (614) Golman, K.; Petersson, J. S.; Ardenkjaer-Larsen, J. H.; Leunbach, I.; Wistrand, L. G.; Ehnholm, G.; Liu, K. Dynamic in Vivo Oxymetry Using Overhauser-Enhanced MR Imaging. J. Magn. Reson. Imaging 2000, 12, 929−938. (615) Alhallaq, H.; River, J.; Zamora, M.; Oikawa, H.; Karczmar, G. Correlation of Magnetic Resonance and Oxygen Microelectrode Measurements of Carbogen-Induced Changes in Tumor Oxygenation. Int. J. Radiat. Oncol., Biol., Phys. 1998, 41, 151−159. (616) Krishna, M. C.; Subramanian, S.; Kuppusamy, P.; Mitchell, J. B. Magnetic Resonance Imaging for in Vivo Assessment of Tissue Oxygen Concentration. Semin. Radiat. Oncol. 2001, 11, 58−69. (617) Velan, S. S.; Spencer, R. G.; Zweier, J. L.; Kuppusamy, P. Electron Paramagnetic Resonance Oxygen Mapping (EPROM): Direct Visualization of Oxygen Concentration in Tissue. Magn. Reson. Med. 2000, 43, 804−809. (618) Liu, K. J.; Gast, P.; Moussavi, M.; Norby, S. W.; Vahidi, N.; Walczak, T.; Wu, M.; Swartz, H. M. Lithium Phthalocyanine: A Probe for Electron Paramagnetic Resonance Oximetry in Viable Biological Systems. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 5438−5442. (619) Vahidi, N.; Clarkson, R. B.; Liu, K. J.; Norby, S. W.; Wu, M.; Swartz, H. M. In Vivo and in Vitro EPR Oximetry with Fusinite: A New Coal-Derived, Particulate EPR Probe. Magn. Reson. Med. 1994, 31, 139−146. (620) Zweier, J. L.; Chzhan, M.; Ewert, U.; Schneider, G.; Kuppusamy, P. Development of a Highly Sensitive Probe for Measuring Oxygen in Biological Tissues. J. Magn. Reson., Ser. B 1994, 105, 52−57. (621) Clarkson, R. B.; Odintsov, B. M.; Ceroke, P. J.; ArdenkjaerLarsen, J. H.; Fruianu, M.; Belford, R. L. Electron Paramagnetic Resonance and Dynamic Nuclear Polarization of Char Suspensions: Surface Science and Oximetry. Phys. Med. Biol. 1998, 43, 1907−1920. (622) Ilangovan, G.; Zweier, J. L.; Kuppusamy, P. Electrochemical Preparation and EPR Studies of Lithium Phthalocyanine: Evaluation of the Nucleation and Growth Mechanism and Evidence for Potential Dependent Phase Formation. J. Phys. Chem. B 2000, 104, 4047−4059. (623) Ilangovan, G.; Zweier, J. L.; Kuppusamy, P. Electrochemical Preparation and EPR Studies of Lithium Phthalocyanine. Part 2: Particle Size-Dependent Line Broadening by Molecular Oxygen and Its Implications as an Oximetry Probe. J. Phys. Chem. B 2000, 104, 9404−9410. (624) Ilangovan, G.; Manivannan, A.; Li, H.; Yanagi, H.; Zweier, J. L.; Kuppusamy, P. A Naphthalocyanine-Based EPR Probe for Localized Measurements of Tissue Oxygenation. Free Radical Biol. Med. 2002, 32, 139−147. (625) Muller, D. Studies on the New Enzyme Glucose Oxidase. I. Biochem. Z. 1928, 199, 136−170. (626) Pauly, H. E.; Pfleiderer, G. Glucose Dehydrogenase from Bacillus Megaterium M 1286: Purification, Properties and Structure. Hoppe-Seyler's Z. Physiol. Chem. 1975, 356, 1613−1623. (627) Alwarappan, S.; Boyapalle, S.; Kumar, A.; Li, C.-Z.; Mohapatra, S. Comparative Study of Single-, Few-, and Multilayered Graphene toward Enzyme Conjugation and Electrochemical Response. J. Phys. Chem. C 2012, 116, 6556−6559. (628) Novoselov, K. S.; Geim, a K.; Morozov, S. V.; Jiang, D.; Zhang, Y.; Dubonos, S. V.; Grigorieva, I. V.; Firsov, A. A. Electric Field Effect in Atomically Thin Carbon Films. Science 2004, 306, 666−669. (629) Geim, A. K. Graphene: Status and Prospects. Science 2009, 324, 1530−1534. (630) Li, L.; Wang, Y.; Pan, L.; Shi, Y.; Cheng, W.; Shi, Y.; Yu, G. A Nanostructured Conductive Hydrogels-Based Biosensor Platform for Human Metabolite Detection. Nano Lett. 2015, 15, 1146−1151. (631) Li, L.; Shi, Y.; Pan, L.; Shi, Y.; Yu, G. Rational Design and Applications of Conducting Polymer Hydrogels as Electrochemical Biosensors. J. Mater. Chem. B 2015, 3, 2920−2930. (632) Zhai, D.; Liu, B.; Shi, Y.; Pan, L.; Wang, Y.; Li, W.; Zhang, R.; Yu, G. Highly Sensitive Glucose Sensor Based on Pt Nanoparticle/ BZ

DOI: 10.1021/acs.chemrev.6b00275 Chem. Rev. XXXX, XXX, XXX−XXX

Conductive Polymers: Opportunities and Challenges in Biomedical

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