Flexible Organic Electronics in Biology: Materials and Devices.

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Flexible Organic Electronics in Biology: Materials and Devices Caizhi Liao, Meng Zhang, Mei Yu Yao, Tao Hua, Li Li,* and Feng Yan*

electronics. Nowadays, there are a variety of commercially available bioelectronic devices that can offer the possibility of improving healthcare conditions, ranging from biosensors and pacemakers to cochlear implants and biomedical instruments.[1,2] A bioelectronic device normally consists of several essential parts, such as active elements to transduce the signals across the electronics/biology interface, electronics to control and record corresponding signals, and power sources, among which the used materials play the most significant role. For example, materials for biological sensing should demonstrate good biocompatibility and stability in physiological conditions.[3,4] The biological interface associated with the implanted device and the surrounding biological systems has a significant effect on the output performance of the bioelectronic devices. For efficient electrical neural recording/stimulating processes, coated materials on the electrodes should decrease the impedance of biological interfaces and be compatible with the surrounding biological environment.[2,5] Therefore, the exploration of novel materials used for bioelectronics will offer more opportunities to boost the development of this emerging area. In the last few decades, the field of organic electronics has developed at a breath-taking speed. The great interest in organic electronics, which is mostly based on π-conjugated organic semiconductors, is originally motivated by the desirable properties (e.g., solution processability; flexibility; light weight, etc.) of the versatile organic materials.[6] Significant progress has been made in organic electronics, such as organic photovoltaic devices (OPVs),[7] organic light-emitting diodes (OLEDs),[8] and organic thin-film transistors (OTFTs).[9] Additionally, the potential use of organic electronics for biological applications has been fueled by the unique mixed electronic and ionic transport properties in conducting polymers. Bioelectronics devices based on organic materials, such as OTFTs for the sensitive detection of biological analytes,[9–12] organic electrochemical ion pumps (OEIPs)[13] for the dynamic control of drug delivery, and polymer electrodes for recording/stimulation of cells and neural,[14] have all been successfully realized through easy fabrication process. As a fastgrowing field of study, organic electronics interfacing with biological worlds, mostly abbreviated as organic bioelectronics, is poised to shape the development of science and technology.

At the convergence of organic electronics and biology, organic bioelectronics attracts great scientific interest. The potential applications of organic semiconductors to reversibly transmit biological signals or stimulate biological tissues inspires many research groups to explore the use of organic electronics in biological systems. Considering the surfaces of movable living tissues being arbitrarily curved at physiological environments, the flexibility of organic bioelectronic devices is of paramount importance in enabling stable and reliable performances by improving the contact and interaction of the devices with biological systems. Significant advances in flexible organic bioelectronics have been achieved in the areas of flexible organic thin film transistors (OTFTs), polymer electrodes, smart textiles, organic electrochemical ion pumps (OEIPs), ion bipolar junction transistors (IBJTs) and chemiresistors. This review will firstly discuss the materials used in flexible organic bioelectronics, which is followed by an overview on various types of flexible organic bioelectronic devices. The versatility of flexible organic bioelectronics promises a bright future for this emerging area.

1. Introduction The pioneering experiments performed by Luigi Galvani in the 1780s at the University of Bologna have blazed the trail for the bioelectronics field. In a famous experiment, he found that muscular activity could be induced by applying a voltage to the detached leg muscle of a frog. In the next two hundred years, this elegant work has inspired many to explore the use of electrical stimulation to control biological events and build an efficient bridge to connect the worlds of biology and electronics. As a multidisciplinary research field, we use the term bioelectronics in this review to define the convergence of biology and

C. Liao, M. Zhang, Prof. F. Yan Department of Applied Physics and Materials Research Centre The Hong Kong Polytechnic University Kowloon, Hong Kong E-mail: [email protected] M. Y. Yao, Dr. T. Hua, Prof. L. Li Institute of Textiles & Clothing The Hong Kong Polytechnic University Kowloon, Hong Kong E-mail: [email protected]

DOI: 10.1002/adma.201402625

Adv. Mater. 2014, DOI: 10.1002/adma.201402625

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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The realization of flexible electronics is one of the most exciting challenges in the research community and is expected to significantly broaden the application scope of electronics. The emerging flexible electronics open the door for the new application paradigm in large-area electronics, typically including photovoltaics, displays, transistors, and actuators.[15] Most importantly, the flexible electronics offer the possibility for the easy spreading of electronics over arbitrarily curved surfaces and movable parts. As a result, flexible organic electronic have experienced a fast growth in the last few years. Bendable and rollable organic electronics have been extensively investigated and used in the applications of pressure sensing and e-skins.[16,17] The softness and flexibility of organic bioelectronics must be improved to increase its biocompatibility because the flexible tissues in the biological systems contain various kinds of movements in their physiological functions. For the applications interfaced with human body or other living biological systems, flexible organic bioelectronic devices are expected to provide a much better connectivity between the electronics and biology than that of their hard-rigid counterparts.[18] Therefore, flexible bioelectronic devices hold great potential for the future high-tech products able to improve the quality of human’s life. On the other hand, flexible bioelectronic devices can be easily integrated with the textiles to fabricate the wearable smart devices.[19,20] For example, in the science fiction blockbuster “After Earth” in 2013, Kitai Raige wears a smart suit able to respond to surrounding environments and his own body conditions by changing color. In the real world, commercially available smart wear devices, such as Google glasses and Fitbit Flex, have already stepped into common people’s life. Versatile organic bioelectronic platforms can be easily fabricated on planar flexible substrates or fibers using low-cost processing approaches. For fiber-based flexible organic bioelectronics, smart e-textiles can be easily realized by the weaving of electronic-material-integrated textile fibers.[21] In this review, we aim to illustrate different aspects of the flexible organic bioelectronics. It is not the intention to fully cover allrelated past work, but rather a selection of highlighted work that can potentially signify the future trends of flexible organic bioelectronics. We hope the presented discussion here will evoke more interest and idea-exchange in this emerging field. The review consists of two major parts: materials and devices (Figure 1). In Section 2, we will discuss the materials used for flexible organic bioelectronics. Essential material properties, classified material types for the active layers, substrates and electrodes will be summarized in detail. In Sections 3–6, we will summarize the most-important flexible organic bioelectronics devices, namely organic thin-film transistors (OTFTs), polymer electrodes, smart textiles, organic electrochemical ion pumps (OEIPs), ion bipolar junction transistors(IBJTs), and chemiresistors. In the end, conclusions and outlook for this field will be addressed.

2. Materials 2.1. Organic Semiconductors The breakthrough in the serendipitous discovery of the first inherently conductive polymer by Hideki Shirakawa and Alan

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Liao Caizhi is a Master of Philosophy (Mphil) student under the supervision of Prof. Feng Yan in the Department of Applied Physics, The Hong Kong Polytechnic University, Hong Kong. His research interests focus on organic semiconducting polymers, organic electronics, chemical and biological sensors, flexible and wearable electronic device, and biomaterials. In 2008, he received his bachelor of engineering degree in polymer science and engineering from Hefei University of Technology, China. Prof. Feng Yan has research interests in thin-film transistors, graphene, organic electronics, biosensors, solar cells, and smart materials. He received his Ph.D. degree in physics from Nanjing University in China. Then he joined the Engineering Department of Cambridge University in February 2001 as a Research Associate and the National Physical Laboratory in the UK in April 2006 as a Higher Research Scientist. He became an Assistant Professor at the Department of Applied Physics of the Hong Kong Polytechnic University in September 2006 and was promoted to Associate Professor in July 2012.

Heeger in 1977 led to a brand-new era for the material science.[22] During the last few decades, conductive organic semiconductors have been developed at a breath-taking speed and already become the versatile “rising-star” material both for the academia and industry.[23] Significant progress has been made by chemists to create a large family of π-conjugated conducting materials, most typically including polypyrrole, polyaniline, and polythiophene, etc. As the future materials for the manufacture of the emerging organic electronics devices, such as organic photovoltaic devices (OPVs),[24] organic light-emitting diodes (OLEDs), and organic thin-film transistors (OTFTs),[9] organic semiconductors have emerged as promising competitive materials to the conventional inorganic semiconductors, such as Si and Ge. Organic semiconductors normally consist of two types: p-type semiconductors with electron-donating groups involving the highest occupied molecular orbital (HOMO) levels and n-type semiconductors with electron-accepting ones involving the lowest unoccupied molecular orbital (LUMO) levels. Both types of semiconducting materials mostly have conjugated molecular structures and exhibit the similar electronic and optical properties to that of inorganic counterparts.[25] On the other hand, organic semiconductors can be classified as two big




REVIEW Figure 1. The relationship between material and device in flexible organic electronics is analogous to that of “Yin” and “Yang” in the traditional Chinese Taiji. Interestingly, Taiji represents a Chinese cosmological term for the supreme ultimate state of infinite “flexibility” and “potentiality”. Similarly, material and device are mutually connected and ultimately merged to become the power source of each other. To fabricate high-performance flexible organic bioelectronics, including OTFTs sensors, polymer electrodes, smart textiles, OEIPs and chemiresistors, the materials should demonstrate adequate solubility, biocompatibility, flexibility, ion-to-electron conversion property, functionality and stability, etc. Images reproduced with permission: “Biocompatibility” image reproduced with permission.[1] Copyright 2007, John Wiley & Sons, Inc. “Flexibility” image reproduced with permission.[96] Copyright 2010, Macmillan Publishers Ltd. “Ion-to-electron” image reproduced with permission.[3] Copyright 2013, The Royal Society of Chemistry. “Functionality” image reproduced with permission.[71] Copyright 2013, American Chemical Society. “OTFTs Sensors” image reproduced with permission[51] Copyright 2011, John Wiley & Sons, Inc. “Electrodes” image reproduced with permission.[164] Copyright 2005, Elsevier. “OEIPs” image reproduced with permission.[198] Copyright 2009, Macmillan Publishers Ltd. “Chemresistor” image reproduced with permission.[207] Copyright 2008, Elsevier.

families: polymer semiconductors and small-molecule organic semiconductors, based on the molecular backbones and structures. Primarily due to their extremely high electrical conductivity, some kind conjugated polymers are also referred as “synthetic metal”.[26] Small-molecule organic semiconductors can form ordered crystal structures, leading to carrier mobilities comparable to or even higher than that of amorphous Si.[27,28] Small-molecule organic devices can be fabricated by thermal evaporation at low temperature, which enables high throughout fabrication processes.[29,30] Distinct from their polymer counterparts, small-molecule organic semiconductors exhibit some identifying features, such as high purity, strictly controlled molecular structure, and well-defined molecular-weight. Smallorganic-molecule-based devices have been extensively used for gas-sensing applications in which the performance was strictly influenced by the morphology of the deposited organic film, grain boundaries, and traps.[31,32] However, for the electronics interfacing with the world of biology, conducting polymers are far more utilized than small-molecule organic semiconductors. Biological system is an aqueous environment in which ion flux carries significant amount of information and regulates the life processes. The mixed ionic and electronic transport ability makes conducting polymers the ideal communication channel to bridges the worlds of electronics and biology, creating countless exciting scenarios for organic electronics.[4,5] Therefore, the afterward-mentioned organic semiconductor materials are mostly related to conducting polymers.


Most organic semiconductors have continuous sp2-hybridized carbon centers along the molecular backbone, giving rise to partially delocalized π-orbital states that will significantly alter the electrical and optical properties of materials.[33] Normally, π-conjugated systems account for the electrical conduction of organic semiconductors. Due to the complicated π-conjugated systems in such materials, organic semiconductors cover a wide range of conductivities for over fifteen orders of magnitude. Quite a few models for the explanation of varied conductivities of organic semiconductors are built on carrier hopping processes.[34] Typically, the electrical conductivity of an organic semiconductor is largely determined by two significant factors of carriers (electron or hole): mobility and density. Most recent case studies have shown that organic semiconductors have relatively low carrier mobilities and limited carrier densities, both of which are influenced by many factors, such as the intrinsic features, film morphology and characterization procedures.[35] The formation of the solid organic semiconductor film usually relies on the weak intermolecular interactions, for example, van der Waals effect and dipole–dipole interactions,[36] leading to a strictly hindered intermolecular charge transport with a very low carrier mobility. To facilitate carrier transport between adjacent molecules, the film morphology should be improved to obtain a more-ordered intermolecular structure, which could effectively increase the π–π overlap between organic molecules. In addition, the properties of organic semiconducting materials can be easily tailored through doping process.[37] Doping



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can oxidize (p-doping) or reduce (n-doping) a neutral polymer by providing a counter dopant. Conducting polymers can be doped chemically or electrochemically, depending on the oxidation potential. Upon the introduction of counter ions into a conducting polymer, the backbone of the polymer will be correspondingly charged to maintain a net charge of zero and consequently have more charge carriers.[38] These charge carriers moving along the conjugated conducting polymer backbone produce the electrical conductivity, which can be significantly influenced by the doping processes (i.e., dopant and doping level).[39] The available library of the molecules for polymer doping ranges from small salt ions, peptides, to large bio-macromolecules, such as polysaccharides and proteins.[40] For example, chloride anions are commonly used to dope conducting polymers primarily due to their excellent biocompatibility. More importantly, some large biological molecules used as the dopant will not be readily leached out from a conducting polymer even under an electrical potential, offering great possibilities for biomolecule immobilization. Therefore, doping provides a feasible way to manipulate the physical, chemical and biological properties of the polymer films. Conducting polymers can be synthesized either chemically or electrochemically, depending on the monomer types and specific applications.[41,42] The chemical-synthesis approach consists of a condensation polymerization (step-growth polymerization) and addition polymerization (chain-growth polymerization). During condensation polymerization, small molecules, such as water and hydrochloric acid, are produced as the waste products. Significantly, the most-common radical and ionic polymerizations (i.e., cation and anion) both belong to the condensation polymerization.[43] Therefore, chemical synthesis approach is a useful toolkit that provides many different possible routes to synthesize a variety of conducting polymers. As a common alternative, electrochemical-synthesis-based methods have emerged as the straightforward strategies to fabricate polymer films.[44] In electrochemical polymerization, threeelectrode configuration, including the working, reference and counter electrodes, is employed in a mixed solution containing the monomer, solvent, electrolyte and/or dopant. When electric field is applied, monomers near the working electrodes are oxidized to form radicals, which can selectively react with other monomers to form insoluble polymer chains anchored on the surface of the electrode. Importantly, the properties of the electrochemically deposited polymer films are strongly influenced by a number of variables, including temperature, solvent, electrolyte, electrode, and deposition time.[45] These parameters can be optimized to obtain suitable film morphology, biocompatibility and conductivity that are all essential to bioelectronics applications. In summary, both chemical and electrochemical approaches are the useful toolbox for the synthesis of conducting polymers.

2.1.1. Identifying Features Flexibility: Materials showing robust mechanical flexibility is at the very heart of the flexible organic bioelectronics. Polymers, sometimes also called “soft materials”, consist of long chains of many repeated monomer units.[46] The unique structure

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and intra-molecular interactions in the solid film make polymers the ideal candidate materials for bendable and rollable electronic devices. The great library of available polymers has sparked the development of flexible organic electronics at an exponential speed.[47] A wide range of flexible electronics based on conducting polymers, ranging from display and electronic skin to sensors and radio-frequency identification (RFID), has been successfully fabricated.[48] More excitingly, some flexible prototype products have been stepping into the commercial market and poise to revolutionize the society. For example, Bao’s group at Stanford University[49] and Someya’s group at Tokyo University[50] have demonstrated many seminal reports on flexible organic electronics and its versatile applications in pressure sensors and e-skins. Compared with other types of flexible materials, like graphene, conducting polymers can even show better stability of electric properties under stress. For example, we recently reported that the flexible OTFTs integrated in microfluidic channels showed very stable performance at different bending status,[51] while flexible solutiongated graphene transistors in the same microfluidic channels showed stress-dependent performances due to changes of the carrier mobilities by stress.[52,53] Therefore, owing to their intrinsic mechanical flexibility, polymers have emerged as the preferred choice for flexible electronic devices. Ion-to-Electron Conversion Properties: Ion fluxes serve as the significant media for the transfer of information and regulate biological systems in balanced conditions.[54] Therefore, the material able to interact with the ion fluxes in biology is of critical importance for the new field of organic bioelectronics. Interestingly, semiconducting polymers afford the conduction of both ions and electronic carriers (i.e., electrons and holes)[55,56] (Figure 2a,b). Being different from the case in their inorganic counterparts, the weak van der Waals interactions between the polymer chains create relatively large space, allowing the ions to move efficiently in the polymer films. The combined ionic and electronic transport ability in a conducting polymer at room temperature makes it an ideal communication channel to bridge the worlds of electronics and biology, offering infinite possibilities for organic bioelectronics[5] (Figure 2c). Poly(3,4ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS), as a degenerately doped p-type organic semiconductor, is the most-common material used in organic bioelectronics. Upon the application of a positive voltage bias in the PEDOT:PSSbased organic electrochemical transistors (OECTs), cations from electrolytes enter the polymer films and couple with PSS anions, which in turn modulate the hole densities of the bulk conducting layers.[57] More importantly, the doping process is reversible.[58,59] The entered ions can move out from the doped polymer films when the positive gate voltages are removed. To further investigate the ion movement in conducting polymer films, Malliaras et al. presented elegant work on the so-called “moving front” experiment to measure the mobility of ions injected into the PEDOT:PSS film from an aqueous electrolyte.[55] They found the very instructive experimental results that the mobilities of ions in the polymer film were in a similar magnitude to those measured in water, which could be attributed to the factor that the PEDOT:PSS film was largely swelled upon the uptake of water in the electrolyte. Therefore, high ion mobility in a polymer film can be achieved by maximizing




REVIEW Figure 2. Ion-to-electron conversion properties of conducting polymers. a) Schematic of an organic device with a PEDOT:PSS layer that is de-doped by the injected cations from the electrolyte under the applied voltage and has a charge distribution during cation injection. b) Transmission change (ΔT) of the PEDOT:PSS film that can represent the evolution of the de-doping front in the film. a,b) Reproduced with permission.[55] Copyright 2013, John Wiley & Sons, Inc. c) Schematic of an organic semiconductor, PEDOT, at the interface with a biological system. Reproduced with permission.[5]Copyright 2014, American Chemical Society.

the uptake of water. Additionally, the swelling property and the corresponding ion mobility could be simultaneously reduced by the cross-linking of the polymer films. These findings not only offer the possibility to better understand the fundamental charge transport in organic semiconductors but also give significant implications in the design of materials for organic bioelectronics. In summary, the ion-to-electron conversion ability affords conducting polymers the ability to interact with the biological world in a 3D manner, opening up a new communication avenue with biology systems. Biocompatibility: Biocompatibility refers to the ability of a biomaterial to perform with an appropriate host response in a human body or other biological systems.[60] Considering the intimate association with the biological interfaces, organic bioelectronics devices require to demonstrate excellent biocompatibility.[1,61] Conducting polymers are versatile biocompatible materials that have been widely used in biological applications. The currently available library of conducting polymers allows for the fabrication of biocompatible organic devices with an unprecedented complexity level.[62] However, the biocompatibility of organic materials is highly determined by many factors, including surface charge, chemical composition and acidity. Depending on the chosen materials and route of synthesis, the polymer films may contain monomers, solvents and excessive surfactants, which may leak gradually in use and become toxic for its surrounding living systems.[63] Although the biocompatibility of conducting polymers is influenced by a large number of factors, many types of these materials have


been systematically investigated and demonstrate excellent biocompatibility in biological applications. For example, PEDOT have been electrochemically polymerized around neurons and maintained high cell viability;[64] OECTs based on PEDOT:PSS have been successfully used as cell-based biosensors.[65,66] Several strategies have been proposed to improve the biocompatibility of conducting polymers: I. To functionalize the organic materials with biomolecules, including peptides, proteins, growth factors and polysaccharides, either by chemically covalent methods or physical entrapment;[67] II. To explore the naturally occurring materials, including the indigo derivatives,[68] carotenoid polyenes[69] and hydrogenbonded analogues of linear acenes,[70] as the active organic materials for bioelectronics. Overall, much effort has been made to develop biocompatible organic materials, which allows for the ultimate integration between the electronics and biological systems. Functionality: The chemical and physical properties of organic semiconducting materials could be easily tailored by modulating the molecular structures (either/both in molecular backbone or/and side groups) or manipulating the physical morphology (i.e., film thickness and surface topography, etc.), to meet the specific requirements of organic bioelectronics.[11] The vast toolbox of organic chemistry enables the facile chemical engineering of molecular structures. The popular strategy to modulate the biological functionality of conducting polymers



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is the integration of the bioactive molecules, which can be efficiently achieved by the physical approaches (i.e., entrapment and adsorption) and chemical approaches(i.e., doping and covalent attachment).[67] A wide range of biological functional elements, including enzymes, antigen/antibodies, DNA, and living cells, have been successfully coupled with conducting polymers toward some specific applications. The biocompatible polymers have shown little or no toxic effects on these biomolecules.[1] Recently, Bao et al. functionalized the 5,50-bis(7-dodecyl-9H-fluoren-2-yl)- 2,20-bithiophene (DDFTTF)-based organic field-effect transistors (OFETs) with the aptamer to sensitively and selectively detect the corresponding thrombin protein.[71] The aptamer covalently anchored on the surface of the polymer layer maintains high level of validity and could significantly improve the performance of the OFET sensors. The ease on the functionalization of polymer materials opens the door for more exciting scenarios in bioelectronics. Solution Processability: As an advantage over their inorganic counterparts, organic-semiconductor-based devices can be easily prepared via many low-cost convenient techniques.[72] Most inorganic-semiconductor-based electronic devices require strictly controlled environments. Normally, high-purity crystalline semiconductors should be processed in an ultraclean room equipped with expensive facilities. In contrast, the weak van der Waals interactions holding the molecular units together in organic semiconductors can be easily overcome by solvents (mostly for conducting polymers) or mild heating (mostly for small organic molecules).[73] Therefore, organic electronics can be readily prepared by the solution-processable techniques or thermal evaporation at low temperatures, which enables the use of wide range of low-cost substrates, including normal glass, flexible plastics, metal foils, textile and even papers.[74] For example, as one kind of the most-studied alkyl-substituted polythiophenes, poly(3-hexylthiophene) (P3HT) demonstrates excellent solubility in a variety of organic solvents, enabling device fabrication with conventional solution processable techniques, including spin-coating, screen-printing and inkjet printing (Figure 3a,b), etc.,[75,76] More importantly, solubility of polymers

could be carefully controlled by modifying the side chains alone the π-conjugated backbone,[77] providing more opportunities for the facile fabrication process of organic electronics. Stability: Long-term stability is an essential issue for organic electronic devices interfacing with biological world. It is particularly important for medical implant devices to maintain high performance for a long period of time even in invasive environments.[78] Since these devices are in direct contact with systems in high levels of complexity, the performance of the devices could be dramatically degraded in characterization processes even when only-one undesirable factor appears. In order to improve the stability of organic bioelectronics, the following approaches are suggested: I. To test new paradigms in the use of novel organic semiconductor materials with higher stability in aqueous environments. In principle, the stability of the polymer materials could be improved by cross-linking or the introduction of strong intermolecular interactions (i.e., hydrogen-bonding, etc) into the polymer systems;[79] II. To carefully package the organic bioelectronic devices. The protective layer deposited to package the device could effectively block the invasive elements, including moisture and oxygen molecules, and consequently improve the stability of the devices. 2.1.2. Material Types

Inherently conducting polymers have emerged as the robust promising materials for organic bioelectronic applications. Conducting polymers offer the versatility because of the huge library of polymer backbones to be chosen from, as well as the diverse dopants to be incorporated.[67] Regarding the polymer backbones, the most-investigated conducting polymers for organic flexible bioelectronics are polythiophenes, PPy and PANI, as shown in Figure 4. Polythiophenes: Polythiophenes, one type of the most-studied conducting polymers, are usually prepared from organic solvents.[80] Normally, polythiophenes are modified with functional groups (R) alone the backbone to improve its solubility and electronic properties. Considering the versatility of organic chemistry toolbox, polythiophenebackbone-based conducting polymers are poised to have a widespread use in organic bioelectronics. Significant effort has been devoted to investigate the polythiophene derivative- poly(3,4-ethylenedioxythiophene (PEDOT), which is electronically stable under physiological conditions.[81] RichardsonBurns et al. demonstrated the successful polymerization of PEDOT around living neuronal cells without introducing any toxic effects.[64] They found that SH-SY5Y neuroblastoma-derived cells display high level of viability in the presence of 3,4-ethyleneFigure 3. Polymer semiconductor devices can be readily prepared by conventional printing techniques. a) FA3300/5 Nilpeter label printing press uses the combined flexo-, rotary screen- dioxythiophene (EDOT) monomer. Upon electrochemical polymerization, the PEDOT and offset-printing. b) Flexo-printing uses the ink-transfer technology. a,b) Reproduced with permission.[74] Copyright 2007, Macmillan Publishers Ltd. can form an intimate connection to the

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adhered neural cells, which holds great potentials for the applications in neural stimulation or recording. Commercially available p-type doped PEDOT exhibits high conductivity over a wide pH range. More interestingly, the conductivity of PEDOT can be easily tuned to cover three orders of magnitude, depending on the incorporated counter ions and doping levels. As the most commonly investigated polythiophene derivative, PEDOT doped with poly(styrene-sulfonate) (PSS) (PEDOT:PSS) has been extensively used in organic bioelectronics, i.e., polymer electrodes, chemiresistors, ionic pumps, actuators, and transistors.[82] Considering its desirable attributes, PEDOT:PSS-based bioelectronic devices have all been successfully realized for the applications in chemical and biological sensing, neural stimulation/recording, cell, drug delivery, and tissue engineering. For example, our group has demonstrated that organic electrochemical transistors (OECTs) based on PEDOT:PSS have broad applications in chemical and biological sensors, including pH,[57] bacteria,[83] ions,[57] glucose,[84] dopamine,[85] DNA,[51,86] and cells,[9] etc,. In addition, PEDOT doped with p-toluenesulfonate (TOS) also showed excellent properties for organic bioelectronics applications. The preparation of the material is described in the literature.[87] Berggren’s group demonstrated that PEDOT:TOSbased OECTs can afford the controllable cell-density gradients on the surface of the conducting polymer PEDOT:TOS films.[87] Madin–Darby canine kidney (MDCK) cells were successful cultured on the surface of the active layers of OECTs and the celldensity gradients could be precisely controlled by the modulation of drain and gate voltages Polypyrrole: Polypyrrole (PPy) is one of the first-studied conducting polymers for its widespread applications in bioelectronics. PPy can be prepared in a simple way from aqueous neutral solutions,[88] in which a voltage (ca. 0.8V) is applied on the anode versus the saturated calomel electrode (SCE) on a conducting substrate. Unmodified PPy film could incorporate the small-molecule anions (e.g., Cl−) as the dopant to provide some additional biological properties. Additionally, dopants can also act as the intermediate “tethers” enabling the further functionalization of PPy. For example, the introduction of poly(glutamic acid) (PGlu) into PPy as the dopant provides the


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Figure 4. Most-commonly used semiconducting polymers in flexible organic bioelectronic devices: a) PEDOT:PSS; b) polypyrrole (PPy); c) poly(3-hexylthiophene) (P3HT); d) polyaniline (PANI).

functional carboxylic acid pendant group for the future functionalization.[89] Apart from using the dopants to modify the PPy, other emerging non-covalent approaches and covalent approaches have also been widely explored. Owing to its high level of biocompatibility and versatility, PPy plays a significant role in the wide range of biological applications, ranging from sensors, actuators and drug delivery to cell, tissue engineering, neural recording and stimulation. PPy have been widely used to immobilize the biological molecules, including enzymes, antibodies and nucleic acids, to improve the performance of the sensing devices. PPy shows excellent biocompatibility to cells and tissue both in vitro and in vivo. For example, a PPy conducting film electrochemically deposited on an electrode could support the secretory function of the cultured chromaffin cells.[90] Cells seeded on PPy in vivo demonstrated a higher survival and proliferation rate than that of control groups.[91] PPy also can modulate the cellular functions using the electrical stimulations. The shifts between the oxidized and neutral PPy states could efficiently induce a corresponding change in cellular morphology, cell viability and adhesion. More importantly, significant progresses of PPy-based devices have been made in neural probe applications. The PPycoated electrodes could greatly decrease the impedance at the interface with neural cells and yield high-quality recording. Polyaniline: Polyaniline (PANI) has attracted intensive attention since the early 1980s because of its high electrical conductivity, superior stability in electrolytes, and good biocompatibility.[92] PANI normally has three idealized oxidation states, including leucoemeraldine, emeraldine, and (per)nigraniline, among which emeraldine state demonstrates the highest conductivity at room temperature and is regarded as the most important one of PANI.[93] PANI has been extensively investigated for many potential applications, including chemical and biological sensors, electrochromic coatings and transparent electronic conductors, etc,. However, the electronic conductivity of PANI would significantly degrade in physiological environments, which could be attributed to the fact that PANI is usually prepared from acidic solutions and its electronic conductivity could only be maintained in the protonated state.[94] To extend the applications of PANI into bioelectronic areas, conducting PANI will be typically functionalized with selected dopants via either non-covalent or covalent approaches. In addition, nanostructured PANI materials, such as nanorods, nanowires and nanofibers,[95] offer the possibilities to improve the performance of the PANI-based devices interfaced with biological systems. PANI has demonstrated its biocompatibility in in vivo environments and sparked great interests in the use for tissue engineering. The biocompatibility of PANI can be further improved by the introduction of biocompatible elements without sacrificing its electric conductivity. Others: The vast amount of available organic semiconductors offers the near-infinite possibilities for organic electronics. However, most organic materials used in bioelectronics have been used for few decades without much change. Meanwhile, further work is needed to more clearly understand the fundamental charge transport in the organic materials. Most recently, some naturally existing organic semiconducting materials,[10] including indigo derivatives,[68] carotenoid polyenes[69] and hydrogen-bonded analogues of linear acenes,[70] have been



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explored and used as the active materials for bioelectronics, which opens the door for the use of natural organic materials in high-performance organic bioelectronics.

2.2. Flexible Substrate Materials As an essential part of electronic devices, substrates play a significant role that can profoundly influence the performance of devices. For flexible electronics, flexibility is the foremost property of the substrates. Since organic bioelectronic devices require the direct contact with physiological environments, the substrates also need to show excellent biocompatibility to their surrounding biological systems (i.e., tissues, living cells, and neurons, etc.), without inducing any toxic effects during the tests. The most commonly used substrates in flexible organic bioelectronics are itemized as follows:

2.2.1. Polyethylene Terephthalate Poly(ethylene terephthalate) (PET), as a well-researched plastic material, has been overwhelmingly used in the fabrication of flexible electronics.[96] The mechanical flexibility of transparent PET substrates can be easily manipulated by geometrical features (i.e., thickness, etc.). More importantly, a PET substrate serves as a good barrier for gas, moisture, and even alcohol, which can significantly improve the stability of an organic electronic device incorporated in an invasive biological system.[97] Meanwhile, its chemical inertness makes PET the ideal choice for the substrate materials of devices that should have stable performances, such as biosensors.[51] PET-substrate-based flexible bioelectronics, including electrodes, actuators, and sensors,[51,52] have all successfully fabricated and demonstrated an even better performance than that of a device fabricated on a conventional hard, rigid substrate (e.g., glass or silicon wafer, etc.).

conforms to virtually any shape, including sharp edges, crevices and points. As the most widely used dimer, parylene C provides extremely low permeability to moisture, chemicals, and other corrosive molecules, making it a very promising substrate material for ultrathin conformal biointegrated electronics.[99] More importantly, film thickness down to several micrometers can be achieved by carefully controlling the deposition parameters, which plays a significant role in the fabrication of ultraflexible organic bioelectronic devices.[100]

2.2.4. Polydimethylsiloxane Polydimethylsiloxane (PDMS) has been widely used in flexible and stretchable electronics because of its desirable properties, including transparency, chemical inertness, and stability over a wide range of temperature.[101] More importantly, the surface properties of this commercially available material can be easily controlled by UV irradiation, through which other electronic components can be strongly bonded to the substrate surface.[102]

2.2.5. Fiber (Textiles) Integration of electronic materials into fibers is a necessary route for the realization of smart e-textiles.[103,104] Similar to planar-substrate-based devices, organic semiconductor devices can be easily fabricated onto fiber substrates by coating. Flexible natural-cotton-fiber-based organic transistors have been successfully fabricated and have demonstrated high performance in biological sensing applications under physiological conditions.[105] More practically, the mechanical flexibility of fibers enables the fabrication of future smart clothing by weaving the electronic-device-integrated textile fibers.[19]

2.2.6. Paper 2.2.2. Polyimide Polyimide (PI) film possesses a unique combination of outstanding properties that make it ideal for a variety of applications. The commercially available DuPont Kapton series polyimide film is able to provide excellent mechanical flexibility and maintain its properties over a wide temperature range, which opens the new paradigm for the design of flexible electronics.[24] Additionally, the surface properties of PI films could be modulated by straightforward physical treatments, making the films compatible with low-cost solution processes.[98] Considering the high stability and biocompatibility of PI films, electronic devices fabricated on flexible PI substrates are poised to hold great potential in organic bioelectronic applications.

2.2.3. Parylene C Parylene is a conformal protective polymer coating material used to uniformly protect electronic devices. Owing to its unique properties, the chemical vapor deposited parylene film

8


As the basic daily necessities in human life, papers have also attracted attention for application in flexible electronics. Owing to its low-cost and easy accessibility, paper resources have emerged as promising alternative materials for device substrates. Organic-transistor-based sensors, displays, and arrays have all been successfully demonstrated on paper substrates.[106,107]

2.2.7. Others In addition to the aforementioned flexible substrates, many other materials also hold great potential for the practical applications in flexible organic bioelectronics. These possible substrate materials include: DuPont Teijin Films Melinex polyester film, DuPont Teijin Films Teonex polyester film, DuPont Teijin Films Mylar polyester film, polyethylene naphthalate (PEN) and polyetherether ketone film. To further improve the biocompatibility of organic bioelectronic devices, resorbablebiomaterial-based flexible substrates have also been explored. Flexible organic electronic devices based on bacterial cellulose




2.3. Flexible Electrode Materials Electrode materials have a huge impact on the overall performance of organic bioelectronic devices. To minimize the interfacial impedances and enhance the corresponding signals in biological systems, the work functions of the electrodes should properly match the energy levels of organic semiconductor layers. Several types of electrode materials have been utilized in flexible organic electronic devices: I.

Ductile metal electrodes. Gold (Au) shows the highest ductility among metals and have been widely utilized as the electrodes of flexible electronics.[110] Normally, a thin metal adhesion layer (e.g., Ti or Cr) should be firstly deposited to improve the adhesion effect between the Au electrodes and the substrates.[51,52] More importantly, the work function of Au (ca. 5.0 eV) can well match the energy levels of various organic semiconductors,[100,111] making it the very-first choice electrode material in flexible electronics. II. Conducting polymers. Highly conductive polymers, such as PEDOT:PSS,[112] can be easily patterned onto substrates to form electrodes. Considering its low cost, superior biocompatibility, high flexibility, and ease of fabrication, conductingpolymer-based electrodes have emerged as the promising alternatives for flexible electronics. Whole-polymer-based flexible organic bioelectronics are expected to be realized using conducting-polymer-based electrodes. III. Carbon-based materials.[113] The big family of carbon materials affords the easy fabrication of highly flexible, conductive, and transparent electrodes. Flexible organic electronics with carbon-based electrodes (i.e., carbon nanotubes, graphene, and reduced graphene oxide, etc.,) have been extensively investigated and excellent performances of many flexible devices have been demonstrated.[24,114–116]

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membrane[108] and poly(L-lactide-co-glycolide) (PLGA)[109] have been successfully demonstrated with high performance for the in vitro evaluation of biological systems.

environmental monitor, healthcare diagnosis, process control, drug delivery and national security.[9,124] Sensors normally consist of a chemically sensitive part that can specially interact with the analytes and a physical transducer that can provide information of its ambient environment. However, most commercially available products are expensive, time-consuming and needing expert operation. Therefore, a novel sensing platform able to efficiently analyze the target elements is in great need. Recently, TFT-based sensors have attracted increasing interest because of their inherent amplification functions, high sensitivities, voltage tunable performance and ease of miniaturization/integration.[125] Compared with the conventional sensing approaches, transistor-based sensors are able to substantially magnify the signals induced by the target analytes. In addition, OTFTs based on organic semiconductors can be conveniently prepared by solution process at low temperature, which is a more cost-effective way for mass production in comparison with other types of transistors based on silicon, carbon nanotube and graphene. These OTFT-based sensors have been successfully fabricated through facile solution approaches, including spin-coating, inkjet printing and screen printing,[126] etc., which can significantly simplify the complex manufacture processes and reduce the costs. Considering their high sensitivity, biocompatibility and flexibility, OTFTs indeed serve as an ideal platform for disposable high-performance sensors.[9] OTFTs are three-terminal electronic devices that consist of electrodes (source, drain, and gate) and the pivotal active layers deposited between the source and drain electrodes. The transistors intrinsically have two states, namely “ON” state with high channel current and “OFF” state with very low channel current, which could be effectively switched by applying a gate voltage. Based on the geometrical structure and operation mechanism, OTFTs can be further divided into two primary categories (Table 1), including organic field-effect transistors (OFETs) and organic electrochemical transistors (OECTs).[9,12] For OTFTbased sensors, when the devices are in contact with the environments containing analytes, the channel currents flowing through the organic semiconductor layers could be significantly modulated by the analytes due to some chemical or biological reactions on the devices.

3. Flexible OTFTs for Bioelectronics 3.1. OFETs Organic electronics, including OPVs,[117] OLEDs[118] and OTFTs,[119] have shaped the field of electronics and are expected to make significant contribution to the development of science and technology. Owing to the unique combination of structural flexibility, low temperature process, and low cost, OTFTs have been emerged as viable alternatives to the conventional mainstream thin film transistors (TFTs) based on inorganic materials, such as Si, Ge, and GaAs.[120,121] It has been recognized that OTFTs are particularly suitable for the low cost radio-frequency identification (RFID),[122] large area display and disposable physical/chemical/biological sensors.[9,123] Sensors with the ability to specifically detect the analytes and convert it into a readable or recordable signal have attracted significant amount of attention in the last few years. The applications of chemical sensors and biological sensors hold great potentials in a wide range of applications, including


Organic field-effect transistors (OFETs) based on small-molecule organic materials or polymeric semiconductors have sparked great interest in the past few years. An OFET is typically composed of an organic semiconducting active layer, an insulating dielectric layer and three conductive electrodes. OFETs have two basic configurations, namely bottom gate device configuration with the gate electrode beneath and the semiconductor channel on top of the insulating layer, and top gate device configuration with the gate electrode fabricated on the top of the insulating layer and the channel on the bottom. The channel carrier density of an OFET can be effectively modulated by the electric field from the gate electrode. To establish a conducting channel, a threshold voltage is required to switch the transistor from “OFF” state to “ON” state. Normally, the channel currents of OFETs could be changed up to several



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www.MaterialsViews.com Table 1. Summary of flexible OTFTs for bioelectronic applications. OTFTs

Substrate

Active organic material

Sensor types

OFETs

Mylar polyester foil

Pentacene

pH sensor

PEN

Kapton PI

OECT

P3HT

pH and

Pentacene

K+

ion sensors

Reference

pH range: 4–10

[133]

pH range: 2.5–7

[134]

pH range: 2.5–7

[135]

K+

i) pH range: 6.7–9.5; ii) down to 33 mM.

ions:

[139]

pH range: 6.7–9.5.

[140]

pH sensor

pH range: 4–7.

[136]

TMA sensor

TMA range: 0–8 ppm.

[138]

PET

DDFTTF

Cysteine and TNB sensor

Detection limit: i) cysteine: 0.1 ppm; ii) TNB: 100ppb.

[142]

PI

Pentacene

/

/

[137]

PET

P3HT

/

/

[143]

Paper

PEDOT:PSS

/

/

[150]

PET

/

i): on/off ratio ≈ 600; ii) Switching time < 100 ms.

[151]

Polyester foils and fine paper

Humidity sensor

Humidity level: 40% to 80%

[106]

Polyester sheet

Glucose sensor

Glucose: 1 µM to 10 mM

[152]

Parylene film

Lactate sensor

Lactate level: 1 µM to 10 mM.

[153]

PET

DNA sensor

Detection Limit: 10 pM DNA

[51]

PEDOT:TOS

Cell cultivation

Cell gradient control

[87]

Parylene

PEDOT:PSS

Electrocorticography (ECoG) probes

In vivo brain activity recording

[100]

Cotton fiber

PEDOT:TOS

/

/

[155]

Silk fiber

PEDOT-S

/

Be woven into fabric

Cotton fiber

PEDOT:PSS

Saline sensor

orders of magnitude by the gate voltages.[127] However, OFETs are not suitable for the applications requiring high switching speeds because of their relative low charge carrier mobilities three or more orders of magnitude lower than that of a singlecrystalline silicon transistor. For sensors based on OFETs, the active layers are either exposed to aqueous or gas environments containing the analytes of interest, which can induce physical or chemical changes in the organic semiconducting layers and modulate the channel currents. Since the performance of an OFET is strongly determined by the morphology of the active layer and the physical interfaces, the functionality of OFETbased sensors can be easily tuned by surface and interface engineering.[128] More recently, electrolyte-gated organic field-effect transistors (EG-OFETs), a brand-new type of OFET, have been successfully fabricated as high-performance sensing devices.[129] Instead of a solid dielectric layer, a liquid electrolyte layer is incorporated between the organic semiconductor layer and the gate electrode. Owing to the high electric double layer (EDL) capacitance (a few to few tens μF/cm2) at the organic semiconductor/electrolyte interface, large-density charge carriers can be induced in the channel even when a small gate voltage is

10

Performance


NaCl:

10−1

[156]

−4

[105]

–10 M

applied.[130] However, no consensus has been reached on the mechanism of the EG-OFETs until now. More work is needed to further clarity that the channel current changes of EG-OFETs are majorly induced by the field-effect doping or the electrochemical doping similar to the case in OECTs to be introduced in the next part.[131] Operation Mechanism of OFETs: OFETs normally operate in accumulation region. The low “OFF” current in an OFET is largely dominated by the inherent conductivity of the organic semiconducting active layer. The channel current flowing through the organic active layer can be effectively modulated by the field-effect doping process upon the introduction of a gate voltage. The channel current of an OFET is given by:[132] W V μC i ⎛⎜ Vg − Vt − DS ⎞⎟ VDS ⋅ VDS Vg − Vt ⎝ 2 ⎠ L 2 W μC i (Vg − Vt ) ⋅ VDS > Vg − Vt = 2L

I DS = I DS

(1)

in which IDS is the channel current flowing in the organic active layer, W and L are the width and length of the channel, respectively, µ is the carrier mobility, Ci is the effective gate




3.2. Flexible OFET Sensors Ion sensitive pentacene OFETs on flexible plastic substrates were reported by Bonfiglio’s group.[133] Thin Mylar polyester foils act as both substrates and gate dielectrics for the OFETs. In the fabrication of the bottom-contact OFETs, one side of the Mylar sheet was pre-patterned with Au source/drain electrodes, followed by the vacuum deposition of the active pentacene thin film. Together with an Ag/AgCl reference electrode, the other side of the flexible sheet was directly exposed to an aqueous electrolyte. The channel current could be effectively modulated by the gate voltage. It was found that the fabricated device was sensitive to H+ ions in the electrolyte, which is similar to typical silicon-based ion-sensitive field-effect transistors reported before.[120] The flowing current in the conducting pentacene layer was correspondingly reduced when the pH was decrease from 10 to 4. Owing to its flexibility and facile fabrication approach, this device opens a door for the flexible sensors can be employed in a wide range of innovative applications. Years later, the same group proposed a dual-gate OFET for pH sensing applications.[134] The flexible OFET pH sensor using pentacene was fabricated on a Mylar plastic film. The device was sensitive to H3O+ ions because of the functionalized floating-gate surface with self-assmbled monolayers (SAMs) ended with −NH2 functional groups. The immobilized thioaminic groups could be protonated proportionally to the concentration of H3O+ ions in the electrolyte. Therefore, the current of the device was significantly changed when the pH value was varied from 2.5 to 7. More importantly, the sensitivity and functionality of the OFET sensors could be easily manipulated by proper modifications of the floating gate surface.[135] Therefore, the flexible OFETs with functionalized floating gates are a very promising platform for a variety of biological sensing applications, including DNA, cell and protein. Flexible ion-sensitive OFETs based on pentacene were also realized on thick PI Kapton films.[136] A thin Parylene-C was deposited on the top of the pentacene layer as the top gate dielectric as well as the encapsulation layer.[137] Then a thin layer of hydrogenated silicon nitride (SiN:H) was deposited by photochemical vapor deposition at a moderate temperature on the surface of Parylene to create proton sensitive sites at the insulator/electrolyte interface. The flexible OFET device with the top gate Parylene/pentacene configuration showed excellent


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capacitance, Vg is the applied gate voltage, Vt is the threshold voltage of the OFET and VDS is the applied source-drain voltage. Therefore, the magnitude of the channel current is significantly influenced by the two primary parameters in the above given equations, namely threshold voltage Vt and carrier mobility µ, both of which play key roles in the performance of OFET-based sensors. The threshold voltage of an OFET sensor is normally determined by the doping effect of the target analyte, while the carrier mobility in the organic layer is dominantly influenced by molecular morphology that may be changed by the analyte diffused into it. To further improve the performance of the OFET-based sensors, it is essential to realize specific interactions between analyte molecules and organic semiconductor layers as well as the rational designs of the organic devices.

responses to the pH variations both in acidic and alkaline ranges. The current was correspondingly reduced when the pH value was decreased from 10 to 4. Similar devices have been successfully used as high-performance trimethylamine (TMA) sensors, which was realized by the incorporation of an enzymatic membrane consisting of flavin-containing mono-oxygenase 3 cross-linked with bovine serum albumin onto the silicon nitride layer.[138] The functionalized enzymatic OFET sensor demonstrated an excellent TMA sensing performance in the range of 0–8 ppm. Ji et al.[139] successfully fabricated a flexible ion sensitive OFET based on the conjugate polymer P3HT. The P3HT semiconducting layer was deposited onto a flexible PEN substrate pre-patterned with Au electrodes. A thin layer of high-k gate dielectric tantalum pentoxide (Ta2O5) was then deposited on top of the P3HT layer to enable the selectivity toward H+ ion detection and the device showed responses to pH values ranged from 6.7 to 9.5. To realize a K+ sensor, an OFET with a Cr/Au floating gate was modified with valinomycin ionophore K+ selective layer. The device can specifically detect K+ ions down to 33 mM (Figure 5a,b). Moreover, the biocompatible shell like the Au floating gate with an ion-selective membrane window should be able to serve as a sampling barrier to keep invasive biological elements away from the sensor array.[140] In addition, for the tests performed in human body with variable temperatures, the performance of the device could be further improved by implementing linear temperature compensation logic circuit. High-performance flexible biosensors should show excellent stability, However, the aforementioned organic semiconductors including pentacene and P3HT are not stable in air and water. 5,5′-bis-(7-dodecyl-9H-fluoren-2-yl)-2,2′-bithiophene (DDFTTF) is a robust p-type organic semiconductor with superior stability in aqueous environments.[141] Roberts et al.[142] reported DDFTTF-based flexible OFET sensors in various biological sensing applications(Figure 5c,d). PEDOT:PSS was patterned on a flexible ITO/PET substrate as conductive electrodes. To avoid the water hydrolysis caused by the applied high operation voltage, a thin poly(4-vinylphenol) (PVP) crosslinked with 4,40-(hexafluoroisopropylidene) diphthalic anhydride (HDA) film was spin coated as the gate dielectric layer, which allowed the low operation voltages typically less than 1 V. The detection limits to cysteine and 2,4,6-trinitrobenzene (TNB) were down to 0.1 ppm and 100 ppb, respectively. In addition, the channel current of the device could be effectively modulated by the change of electrolyte pH. Similar to that of an organic chemical vapor sensor, the underlying sensing mechanism could be attributed to the changed carrier mobility induced by the diffusion of analytes into the organic semiconductor layer and interfaces. Such flexible OFET sensors have potential applications in implantable medical packaging. For example, flexible OFET ion sensors can be used to monitor cardiovascular diseases by detecting the ion (e.g., K+, H+) concentrations in a human body because cardiovascular diseases are always associated with the abnormal levels of ions. Flexible OFETs are potentially useful for biomedical microimplants used as neural prostheses to restore body functions after paraplegia by means of functional electrical stimulation (FES).[137] Moreover, it is essential to integrate bioelectronics devices with complex systems to realize viable point of care (POC) diagnostics. Microfluidic systems



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Figure 5. a) Schematic of the ion sensitive field effect transistor (ISFET) on a flexible PEN substrate for K+ sensing. b) The device shows current response to K+ and no response to Na+. a,b) Reproduced with permission.[139] Copyright 2008, American Institute of Physics. c) Normalized current response to solutions of TNB with concentrations down to 100 ppb. Inset: photo of the flexible device. d) Normalized current response to solutions of cysteine with various concentrations down to 0.1 ppm. Inset: The current change for the devices fabricated on PET and silicon substrates, respectively. Reproduced with permission.[142] Copyright 2009, Elsevier.

can precisely control the amount of sensed analyte and provide protection against ambient environment during measurements. Recently, Wang et al. [143] reported printable microfluidic systems integrated with OFETs on Upilex PI substrates or PET polyfoils. Two different types of pressure sensitive and screen printable adhesive materials have been used to fabricate the microfluidic systems. The printed electrolyte-gated OFETs integrated in the microfluidic channels have demonstrated reliable performance when deionized (DI) water was filled in the channels by capillary force in the tests. However, further biosensing applications of the flexible devices should be developed.[51,144]

3.3. OECTs Typically, an OECT consists of three deposited conductive electrodes (source, drain and gate) on a supporting substrate and an organic active layer coated between the source and drain electrodes (Figure 6). An aqueous media (electrolyte) is incorporated between the organic semiconducting channel and the gate electrode. The operation mechanism of an OECT is primarily

12


based on the electrochemical doping/de-doping processes that can modulate the conductivity of the organic semiconductor channel by oxidation/reduction. More importantly, the doping/ de-doping process is reversible and associated with the migration of ions in/out of the organic active layer. The unique ion-to-electron conversion property of the OECT serves as the intimate connection to bridge the worlds between electronics and biology. In addition, the channel current of the OECT can be modulated up to several orders of magnitude by slightly changing the applied gate voltage by ca. 1 V.[58,59] Compared with OFETs, OECTs show simpler structures and lower working voltages, both of which are all important for disposable and low-cost biosensing applications. OECT-based sensors demonstrate high stability in aqueous electrolytes for long time, which is essential for the real-time chemical and biological sensing applications in aqueous environments. More importantly, the operational gate voltage is typically less than 1 V, which can effectively prohibit the risk for hydrolysis during operation. Considering the unique combination of these desirable properties, OECTs have been extensively investigated as the viable platform for a wide range of sensing applications,




REVIEW Figure 6. Schematic of an OECT. During device operation, cations in the electrolyte can migrate into or out of the organic semiconducting layer very conveniently under different gate voltages that, in turn, modulate the hole density in the channel and consequently the channel current.

including pH, ions,[57] glucose,[84] dopamine,[85] DNA,[51] bacteria[83] and cells,[65] etc. OECT-based sensors have exhibited high sensitivity, good selectivity, superior biocompatibility, and can be easily miniaturized and integrated into complex systems, including microfluidic channels for real time detections, or sensor arrays for high throughput sensing applications. Operation Mechanism of OECTs: The channel current of an OECT operated in an electrolyte can be significantly changed when a small gate voltage is applied, which can drive the cations of the electrolyte into the polymer layer and subsequently change the conductivity. At a low source-drain voltage, the channel current is proportional to the carrier density in the active layer when an effective gate voltage is applied and is given by:[145,146] qμ p0 tW ⎛ VDS ⎞ eff eff ⎜ Vp − Vg + ⎟ VDS ⋅ VDS Vp − Vg 2 ⎠ LVp ⎝ Vp = qp0 t / C i Vgeff = VG + Voffset I DS =

(2)

in which IDS is the channel current; Vp is the pinch-off voltage; Vgeff is the effective gate voltage; q is the electric charge; µ is the hole mobility; p0 is the initial hole density in the active layer; t is the thickness of the organic active layer; W and L are the channel width and length, respectively; Ci is the effective gate capacitance of the transistor; and Voffset is the offset voltage both determined by the interfacial potential drops at the gate/electrolyte interface and the electrolyte/channel interface. According to these equations, the performance of an OECTbased sensor is dominantly influenced by the ion diffusion process upon the application of an effective gate voltage. To further clarify the underlying mechanism, the device can be regarded as two fundamental circuits, namely, ionic circuits and electronic circuits. Ionic circuits are strongly determined by the ionic migration processes both in the electrolyte and the organic active layer, while electronic circuits are majorly


influenced by the carrier mobility and density in the organic channel. More importantly, the performance of an OECT is closely related to its physical geometry.[147,148] It has been reported that small-sized devices with a short channel length and a small distance between gate and channel area are able to show fast response time down to several milliseconds,[66,149] which holds great potential for the fast detection of target analytes in sensing environments.

3.4. Flexible OECT Sensors OECTs have simple device structures and thus can be easily prepared on various substrates by solution process. In 2008, Mannerbro et al.[150] successfully fabricated high-performance flexible OECTs using an inkjet printing technique. The devices fabricated on flexible standard inkjet photo papers (ISOTECH Glossy Photo Paper, and inkjet transparency film (Brilliant)) showed good performance, which offered the possibilities for the low-cost fabrication of OECT-based bioelectronics devices. More recently, Blaudeck et al.[151] reported the fabrication of PEDOT:PSS OECTs on flexible PET substrates. The devices showed on/off ratios up to 600 and switching times of 100 milliseconds at gate voltages less than 1 V (Figure 7a), making them suitable for various biosensing applications. The proposed hybrid manufacturing strategy was based on conventional digital printing (screen and inkjet printing), laser processing, and post-press technologies, which was fully compatible with standard package printing and offered great possibility for the fabrication of personalized devices, such as OECT arrays with various electrolytes as the high-throughout sensing platforms. Flexible OECTs have been emerged as the versatile platform for various biological sensing applications. Nilsson et al.[106] demonstrated flexible OECT-based humidity sensors on fine papers or thin polyester foils. Commercially available PEDOT:PSS was printed onto a flexible substrate both as the



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Figure 7. a) Switching behavior of an OECT fabricated by the hybrid manufacturing strategy including printing and laser ablation. Reproduced with permission.[151] Copyright 2012, John Wiley & Sons, Inc. b) The responses of the sensor to humidity levels. Inset: Picture of the flexible humidity sensor. Reproduced with permission.[106] Copyright 2002, Elsevier. c) Channel current (Ids) as a function of drain voltage (Vds) under different glucose concentrations. Inset: Picture of the flexible glucose sensor. Reproduced with permission.[152] Copyright 2011, Elsevier. d) Normalized current response of the OECT vs. lactate concentration. Inset: Picture of the flexible sensor. Reproduced with permission.[153] Copyright 2012, The Royal Society of Chemistry.

three terminal conductive electrodes and the organic active layer of an OECT. A thin layer of Nafion, a widely used proton conducting material, was deposited to cover the channel area and the gate electrode to serve as a solid-state electrolyte. Since the conductivity of Nafion could be dramatically modulated by the change of ambient humidity level, the resulted device can be used as a humidity sensor. As shown in Figure 7b, the channel current of the OECT at a fixed gate voltage (Vg = 1.2 V) experienced an exponential decreased (approximately two orders of magnitude) when the ambient humidity level increased from 40% to 80%. Kanakamedala et al. reported flexible glucose sensors based on OECTs prepared by a simple one-step fabrication process.[152] As shown in the inset of Figure 7c, PEDOT:PSS was patterned on a flexible polyester substrate to act as both the conductive electrodes and the active channel area. A polymer well was attached on the device to contain phosphate buffered saline (PBS) solution and glucose oxidase (GOx) for glucose tests. The OECT glucose sensors demonstrated a linear response to the glucose concentrations from 1 μM to 10 mM and showed adequate changes for glucose levels in the physiological ranges of human blood and body fluid. One drawback in the use of the device is the enzyme GOx not immobilized on the device. Another problem of the device is the poor selectivity, which is

14


essential to the practical applications of the biosensors. Our group reported the highly sensitive glucose sensors based on OECTs with enzyme gate electrodes.[58,59,84] The sensitivity of the devices was substantially enhanced by modifying nanomaterials (e.g., Pt nanoparticles, graphene and carbon nanotubes, etc.) on the gate electrodes. The selectivity of the devices can be effective improved by coating a Nafion or Chitosan layer on the gate electrode. Therefore, the performance of the flexible OECT-based glucose sensors can be easily improved by using these approaches. Considering the big market of glucose meters, the devices have promising applications in healthcare products in the future. Physiological detection of lactate in blood provides an excellent biomarker for anaerobic metabolism. Khodagholy et al.[153] successfully fabricated an OECT-based lactate sensor using room temperature ionic liquids (RTILs) as solid-state electrolytes. The ionogel containing enzyme lysyl oxidase (LOx) was coated on top of the channel area, which could catalyze the electrochemical oxidation of lactate and modulate the channel current of the device. The OECT lactate sensors demonstrated adequate responses to the lactate concentration in the range of 10–100 mM, covering the physiological ranges of lactate both in saliva and blood. More importantly, the OECT sensor arrays could be deposited onto a flexible parylene substrate to form a




REVIEW Figure 8. a) Schematic diagram of an OECT integrated with a flexible microfluidic system. The device is characterized before and after the modification and hybridization of DNA molecules on the surface of the Au gate electrode. b) Photographs of a flexible OECT device bent to both sides. c) Transfer characteristics (IDS vs VG) of an OECT measured at different bending status when the microfluidic channel was filled with PBS solution. Inset: output characteristics (IDS vs VDS) of the device. d) The gate voltage shifts of OECTs induced by the hybridization of DNA on gate electrodes as a function of the concentrations of the DNA target in PBS solutions. Both the conventional passive hybridization (in blue) and the pulse-enhanced hybridization (in red) methods were used. The inset shows the parameters of the applied electric field pulse used to enhance the hybridization of DNA. a–d) Reproduced with permission.[51] Copyright 2011, John Wiley & Sons, Inc.

conformal configuration on a human forearm (Figure 7d). Due to the stability of enzyme in the ionogel, wearable bandage-type sensor could be realized and worn during exercise or health monitoring, allowing sweat to diffuse into the sensor with noninvasive real time lactate analysis. Owing to its significance in monitoring of gene expression, bacterial identification, detection of bioterrorism agents, and clinical medicine, nucleic acid diagnostics have attracted much attention in the last few years. Recently, our group demonstrated the functionalized OECTs for labeling-free DNA detection with an unprecedented detection limit to DNA targets[51] (Figure 8). The PEDOT:PSS-based OECTs were fabricated on flexible PET substrates with Au electrodes and integrated with PDMS microfluidic channels. Before measurements, single stranded DNA probes were firstly immobilized on the Au gate electrodes. Since DNA molecules were negatively charged in PBS solution, the work function of the DNA probe modified Au electrode would be decreased upon the immobilization or the hybridization of DNA, which in turn change the performance of the OECT. More importantly, the flexible devices showed very stable performance in various bending status. Little change in the device performance was observed when the devices were bent to both sides. The detection limit of the labeling-free DNA


sensor was about 1 nM initially and was further extended down to 10 pM by applying continuous voltage pulses on the gate electrode via another Au electrode during DNA hybridization process. Besides the DNA analysis, OECT-based sensors incorporated with flexible microfluidic systems are suitable for many other highly sensitive, cost-effective, and disposable biological sensing applications. Active control over gradient parameters offers the great opportunity for regulating a vast array of activities in biological systems. Berggren’s group[87] demonstrated that cell-density gradients could be carefully controlled in PEDOT:TOS-based OECTs. Madin–Darby canine kidney (MDCK) cells were successful cultured on top of the PEDOT:TOS organic semiconducting layers of the OECTs fabricated on flexible PET films. The cell-density gradient profile could be precisely manipulated by modifying the drain and gate voltages, providing a feasible tool for the exact control of gradient characteristics of tissues and cell clusters in biological experiments. Abnormalities in bioelectric signals of our bodies are associated with many severe diseases. As an alternative to the traditional pharmaceuticals, electrical devices have emerged as an versatile technological strategy for the diagnosis and treatment of illnesses. Most recently, Campana et al.[154] demonstrated a



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Figure 9. a) Optical microscopy image of a flexible OECT. The darker color regions of the electrodes are covered with PEDOT:PSS. b) Photograph of the transparent and conformable device attached to curved human skin. c) ECG recording operated in direct contact with the skin (red) and comparison to a conventional potentiometric recording using standard disposable leads (black). VGS = 0.5 V, VDS = −0.3 V. a–c) Reproduced with permission.[154] Copyright 2014, John Wiley & Sons, Inc.

conformable OECT fabricated on resorbable bioscaffold for electrocardiographic (ECG) recordings of heart muscular tissue (Figure 9). The device was assembled on a flexible bioresorbable poly(L-lactide-co-glycolide) (PLGA) bioscaffold substrate. As PLGA is highly soluble, the micropatterning of PEDOT:PSS could be accomplished without solvent-based lithographic procedures. The OECT shows a fast response as well as high bending stability in an aqueous electrolyte, making it promising for the biological applications directly in contact with the physiological environments. The OECT demonstrates a high sensitivity in human ECG signal recording. During each heart beat cycle, the ordered continuous contraction throughout the heart muscle will induce ionic current wave spreading throughout the entire body, which give rise to tiny potential changes on the skin. Time-varying signals could be recorded by the attached OECT sensor and provide important information of the human body, including pulse rate, pulse regularity, and heart dimensions.

16


Highly conformal OECTs are also suitable for in vivo electrophysiological recordings of brain activity because of their mechanical flexibility and biocompatibility[100] (Figure 10a,b). The electrocorticography (ECoG) probes used to record electrophysiological signals on the surface of the brain were composed of PEDOT:PSS-based OECT arrays on an ultrathin (2μm) flexible parylene substrate. The microsized OECTs patterned by conventional photolithography allow easy manipulation of the device physical geometry. The flexible parylene substrate and the conductive PEDOT:PSS layer both showed excellent biocompatibility in the harsh human environment. Compared with the conventional surface electrodes, the flexible OECT probes were able to display superior signal-tonoise ratio because of the ultrahigh transconductance of the devices. In addition, the highly flexible organic transistors had the capability to record the surface low-amplitude brain activities that were poorly achieved by traditional surface




REVIEW Figure 10. a) Optical microscopy image of the ECoG probe conforming onto a curvilinear surface. b) Time-frequency analysis of epileptiform activity over a short period, recorded by an OECT (top), a PEDOT:PSS surface electrode (middle) and an Ir-penetrating electrode (bottom). a,b) Reproduced with permission.[100] Copyright 2013, Macmillan Publishers Ltd. c) The picture of the single-cotton-thread-based OECT directly integrated on cloth. The overlapping between the liquid electrolyte and the PEDOT:PSS wire defines the channel area of the OECT device. The silver wire dipped into the electrolyte acts as the gate. d) The normalized transistor response as a function of the salt concentration at different gate voltages. c,d) Reproduced with permission.[105] Copyright 2012, The Royal Society of Chemistry.

electrodes, which holds great promise for future medical applications. Recently, fiber-based electronic devices have attracted increasing attention for their flexible non-planar configurations. The electronic material deposited fibers allows the integration into the e-textile through conventional weaving techniques. Owing to its solution processability and mechanical flexibility, polymer semiconductors have emerged as the robust materials for fiber electronics. Mattana et al.[155] demonstrated highperformance fiber-based OECTs by conformally coating cotton yarns with tosylate-doped PEDOT (PEDOT:TOS) through the vapor phase polymerization (VPP) process. Müller et al.[156] also fabricated an OECT based on arranged PEDOT-S stained silk fibers. The mixture of imidazolium-based ionic liquid ([bmim][Tf2N]) and polymer ionic liquid (poly[ViEtIm][Tf2N]) was used as the electrolyte to bridge the gap between two silk monofilaments. The fiber-based electrochemical transistors demonstrated an appreciable level of electrical conductivity. More importantly, these conductive silk fibers showed excellent mechanical toughness and can be easily woven into fabrics. The fiber-based devices were also expected to have a higher area to volume ratio in compression with their planar counterparts, making it possible to design novel device paradigms that can


intimately interact with living systems. To further explore the role of fiber-based organic electronics in the biological applications. Tarabella et al.[105] proposed an elegant OECT architecture based on a single cotton fiber for liquid electrolyte saline sensing (Figure 10c,d). The natural cotton fiber functionalized with PEDOT:PSS was used as the active channel of the OECT. The device showed a good linear response to NaCl in the range of 10−1–10−4 M, which could be attributed to the redox reaction between ions in solution and the Ag gate electrode. The test using real sweat demonstrated that this flexible sensor can effectively detect the physiological range of salts in sweat. In summary, OECTs are promising in the applications of biosensors due to the high sensitivity and the convenient fabrication process. The devices can be easily fabricated on flexible substrates and show excellent bending stability. Although some people considered that the main disadvantage of OECTs is the long response time, the miniaturized devices with the size of micrometers can show the response time down to milliseconds,[149] which is fast enough for many biological experiments. Flexible OECTs have been successfully used in many types of biosensors that are mainly based on the chemical or biological reactions on the surface of organic active layers or gate electrodes.[9] In principle, many novel biosensors can be developed



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www.MaterialsViews.com Table 2. Summary of flexible polymer electrodes for bioelectronic applications. Types Sensing

Neural recording/ stimulation

Drug delivery

Cell

Substrate

Active organic material

Applications

Performance

Reference

PI

PVC

pH, glucose sensor

glucose: 5 mM to 30 mM

[159]

PET

PEDOT:PSS

Glucose sensor

Glucose: 100 µM to 1 M

[161]

Polymer film

Polyaniline

pH sensor

pH: 1 to 13

[160]

Carbon fiber

Doped PPy

Nitrate ion sensor

Polymer substrates

PPy

Neural prosthetics

[164] [166]

PPy

Neural communication

/

[167]

Parylene C

PEDOT:PSS

Electrocorticography (ECoG)

Recording of brain activity

[168]

PI

Electroencephalography (EEG)

Recording of brain activity

[169]

Kapton PI

Cutaneous electrophysiological recordings

long-term recording of cutaneous nerve

[163]

Plastic coverslips

PPy

Controlled release of dexamethasone

Localized delivery of dexamethasone

[172]

Kapton PI

PEDOT: PSS- carbon nanotube composite

Drug delivery

/

[173]

PET

PEDOT:TOS

Controlled cell activity

Control of epithelial cell adhesion and

[176]

Hydrogel

PEDOT

Induce contraction of muscle cells

[177]

4. Flexible Polymer Electrodes for Bioelectronics The unprecedented interest in the field of disposable analytical devices for the fast, low-cost detection of specific chemical and biological species has lead to the rapid development of bioelectronics that explores the interfacial relations between the electronic devices and target living tissues/biomolecules.[2,5] Owing to its desirable properties, conducting polymers integrated with electronic device have reshaped the area of electronics in the last few decades. Electrode is an interface between the electronbased charge transport in any electronic devices and the ionic charge transport in the body.[157] It is usually used in pairs with anode (positive electrode) and cathode (negative electrode), at which oxidation and reduction occur, respectively. As one of the simplest organic electronic devices, polymer-based electrodes have emerged as a viable platform for various stimulation and sensing applications (Table 2), including medical diagnose, cell monitoring and drug delivery.[158]

4.1. Biosensing The unique ion-to-electron conversion properties of conducting polymers make them excellent materials for biological applications. Conducting polymers have been widely explored as coatings on conductive electrodes in potentiometric sensing devices.[62,67] Those polymers are usually


M

/

Flexible elastomer

based on the surface functionalization of the gate or the organic channel of an OECT. Therefore, the flexible OECTs will find more and more biosensing applications in the future.

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Nitrate ion: ca.

10−6

designed to immobilize enzymes, mediators or even larger biomolecules. pH sensors can be developed as many types of biosensors by the modification of specific biomolecules (e.g., enzymes) on the devices.[120] In 1992, Urban et al.[159] demonstrated a flexible potentiometric pH sensor fabricated on a polyimide substrate. The solid-state pH sensitive device employed a H+ neutral carrier membrane coated on a conducting polymer polypyrrole film. The device showed excellent stability both in non-thermostatted buffer solution and plasma over a long period of time. More importantly, the pH sensitive polymer electrode could be miniaturized and integrated with the enzyme glucose oxidase (GOx) for in vivo glucose sensing that is important in clinical analysis. They found that the integrated device showed a good linear response to the glucose levels ranged from 5 mM to 30 mM and a very stable performance in undiluted heparinized blood for long-term tests. Potentiometric pH sensors have also been realized by using transparent CNT network as the electrical contact and the conducting polymer PANI film coated onto the CNT network as a pH sensitive organic transducer layer,[160] which was fabricated on a flexible PET substrate (Figure 11a). PANI was electrochemically deposited onto the CNT network under a potentiostatic mode. The device displayed a stable response to a wide range of pH values from 1 to 13 (Figure 11b). In addition, the PANI-coated CNT network was highly selective for H+ ions when major metal interfering ions (Li+, Na+ and K+) were simultaneously evaluated. Enzyme electrodes have important applications in various types of biosensors. Chiu et al.[161] reported high-performance PEDOT-based enzyme electrodes fabricated on flexible PET thin substrates (150μm in thickness). PEDOT is a versatile




REVIEW Figure 11. a) Picture of a transparent and flexible pH sensor. b) The potential response to the variation of pH. a,b) Reproduced with permission.[160] Copyright 2006, Elsevier. c) SEM image of PPy(NO3−) microsensor assembled on the carbon fiber cross section. (d) Potentiometric responses of three identically prepared PPy(NO3−) microsensor. c,d) Reproduced with permission.[164] Copyright 2007, Elsevier.

material widely used in organic bioelectronics. The prepared bilayer structure PEDOT/Prussian blue (PB) plays a significant role in glucose sensing. The firstly electrodeposited inner PB layer was responsible for the detection of H2O2 from glucose oxidation, while the outer electropolymerized PEDOT layer was used to entrap the enzyme GOx which can accelerate the eletrooxidation reaction of glucose. Interestingly, they demonstrated that the baked inner PB layer could improve the stability of the device and the subsequent PEDOT growth, which in turn could enhance the corresponding GOx entrapment for glucose oxidation. The optimized device presented highly reliable amperometric signals in response to glucose concentrations ranging from 100 μM to 1 M, which covers the normal range of glucose level in human serum. Additionally, the electrode showed long time stability in PBS solution and can accurately determine the glucose level in human serum even after one month storage (Figure 12a,b). Yang et al. [162] demonstrated that glucose sensors fabricated with enzyme entrapped-PEDOT nanofibers offer higher sensitivity and increased lifetime in comparison with the devices based on planar PEDOT films. The PEDOT nanofibers coated on the microelectrodes provide a suitable nanoscale matrix to entrap GOx and reduce the impedance, and thus can significantly enhance the performance in sensitivity, detection limit, and longevity. Most recently, flexible PEDOT:PSS electrodes coated on a 2-μm-thick layer of parylene C have also been reported for long-term cutaneous recording[163] (Figure 12c,d). The polymer electrodes were fabricated by incorporating an ionic liquid gel on the surface that can improve the contact with


skin and help to maintain a low impedance over longer periods of time. The PEDOT:PSS electrode showed a much improved performance for the cutaneous recording in comparison with a metal electrode due to its lower impedance. This work paves the way for non-invasive, long-term monitoring of human electrophysiological activity by using low cost polymer electrodes. Apart from the most-common planar flexible polymer electrodes, fiber-based plastic devices also affords various applications. Bendikov et al. [164] reported a potentiometric microsensor for nitrate (NO3−) ion based on ion doped polypyrrole (PPy(NO3−)) films. The sensor was fabricated on a microsized single carbon fiber filament coated with a thin protective layer of parylene C. The ion sensitive PPy(NO3−) was electrodeposited onto the open end of the carbon fiber (Figure 11c). The flexible fiber-based sensor could detect NO3− ion as low as 10−6 M and demonstrated excellent linear response to a wide range of the analyte levels from 10−5 M to 10−1 M (Figure 11d). On the other hand, the potentiometric response of the microsensor to NO3− ion was largely influenced by the film thickness of the electrodeposited PPy film, which could be carefully controlled by the deposition time.

4.2. Neural Recording/Stimulation Electronic devices interfacing with biological systems have become the new trend in clinics to improve the medical diagnosis and treatments. The crucial part of the devices is the



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Figure 12. a) Flow-injection assay (FIA) response of the flexible electrode: PET/PB/PEDOT+GOx. b) FIA responses of electrode to successive injections of different human serum samples. a,b) Reproduced with permission.[161] Copyright 2009, Elsevier. c) Cross-sectional view of the flexible electrodes and the positions on human’s arm with the electrodes. d) Electrical impedance spectra for the dry Au and PEDOT:PSS electrodes, IL gel-assisted Au and PEDOT:PSS electrodes, and a commercial Ag/AgCl electrode with an aqueous gel, respectively. All were in contact with skin. c,d) Reproduced with permission.[163] Copyright 2014, John Wiley & Sons, Inc.

materials coated on the electrodes that afford to meet both the biological and electrochemical requirements of interfacial interactions. Compared with conventional metal electrodes, conducting polymer electrodes show many identifying features for neural recording and stimulation. i) Conducting polymer films could increase the effective surface area hence decrease the impedance at the interfaces with neurons and yield high quality signals; ii) Conducting polymers are biocompatible with surrounding biological environments and will not cause inflammation or infection; iii) The polymer films could be functionalized with various biomolecules, such as growth factors and neurotransmitters, to better stimulate and monitor the biological process.[2,4] iv)The hybrid charge transfer properties involving both electronic and ionic charge transports in the conjugated conducting polymers have become the very heart of organic bioelectronics.[165] The electron/ion transition is highly efficient in eletroactive polymer layer/electrolyte interfaces, which in turn facilitate the electrical interfacing between electrodes and neurons. PPy and PEDOT:PSS have been emerged as ideal materials for polymer electrodes in neural applications. Many seminal works have demonstrated promising results on the use of the two polymers that can significantly enhance both recording and stimulation properties at neural interfaces. George et al.[166] demonstrated a biocompatible PPy-based electrode for neural prosthetics. PPy was electrodeposited on flexible substrates with different dopants and showed excellent biocompatibility within

20


the central nervous systems (CNS) parenchyma in vivo. Owing to its desirable chemical and physical properties, polymer electrodes based on PPy are capable of integrating with CNS tissues and even afford controlled transmission of internal and external electrical signals for significant postoperative periods. In addition, the flexible neural prosthetics hold great potential in repairing damaged neural tissues. Nybery et al. [167] fabricated polymer hydrogel microelectrodes on a flexible elastomer substrate for neural communication. They found that the electrodes with PEDOT:PSS and PPy exhibit even better electronic characteristic than the standard ones, which could be attributed to its controllable charge delivery capacity and low impedance at the neural interfaces. Flexible implantable electrodes with high biocompatibility are in great demand for in vivo applications. Khodagholy et al. [168] demonstrated highly conformable electrode arrays for electrocorticography (ECoG) applications (Figure 13a,b). The arrays fabricated on ultra-flexible Parylene C films contain the photolithographically defined PEDOT:PSS microelectrodes. Considering the biocompatibility, flexibility and insulation properties, parylene C is an ideal choice for the substrates and the insulating layers. The electrode arrays were used for in vivo electrocorticography in rats and were capable of recording the sharp-wave events mimicking epileptic spikes. To validate PEDOT:PSS in recording the signals of biological systems, the array was attached to a printed circuit board, which could help to provide connections to the recording electronics and anchor




REVIEW Figure 13. a) The photos of the transparent and flexible electrodes. b) Recordings from 25 PEDOT:PSS array electrodes, and from 10 silicon probe electrodes, ordered from superficial to deeper in the cortex. a,b) Reproduced with permission.[168] Copyright 2011, John Wiley & Sons, Inc. c) Photograph of Au and PEDOT:PSS electrodes. d) Recordings and time-frequency analysis of brain activity from a gel-assisted Ag/AgCl electrode (top), a dry Au electrode (middle) and a dry PEDOT:PSS electrode (bottom), respectively. c,d) Reproduced with permission.[169] Copyright 2013, John Wiley & Sons, Inc.

the electrode array onto the brain of an anesthetized rat. A small craniotomy above the somatosensory cortex was performed to place the array. Meanwhile, a silicon probe (Neuronexus) was also implanted through the hole in the center of the array. Interestingly, they found that simultaneous recordings obtained from PEDOT:PSS electrodes placed on the surface of the brain and Ir electrodes on the silicon probe implanted in the cortex displayed similar signals, which successful validate the ECoG recording ability of the PEDOT:PSS electrodes. Apart from their application in ECoG, these polymer electrodes array may offer enormous possibilities for other applications in neuroscience. In addition, the array was less invasive than the traditional electrode arrays made from hard metal materials because of its high mechanical flexibility. Most recently, Leleux et al. reported a flexible PEDOT:PSS electrode for electroencephalography[169] (Figure 13c,d). The used PI (Kapton) substrate is flexible enough for the PEDOT:PSS electrodes to perfectly conform to the surface of skin. Spontaneous brain activities were recorded with the polymer electrodes. They found that the PEDOT:PSS electrodes even showed better resolution than Au electrodes in the band of interest (8–13 Hz). To further quantify the performance of the conducting polymer electrode, somatosensory evoked potentials (SEPs) was performed. The results indicated that the flexible polymer electrode offers a good alternative for the long-term


recording of pathologic electrical activity of the brain in a noninvasive way and serves as a versatile toolkit to understand the physiology and the pathology of brain. Conducting polymer composite films also demonstrated significant usefulness in neural applications. Guo et al. fabricated stretchable polymeric multielectrode array (SPMEA) for conformal neural interfacing.[170] A polypyrrole/diol (polycaprolactone-block-polytetrahydrofuran-block-polyCaprolactone (PPy/ PCTC) composite polymer film that offers superior mechanical strength and flexibility with favorable electrical conductivity was used as the sole conductor for both electrodes and leads of the SPMEA. The stretchable neural interface fabricated in a sandwiched structure using polydimethylsiloxane(PDMS) as the substrate and the top passivation layer still retained a relative high electrical conductivity with a uniaxial tensile strain of ca. 20%. Electrical impedance spectroscopy of the PPy/PCTC electrodes revealed high quality responses across the low frequency range of 0.1 Hz to 100 kHz, offering great possibilities for recording local field potentials (LFPs), such as electromyograms (EMG), electrocardiograms (ECG), electrocorticograms (ECoG) and electroencephalograms (EEG). More importantly, cyclic voltammetry measurements validated the impressive charge storage/injection capacities (48.8 mC cm−2) of SPMEA, which was even better than those of common stimulation electrode materials, such as iridium oxide.



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Figure 14. a) Schematic of the wearable “smart bandage”. Reproduced with permission.[173] Copyright 2014, John Wiley & Sons, Inc. b,c) Schematic pictures of the proposed mechanisms for cell interactions with the reduced (b) and oxidized (c) PEDOT:tosylate-coated electrode surfaces. b,c) Reproduced with permission.[176] Copyright 2009, Elsevier. d) Picture of the PEDOT/agarose gel electrode. Reproduced with permission.[177] Copyright 2010, American Chemical Society.

4.3. Drug Delivery Controlled drug delivery technology affords the tailored release profiles to well match the physiologic processes. Conducting polymer coatings on electrodes offer the possibility of controllable drug delivery through external stimulations.[171] More importantly, the surface properties of the polymer film could be selectively tuned by the incorporation of functionalized elements or physical treatments to meet specific requirements. Wadhwa et al.[172] successfully fabricated a PPy coated electrode for electrochemically controlled release and local delivery of dexamethasone. The flexible drug delivery system was prepared on plastic coverslips (Fisher). In vitro studies on murine glial cells suggest that the drug was released in a well controlled manner. More importantly, the coated polymer was biocompatible with the surrounding cells and did not induce any toxic side effect. The polymer-electrode-based delivery system can be further developed to deliver a wide variety of substances, including drugs, growth factors and neurotransmitters, in both central nervous systems (CNS) and peripheral nervous systems (PNS). Wearable human-interactive devices offer great possibilities in a wide range of applications from remote control to clinical health analysis. The proof of concept “smart bandage” is recently proposed by Takei’s group[173] (Figure 14a). The flexible human-interactive device is a highly integrated system

22


containing sensors to monitor health and a drug-delivery system to improve health. A temperature sensor was fabricated on a PI Kapton substrate using the composite material PEDOT:PSS/ carbon nanotube by photolithography-free printing techniques. The drug delivery pump (DDP) with a microfluidic channel for drug ejection was then integrated into the system. These types of wearable human-interactive devices represent a promising platform for future integrated flexible electronics.

4.4. Cell Regulations The redox states of conducting polymers can be reversibly changed by electrochemical stimulation, which in turn tailor the surface chemistry of the polymer films. As the surface property is an important determinant for the molecular events of cell adhesion, cell differentiation and cell proliferation, the electrochemical modulation of the conducting polymer films is expect to have huge impact on the activities of the anchored cells.[174] It has been reported that patterned PEDOT: PSS electrodes under electronic field could effectively control the conformation of protein and regulate the proangiogenic capability of tumor-associated adipogenic stromal cells.[175] Therefore, conducting polymer electrodes are a very promising platform for the non-invasive, disposal and low-cost cell regulations. Svennersten et al.[176] reported that conducting polymer




5. Smart Textiles 5.1. Introduction of Smart Textiles A textile is a flexible woven material formed by crocheting, weaving, knitting, knotting, or pressing fibers together, consisting of a network of natural or artificial threads or yarns made of raw fibers of cotton, wool, flax, or other organic materials. The ubiquitous textiles dated to 30,000 years ago have important applications in very broad areas including medicine and healthcare products.[178] The integration of electronics devices in textiles referred to as smart textiles implies innovative technologies that are expected to substantially improve the quality of our life.[179] Considering most textiles being organic, the smart textiles integrated with functionalized organic devices for biological applications, such as the aforementioned organic transistor-based biosensors and polymer electrodes, should be regarded as one major part of organic bioelectronics. Although the study of textile-based organic bioelectronics has just been started and only a few examples in related applications have been reported,[180] this area has great potential in the future for its numerous advantages including wearability, flexibility, low cost and feasibility for mass production. Present research in smart textiles covers a wide range of spectrum, ranges from sensors and actuators to signal transmission, processing and control units, making it hard to classify smart textiles. Some researchers classify them according to their specific applications, including body and environment-monitoring


REVIEW

PEDOT:Tosylate could be used for the electrochemical control of epithelial cell adhesion and proliferation (Figure 14b,c). The functionalized cell culture dish comprising two adjacent electrode surfaces was fabricated by chemically depositing the conducting polymer on a flexible PET substrate. When the electric field was addressed, the cell culture dish with two adjacent PEDOT:Tosylate electrode surfaces would become reduced and oxidized, respectively. The results indicated that the reduced polymer surface could efficiently promote the cell proliferation in comparison with the oxidized polymer electrode, while the oxidized polymer would alter the conformation of functional fibronectin and severely compromise the viability of cells. This work successfully demonstrated that cell adhesion and proliferation could be effectively controlled by electrochemical modulation of polymer films. PEDOT electrodes on flexible hydrogel substrates for the cultivation of contractile myotubes have also been reported[177] (Figure 14d). The PEDOT/agarose electrodes for cell cultivation were fabricated by two electrochemical processes: electropolymerization of PEDOT into the agarose hydrogel and electrochemical-actuation-assisted peeling from the mask. Such fully organic, moist, flexible electrodes still exhibit excellent biocompatibility. The fibrin-supported myotubes maintain a high level contractile activity for a long period of time. In addition, the electrical stimulations applied on the PEDOT/ agarose electrode could induce contraction of muscle cells. More importantly, the capacity of the PEDOT-based polymer electrode is very high, making it the ideal platform for non-invasive electric stimulations without electrolysis.

clothing, IT device–equipped clothing, digital color clothing, and extra functional clothing; while others grouped by the utilized materials, such as conductive yarns, thermal sensitive materials and shape memory materials.[181] Regardless varying versions of classification, smart textiles should fulfill the following definition to be clarified as “smart”. Smart textiles can sense or react to the change of environmental conditions and stimuli, such as those from mechanical, thermal, chemical, electromagnetic or others.[182] Additionally, it is primarily used to augment memory, intellect, creativity, communication and physical senses. On the other hand, smart textiles should be worn rather than carried by the users and the basic requirements of a textile product, such as comfort level, washability and flexibility, should not be sacrificed, as shown in Figure 15. It is differed from wearable computing, in which conventional technologies are attached to clothing. Those wearable technologies are apparel with unobtrusively built-in electronic and photonic functions that can be worn and used for different purposes.[183] Regardless of its end-use, a wearable electronic usually contains interfaces, energy supplies, data storage and transmission systems, etc.[184] To realize smart textiles, significant amount of efforts were devoted to invent novel active materials and develop new fabrication strategies.[185] Instead of wires, electro-textiles and conductive fiber materials, such as conductive yarns and threads, are employed for the development of functional e-textiles.[186] Owing to its unique combination properties of adequate flexibility, tunable conductivity and solution processability, organic semiconducting polymers have emerged as the candidate material for the fabrication of conductive electronic textiles. For instance, PEDOT-PSS-based flexible textile could be realized by drop coating the textile fiber substrates or simply soaking the fabric in a conductive polymer aqueous dispersion.[187] PPycoated textile fabrics could be prepared by in situ polymerization of pyrrole in the presence of textile substrates.[188] The conductive cotton fabrics were coated with PANI by using chemical oxidative polymerization method, the property of which was significantly influenced by the used protonic acid, the polymerization time, the type and concentration of dopant.[189] Conductive-polymer-coated textiles can be further explored for many applications, such as complex logic circuits for wearable electronics and bioelectronics. Hamedi et al.[19] presented elegant work on wire electrochemical transistors (WECTs) using conducting polymer coated fibers. For the fabrication of a single WECT, two PEDOT/PSS coated fibers were suspended in a cross geometry and created an ionic contact by adding a solid polymer electrolyte from solution (Figure 16a–d). The fabricated single WECT demonstrated a performance even outperforms the OECTs assembled on planar substrates. More importantly, organic electronic textiles could be created by weaving PEDOT:PSS coated monofilaments. The realization of fabric circuit diagram (FCD) containing the electrically active monofilaments together with the construction of WECTs constitute a new step towards the realization of analogue and digital microelectronics directly into textile, offering many new possibilities for biological applications using the devices integrated with organic bioelectronic devices. Silk-fiber-based OECTs were also fabricated by arranging poly(4-(2,3-dihydrothieno[3,4-b]-[1,4]dioxin-2-yl-methoxy)-



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Figure 15. a) A typical smart textile: electric heating knitwear. Right photos: 1) Infra-red image of the back of a nude human subject; 2) after the knitwear was applied to the human subject for 3 minutes; 3) After 20 minutes; 4) The knitwear was removed. The red and green indicates the high and low temperatures, respectively. The high temperature regions show that more blood flows to the skin surface of the body so as to alleviate the symptoms of the pains. b) Weaving machine used in industry. b) Reproduced with permission.[179] Copyright 2012, American Institute of Physics.

1-butanesulfonic acid) (PEDOT-S) stained silk fibers consisting of a number of monofilaments in a simple cross-junction configuration[156] (Figure 16e,f). A 1:1 electrolyte mixture by weight of the ionic liquid [bmim][Tf2N] and the corresponding polymer ionic liquid poly[ViEtIm][Tf2N] was employed as the electrolyte to bridge these two conductive fibers. The current flow of the fiber OECT could be modulated up to three orders of magnitude when the gate voltage was varied from 0 to 1.4 V. Additionally, a basket-weave fabric was realized by manually weaving the pristine as well as PEDOT-S stained silk fibers. The demonstration of silk fiber-based OECTs is a significant step towards the

24


realization of flexible organic electronics and electronic textiles primarily through the integration of traditional textile material and carefully chosen biologically relevant electrochemical media, both of which provide great potential to interrogate novel device paradigms that afford the direct interactions with living systems. Meanwhile, in the commercial market, Peratechand and Fibertronic are the two major manufacturers of soft electronic products, providing a wide range of flexible keypads, sensors and controllers that can incorporate into smart textiles. Nevertheless, most of the reported smart textiles, to some extent, are still not able to provide a comfortable wear due to




REVIEW Figure 16. a) Channel current versus gate voltage (transfer characteristic) of a wire electrochemical transistors (WECT) based on fibers. Inset: Optical micrograph of a WECT assembled from the cross junction of two PEDOT/PSS-coated polyamide monofilaments. b) Channel current versus drain voltage (output characteristics) of the WECT. a,b) Reproduced with permission.[19] Copyright 2007, Macmillan Publishers Ltd. c) Photograph of a binary tree multiplexer on a fabric mesh. d) Dynamic electrical performance of the multiplexer. e) Photograph of a basket-weave fabric manually woven with pristine and PEDOT-S stained Bombyx mori silk threads. (f) Transient characteristics of Ids as a function of time t when Vg is switched between 0 and 1.2 V. c–f)) Reproduced with permission.[156] Copyright 2011, John Wiley & Sons, Inc.

many problems, such as power generation and storage, durability and washability, which hinder the development and commercialization of smart textiles.

5.2. Smart Textiles in Biomedical Applications Smart textiles serve as the catalyst to revolutionize the traditional medical practice and are expected to continuously


improve the quality of life. The ubiquitous textile materials in intimate contact with human body have been emerged as the viable platform for medical and healthcare applications, such as health situation monitoring system, electrotherapeutic smart textile, drug delivery system, smart wound-dressing system, smart textiles for implantation surgery and smart textiles for phototherapy.[190] Owing to the increasing amount of aging population, textile electronics able to be integrated with clothing are in great need to alleviate the expensive health



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caring and monitoring problems. Wearable smart textile electronics, such as those using wearable textile to record and realtime monitor the daily function of body organs over periods of time, have been successfully fabricated recently, which can be used to enhance performance and reduce the risk of injury of the patients or the elderly.[191] Biometric Measurements: Recently, plentiful monitoring scenarios using smart textiles integrated with flexible organic electronics, such as polymer electrodes, electro-active polymers sensors and actuators, are proposed and investigated in biomedical applications. In particularly, smart textiles are widely explored for the use in biometric measurements, including the measurements of heart rate, respiration rate, body temperature, blood sugar level, stress level, skin conductivity and so on. For example, Coyle et al. reported a fabric-integrated sweat analysis system that can be used for real-time analysis of sweat during exercise. Many textile-based sensors, including a multiparametric patch to measure the pH, sodium concentration, and conductivity of sweat, are distributed around the body.[180] In the monitoring of cardiopulmonary functions, textile-based sensors and electrodes were used as the signal obtaining apparatus of electrocardiogram (ECG) because of the modulation of the electrical currents induced by the depolarization and repolarization of the cardiac cells.[192] Meanwhile, a number of projects have been carried out by different companies in this field, aiming to detect and prevent cardiovascular diseases by smart electronic and textile systems.[190] Electrotherapy: The electrotherapeutic method has been employed in rehabilitation and physiotherapy. It is a non-pharmacological and non-invasive treatment of various types of diseases, pains and disorders of the body.[193] Textile electrodes, as a type of passive smart textile, are usually utilized for nerve stimulation and other electrotherapeutic treatments. Electricity is applied to the intact skin to activate afferent fibers through electrodes. One typical example of the electrotherapeutic smart textile is the transcutaneous electrical nerve stimulation (TENS) device, which can activate afferent fibers and eventually reduce the transmission of pain signals.[194] Although they have good conductivity and low contact impedance, if it is supplemented with external electrolyte, hygienic problems exist and cause uncomfortable feeling to the patients. Thus, textile electrodes are explored to substitute conventional electrodes and incorporated into garments. According to previous studies, wearable TENS garment was developed by incorporating conductive yarns on a knitted garment,[195] by fitting the electrode pads to the garment or by applying electrically conductive liquid on selected points on the garment. On the other hand, as evidenced by many experiments,[167,169] conductive polymer electrodes can have better contact and lower impedance with human body compared with conventional metal electrodes. Therefore, textile-based conductive polymer electrodes may find promising applications in this area. Nevertheless, many technical problems still exist in textile electrodes and need to be solved for practical applications of electrotherapeutic smart textiles: i) the signal-to-noise ratio of the textile electrode is lower than that of conventional electrode, further works should be done to improve the electrical properties of the textile electrodes; ii) body movement may leads to displacement of a textile electrode because of the flexible

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nature of the textile and absent of external electrolyte, leading to a result with more noise; iii) the properties of skin keep on changing within a short period of time. So the textile electrodes should be optimized to tolerate these changes and work stable for a long time. Epidemiology Control: Apart from the versatile applications in healthcare fields, smart textiles integrated with multifunctional biosensors will also play a significantly role in investigating illness and detecting abnormal diseases. Macroscopically understanding and maintaining public health condition could be realized by analyzing the epidemiological information acquired through smart textiles systems, which can help to significantly reduce infection rate and even death rate. In summary, although there are lots of prototypes and great innovative ideas of smart textiles for bioelectronic applications, most of them are still not mature enough to be realized and commercialized. In addition, more attention should be paid to the safety and the stability of the wearable electronics. Since the active materials used to fabricate the textile sensors or actuators are mainly conductive yarns that are filled or coated with organic semiconducting materials on ordinary textiles, washing may remove or damage the structure of the materials, and sweats, which is slightly acidic, may also affect the performance of them. Therefore, for the real applications, the smart electronic textiles should tolerate daily damage, such as laundering and abrasion, otherwise, they may target for disposable applications. Another concern about smart textiles is the power sources. Although today there are many elegant works presented on the power issues for smart textiles, such as embedded alkaline battery[196] and photovoltaic fibers,[197] further investigation is required to maximize the capability and minimize the sizes of power sources.

6. Others Flexible Organic Bioelectronic Devices 6.1. Organic Electronic Ion Pumps (OEIPs) Precise, localized, and minimized disruptive electronic-tobiology interfacing is critical to the successful implement of cell stimulation in biological systems. However, present technologies suffer from a variety of drawbacks, including time consuming, inconvenient operation and high cost. Owing to their unique ion-to-electron conversion property, conducting polymers serve as natural candidate materials to intimately bridge the gaps between electronic machines and biological systems. The organic electronic ion pump (OEIP), as a novel type of organic bioelectronics device, has attracted an increasing amount of interest over the last few years.[198] Typically, PEDOT:PSS patterned on a planar substrate serves as the source (anode) and target (cathode) electrodes of an OEIP, between which a thin layer of over-oxidized PEDOT:PSS is covered as the active channel region. The channel and electrodes of the device are patterned with hydrophobic photoresist, which defines the opening areas for the addressing of electrolytes on the two electrodes as well as the contact points for external electronic control. Positively charged ions to be delivered to the target electrolyte are added into the source electrolyte. The following redox reactions occur upon the addressing of the




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voltage, in which the source electrode is oxidized and the target electrode is reduced: Positively charged ions Mn+ in the source electrolyte will enter the oxidized source electrode and migrate into the target electrode through the ionically conductive channel. It is worth noting that the transported Mn+ is compensated by electrons transferred between the electrodes. Therefore, the transfer velocity of Mn+ is directly dependent on the current in the electronic circuit, which provides a feasible way to quantitatively control and deliver positively charged ions to electrolytes. OEIPs have been extensively investigated in the delivery of various kinds of ions (H+, Ca2+, K+, Na+) and neurotransm itters(acetylcholine, aspartate, GABA, glutamate) for cell signaling both in vitro and in vivo.[198] OEIPs acting as an actuator to pump small ions (Ca2+ and K+) from reservoir electrolytes to target electrolytes were firstly reported by Isaksson et al.[13] (Figure 17). OEIPs based on PEDOT:PSS were fabricated on flexible PET substrates. They found that the OEIP devices could electronically control the ion homeostasis process in neurons. Target ions were effectively delivered from the source reservoir to the receiving electrolyte via a PEDOT:PSS thin-film channel by the addressing of an electronic field in several minutes. In

addition, the ion transport rate could be precisely controlled by modifying the applied electronic field. The high performance of the device could be attributed to its high on/off ratio exceeding 300. More importantly, a PEDOT:PSS-based OEIP could be miniaturized into a microsized configuration, which allows the high-quality recording and stimulation of physiological signalling events even at a single-cell level. Therefore, the use of OEIP to regulate the intracellular ion signalling with proper spatial and temporal resolution in individual neuronal cells offers great opportunity for the study of cell communications in biological systems. In addition, the pH gradients and local proton oscillations of the electrolyte could also be electronically controlled via OEIPs.[199] The positively charged ion profile in the source electrolyte and the transport of the protons between the source and target electrolytes could be quantitatively controlled by the electrical field, which in turn change the pH of the target electrolyte from 7 to 3 in a few minutes with an enhanced delivery rate. Owing to its high overall proton delivery and on/off ratio exceeding 1000, no detectable leakage induced by the diffusion was observed when no voltage was applied. More importantly, local pH oscillations were created by applying a short electric pulse. The OEIPs presented here can be further explored for

Figure 17. a) Schematic top view of an organic electronic ion pumps (OEIP). b) Ca2+ transport as a function of time (VAB = 1 V, VBC = 10 V, VCD = 1 V). c) pH gradient formed in the CD electrolyte during proton pumping. The deep red color represents pH = 2 and clear yellow represents pH = 5. d) Solid line: time-lapse microscopy of intracellular [Ca2+] in FURA-2-AM-loaded HCN-2 cells located adjacent to the 4-mm-wide barrier. Dotted lines: cells located 1 mm from the barrier. dashed lines: cells located 2 mm from the barrier. a–d) Reproduced with permission.[13] Copyright 2007, Macmillan Publishers Ltd.




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the transport of other small sized ions, making the devices promising for variety of biological applications, including cell signaling study, lab-on- chip and drug delivery. Apart from positively charged ions, OEIPs also play a significant role in the precise control of neurotransmitters associated with cell signaling. Simon et al. demonstrated an OEIP-based device that afforded the precise delivery of several neurotransmitters both in vitro and in vivo[200] (Figure 18a,b). The positively charged glutamate (Glu), aspartate (Asp) and γ-amino butyric acid (GABA) were employed as the neurotransmitters for the investigations through OEIP system. The transport efficiency (electron/molecule ratio) of these positively charged molecules were 2.7± 0.2 for Glu, 6.3 ± 0.5 for Asp and 1.3 ± 0.1 for GABA respectively, all of which could be tuned by the operational voltage. To explore its use in vivo, they fabricated an encapsulated, syringe-like device as an interface between electronics and biological systems. The syringe-like device demonstrated a similar performance to that of planar devices. It was found that intracellular Ca2+ profile was modified by the controlled Glu delivery in the encapsulated device. In the further investigations, an auditory system of guinea pig was adopted as an in vivo experimental platform. The auditory brainstem response

(ABR) was monitored to estimate the hearing sensitivity before and after the Glu transport using the OEIP. The device could selectively stimulate nerve cells to response to specific neurotransmitters. Additionally, another highly desired feature – pulsed delivery – could be achieved to alleviate the problems, such as malfunctioning signalling pathways and down regulation of receptor expression that were normally occurred in the continuous delivery. The successful demonstration of the ability to translate electronic addressing signals through neurotransmitter signalling into brainstem cell stimulation represents a new paradigm in the electronics-to-brain interfacing and holds great potential as the versatile communication interfaces for biomedical applications. Ionic conductive polymers can not only fulfill the requirements for the transport of small cations but also enable the precise lateral transport of large-sized biomolecules. Tybrandt et al.[201] further expanded the transport repertoire to neurotransmitter acetycholine (Ach). The neuronal signalling induced by Ach could be precisely controlled by electronic currents. The size of the outlet transfer channel in an OEIP was miniaturized to 10 μm, which was comparable to or even smaller than that of an individual neuronal cell. Moreover, the delay time of the delivery

Figure 18. a) Photograph of an OEIP device mounted on the round window membrane (RWM). The visible dark blue strips on the transparent substrate indicate the two ion channels. b) Schematic of the experimental scheme. a,b) Reproduced with permission.[200] Copyright 2009, Macmillan Publishers Ltd. c) Schematic top view of an OEIP. Electrodes are labeled source (S), target (T) and waste (W). d) Microscopy image of SH-SY5Y cells at various distances (50 and 150 mm) from the channel outlet of OEIP. c,d) Reproduced with permission.[201] Copyright 2009, John Wiley & Sons, Inc.

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6.2. Ion Bipolar Junction Transistors (IBJTs) Dynamic control of chemical microenvironments using active circuits is essential for the precise delivery of ions and

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system was reduced from minutes to seconds by incorporating a preloading circuit, which also minimized the undesired delivery of residual ions. The precisely controlled delivery rate of Ach through the addressing signal on the OEIP enables the efficient stimulation of single SH-SY5Y neuroblastoma cells via Ach with the local concentration in the micromolar range. They also found that Ca2+ responses could electronically regulate the dynamic parameters, including amplitude and frequency. Therefore, the fabricated OEIP device is promising for the further exploration of spatiotemporal regulation of cell signaling systems. Organic electro-active materials and devices have been widely investigated to stimulate and regulate functions in biological systems. Since the cation ion concentration of the electrolyte in an OEIP is quantitatively determined by the addressing voltage, OEIPs have emerged as a viable platform to regulate the microenvironment in the biological systems. Gabrielsson et al. proposed a flexible OEIP device designed for manufacturing and controlling the assembly of amyloid-like structures[202] (Figure 18c,d). Cations (H+, Na+) were pumped to a reservoir containing a negatively charged polypeptide and poly(glutamic acid) (poly-E). They found that the OEIP could selectively modulate the confined microenvironment and therefore stimulate the poly-E to generate amyloid fibrils with vastly different aggregate morphologies, depending on the alteration of micro-environment. More importantly, the formation of amyloid fibrils aggregated structures was determined by the types of ions and the ion delivery rate, which could be effectively controlled by the OEIP device by electronic addressing. The OEIP capable of delivering cationic species to the microenvironment containing biomolecules at high spatiotemporal resolution offers great opportunities for the biological study on amyloid assembly and fibrillogenesis.

biomolecules in the biological world. As an emerging type of organic electronics, solid-state ion bipolar junction transistors (IBJT) based on conducting polymers and integrated with thin films of anion- and cation-selective membranes have been successfully manufactured via the standard microfabrication techniques.[203] An IBJT consists of an emitter-base (E-B) and a collector-base (C-B) and can be easily fabricated on a flexible substrate. The operation mode of the transistor could be reversely switched via the voltage bias on the E-B diode. It is worth noting that the IBJT can act as active control element for the localized neurotransmitter delivery, which in turn dynamically control the physiological microenvironment of neuronal cells. Furthermore, a complementary npn-IBJT could be fabricated to regulate anion transport, creating a new avenue for the complex delivery systems to enable the transport of both positively and negatively charged ions and biomolecules, as shown in Figure 19.[204] The flexible npn-IBJT demonstrated stable transistor characteristics over extensive operation time with a current switch time less than 10 s. The npn-IBJT also showed many outstanding features, including high on/off ratio, high stability, and dynamic modulation, far outweigh that of other kinds of ion transistors operated in the physiological environment. The delivery of neurotransmitter glutamic acid could be actively modulated through the anionic currents in the npnIBJT. Additionally, the presented fabrication strategy allows the integration of both npn- and pnp-IBJTs manufactured on the same flexible PET substrate without introducing any additional fabrication steps. Most recently, Berggren’s group presented an elegant work on the logic gates using the ion transistors.[205] The integrated chemical logical gates consisted of inverters and NAND gates were demonstrated using the IBJTs. Compared with the single transistor-type gates, the complementary ion gates have higher gain and lower power consumption. The NOT and NAND logical gates were successfully realized with the IBJTs, offering the possibility for the implement of arbitrary logical expressions. Therefore, ion inverters and NAND gates based on the IBJTs lay the solid foundation for the further development of chemical delivery circuits. In sum, the

Figure 19. Ion bipolar junction transistors (IBJT): a) the npn-IBJT; b) the pnp-IBJT. a,b) Reproduced with permission.[205] Copyright 2012, Macmillan Publishers Ltd.




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Figure 20. a) Image of the emblem printed by an inkjet printer on a photopaper using PANI–PSS ink. b) The response of a printed PANI–PSS chemiresistor to NH3 vapor concentration. a,b) Reproduced with permission.[208] Copyright 2007, John Wiley & Sons, Inc. c) Photograph of PANI nanowire arrays patterned on a flexible PET substrate. d) Time-dependent response of a PANI nanowire chemiresistor to different H2 concentrations. c,d) Reproduced with permission.[210] Copyright 2011, John Wiley & Sons, Inc.

use of IBJTs as a key amplification element has huge impact on the drug delivery, neuronal cell stimulation, lab-on-chip and sensing applications.

6.3. Chemiresistors Organic materials such as PPy, PANI, polythiophene (PTh), PEDOT, and their derivatives have been investigated for vapor detection as chemiresistors since early 1980s.[206] A typical chemiresistor consists of two electrodes and an organic conducting polymer channel.[207] The change of the conductivity of the channel would be monitored as the function of target analytes, such as H2S, NH3, NO2, H2, O2, H2O, and so on. Many investigations focused on the assembling of high-quality organic materials on flexible substrates, including organic nanowires, nanoparticles, and hybrids materials. Jang et al. demonstrated a method for the fabrication of water-dispersible PANI-poly(4-styrenesulfonate) (PANI-PSS) nanoparticles, and its application for gas detection[208] (Figure 20a,b). The PANI-PSS nanoparticles were printed on normal photopapers by an inkjet printer and used as ammonia vapor (NH3) sensors. The as-prepared sensor demonstrated reproducible and reversible responses to gaseous NH3 at the parts-per-million (ppm) scale.

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Crowley et al. developed a H2S sensor by printing PANIcopper(II) chloride on a PET substrate as a chemiresistor. Concentrations as low as 2.5 ppm were detectable. The flexible sensor showed a good linear response to H2S in the range of 10–100 ppm.[209] Zou et al. also reported an approach to fabricate patterned PANI nanowire arrays on flexible PET substrates by using photolithography and polymerization processes. The patterned nanowire arrays exhibited high sensitivity to NH3 and H2 (100 ppm)[210] (Figure 20c,d). There are several advantages of chemiresistor-based gas sensors such as good sensitivity, low cost, and feasible production process. Nevertheless, there are problems prohibit the practical applications of chemiresistors. One critical thing is the longterm stability of chemiresistors. The performance of a chemiresistor could decrease dramatically due to the de-doping effect of organic materials when stored in air for a long period of time.[206] On the other hand, sensing signal cannot fully reach the original value after analyte detections because of the poor reversibility. To alleviate these drawbacks, Dua et al. used UV radiation to improve the reversibility. With the aid of 254nm UV light treatment, the signal of a PTh fiber device can be reversed readily even after exposing to strong oxidants.[211] Surwade et al. also reported a reversible NO2 sensor. The high level of signal reversibility was achieved by using a short burst of UV irradiation at room temperature in ambient air.[212] In addition,




6.4. Microfluidic Systems Microfluidic systems are devices containing webs of channels, sensors, pumps, valves, and filters etc. for the analysis and transfer of samples. The systems are normally sub-millimeter scale and thus can enable the analysis of DNA, proteins, cells, etc. presented in nano or even picoliter volumes. Therefore, the microfluidic systems have the major advantages in precise analysis with only a small amount of sample, fast reaction times, and ease of automation, and are ideal for applications in the fields of biomedical, clinical, pharmaceutical, or biotechnological science. Small-size organic electronic devices can be prepared by solution process and are thus suitable for the applications in microfluidic systems, such as the aforementioned OFET or OECT -based biosensors integrated in flexible microfluidic channels.[51,144] Moreover, polymer semiconductors have been successfully used as surface tension switches that are able to guide aqueous electrolytes in biological “lab-on-chip” microfluidic systems.[213,214] Robinson et al.[215] reported a PET-based flexible microfluidic system in which poly(3-alkylthiophenes) (P3AT) was deposited as the surface tension switch. Water contact angles on the P3AT films in neutral and electrochemically doped states and the effect of alkyl side-chain length on the contact angles are systematically investigated. They found that the increase of the side-chain length will increase the contact angle of water on the conjugated polymer films in both states, however minimize the angle difference between the neutral and doped states. Similar results have been observed by our group.[214] Then they demonstrated a P3HT wettability switch as the floor in a PDMS microfluidic capillary channel. The device can be programmed to direct water along a desired path in a junction system.[216] Therefore, electrochemical control of the surface wettability of a conjugated polymer will be a useful technique that can be used in complex flexible microfluidic systems for biological sensing applications.

7. Conclusions and Outlook Organic bioelectronics, serving as an outstanding tool to bridge the worlds of electronics and biology, has experienced a dramatic development in the past few years. However, these recording and regulating devices interfacing with biological systems are normally fabricated on hard, rigid planar substrates. Considering that the surfaces of movable tissues are arbitrarily curved in a physiological environment, the flexibility of organic bioelectronic devices is essential for improving contact and interaction with biological systems and increasing the stability and reliability of the tests. Therefore, flexible organic bioelectronics indeed has a promising outlook for various novel applications in medicine, healthcare, and biology. Significant progress has been achieved within this emerging interdisciplinary field; flexible organic bioelectronics devices, including


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the selectivity of chemiresistors still need to be improved. The inteferents, including redox-active vapors, organic vapors, and humidity in the environment, could significantly influence the capability of chemiresistor sensors to distinguish target analytes from complex environments.

OTFT-based sensors for sensitive biological-sensing applications, polymer electrodes for recording/stimulation of cells and neurons, smart textiles for wearable electronics, OEIPs and IBJTs for controlled drug delivery, and chemiresistors for sensing, have all been successfully demonstrated recently. Today, several cross-disciplinary research groups in Europe, Asia, the Americas, and Australia have been intensively engaged with the multidisciplinary research area defined by the scientific collaborations between chemists, physicists, biologists, materials scientists, and electrical engineers. Although the area of flexible organic bioelectronics is shaped by several different factors, materials still play the most significant role. The unique mixed electronic and ionic transport properties of the organic materials are at the very heart of organic bioelectronics, and can interface with the ion flux in biological world. However, a fundamental understanding of the ion transport in these organic materials is not well-documented, and few efforts have been devoted to the rational design of optimized materials able to simultaneously improve the electronic and ionic transport. What’s more, little work has been done toward the synthesis of novel organic materials that can offer more-desirable properties for interfacing with biological systems. Most organic materials used in flexible organic bioelectronic devices are common ones that have been developed for many years, which brings great opportunities for chemists to synthesize suitable materials for flexible organic bioelectronics by taking advantage of the versatile toolkit of organic chemistry. On the other hand, further improvement of flexible organic bioelectronics may be achieved by optimizing the design of devices by several possible approaches. One is to improve the performance of existing flexible organic bioelectronic device by optimizing the geometric features of the devices or adopting new techniques in the device fabrication processes. Another is to explore new types of devices based on the flexible organic bioelectronic platform and further expand the biological application scope of these devices. In our opinion, organic semiconductor materials have inherent advantages in combination with biological systems because both are organic systems. Secondly, the development of microfabrication techniques, including soft lithography, 2D and 3D inkjet printing, gravure printing, and nanotechnologies for realizing delicate nanostructures, like nanotubes, nanowires, and quantum dots of organic materials, paves the way for the integration of flexible organic bioelectronics devices in various biological systems, that are, however, yet to be investigated. Nevertheless, the beautiful marriage between flexible organic electronics and biology will be further developed to serve as a versatile platform for biological applications.

Acknowledgements This work was financially supported by the Research Grants Council (RGC) of Hong Kong, China (project number: N_PolyU506/13 and PolyU5324/12E) and the Hong Kong Polytechnic University (project number: G-SB07, A-PL49, G-YM45).


Received: June 13, 2014 Revised: August 25, 2014 Published online:


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35

25th anniversary article: organic electronics marries photochromism: generation of multifunctional interfaces, materials, and devices.

Spiers memorial lecture. Organic electronics: an organic materials perspective.

Organic Materials for Time-Temperature Integrator Devices.

Nature-Inspired Structural Materials for Flexible Electronic Devices.

From molecular design and materials construction to organic nanophotonic devices.

Stretchable Hydrogel Electronics and Devices.

Metal-Organic Frameworks as Active Materials in Electronic Sensor Devices.

Organic flash memory on various flexible substrates for foldable and disposable electronics.

Fiber-based wearable electronics: a review of materials, fabrication, devices, and applications.

Carbon Nanotube Flexible and Stretchable Electronics.

Organic electronics: recent developments.

Organic electronics: addressing challenges.

Low-voltage flexible organic electronics based on high-performance sol-gel titanium dioxide dielectric.

Organic electronics and photonics: concluding remarks.

Ion age transport: developing devices beyond electronics.

Scalable Sub-micron Patterning of Organic Materials Toward High Density Soft Electronics.

Electronics based on two-dimensional materials.

Neurosurgical materials and devices.

Organic semiconductor spintronics: utilizing triplet excitons in organic electronics.

Y₂O₃ Composite Materials in Flexible Organic Thin-Film Transistors.

Ultrahigh performance C60 nanorod large area flexible photoconductor devices via ultralow organic and inorganic photodoping.

Naphthodithiophenes: emerging building blocks for organic electronics.

Highly Flexible and Efficient Fabric-Based Organic Light-Emitting Devices for Clothing-Shaped Wearable Displays.

Two-dimensional materials and their prospects in transistor electronics.