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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Received: May 4, 2016

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

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


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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.

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