BBA - General Subjects (v.1830, #9)

Organic bioelectronics — Novel applications in biomedicine by Róisín Owens; Peter Kjall; Agneta Richter-Dahlfors; Fabio Cicoira (4283-4285).

Organic bioelectronics: A new era for organic electronics by George G. Malliaras (4286-4287).
This issue of “Biochimica et Biophysica Acta — General Subjects” is dedicated to organic bioelectronics, an interdisciplinary field that has been growing at a fast pace. Bioelectronics creates tremendous promise, excitement, and hype. The application of organic electronic materials in bioelectronics offers many opportunities and is fuelled by some unique features of these materials, such as the ability to transport ions.This is a perspective on the history and current status of the field.Organic bioelectronics currently encompasses many different applications, including neural interfaces, tissue engineering, drug delivery, and biosensors. The interdisciplinary nature of the field necessitates collaborations across traditional scientific boundaries.Organic bioelectronics is a young and exciting interdisciplinary field. This article is part of a Special Issue entitled Organic Bioelectronics — Novel Applications in Biomedicine.► This issue is dedicated to organic bioelectronics. ► The application of organic electronic materials in bioelectronics offers many opportunities. ► Organic bioelectronics currently encompasses many different applications.
Keywords: Organic bioelectronics;

Synthesis, copolymerization and peptide-modification of carboxylic acid-functionalized 3,4-ethylenedioxythiophene (EDOTacid) for neural electrode interfaces by Laura K. Povlich; Jae Cheol Cho; Michelle K. Leach; Joseph M. Corey; Jinsang Kim; David C. Martin (4288-4293).
Conjugated polymers have been developed as effective materials for interfacing prosthetic device electrodes with neural tissue. Recent focus has been on the development of conjugated polymers that contain biological components in order to improve the tissue response upon implantation of these electrodes.Carboxylic acid-functionalized 3,4-ethylenedioxythiophene (EDOTacid) monomer was synthesized in order to covalently bind peptides to the surface of conjugated polymer films. EDOTacid was copolymerized with EDOT monomer to form stable, electrically conductive copolymer films referred to as PEDOT-PEDOTacid. The peptide GGGGRGDS was bound to PEDOT-PEDOTacid to create peptide functionalized PEDOT films.The PEDOT-PEDOTacid-peptide films increased the adhesion of primary rat motor neurons between 3 and 9 times higher than controls, thus demonstrating that the peptide maintained its biological activity.The EDOT-acid monomer can be used to create functionalized PEDOT-PEDOTacid copolymer films that can have controlled bioactivity.PEDOT-PEDOTacid-peptide films have the potential to control the behavior of neurons and vastly improve the performance of implanted electrodes. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.Display Omitted► We describe the synthesis and characterization of an acid-functionalized EDOT monomer. ► The EDOTacid monomer is combined with EDOT to create a P(EDOT-EDOTacid) copolymer. ► The copolymer is functionalized by RGD peptide, and dramatically improves neural cell adhesion.
Keywords: Conjugated polymer; Electrochemical; Biomaterial; RGD; Neuron; Adhesion;

Bioelectronics meets nanomedicine for cardiovascular implants: PEDOT-based nanocoatings for tissue regeneration by V. Karagkiozaki; P.G. Karagiannidis; M. Gioti; P. Kavatzikidou; D. Georgiou; E. Georgaraki; S. Logothetidis (4294-4304).
An exciting direction in nanomedicine would be to analyze how living cells respond to conducting polymers. Their application for tissue regeneration may advance the performance of drug eluting stents by addressing the delayed stent re-endothelialization and late stent thrombosis.The suitability of poly (3, 4-ethylenedioxythiophene) (PEDOT) thin films for stents to promote cell adhesion and proliferation is tested in correlation with doping and physicochemical properties. PEDOT doped either with poly (styrenesulfonate) (PSS) or tosylate anion (TOS) was used for films' fabrication by spin coating and vapor phase polymerization respectively. PEGylation of PEDOT: TOS for reduced immunogenicity and biofunctionalization of PEDOT: PSS with RGD peptides for induced cell proliferation was further applied. Atomic Force Microscopy and Spectroscopic Ellipsometry were implemented for nanotopographical, structural, optical and conductivity measurements in parallel with wettability and protein adsorption studies. Direct and extract testing of cell viability and proliferation of L929 fibroblasts on PEDOT samples by MTT assay in line with SEM studies follow.All PEDOT thin films are cytocompatible and promote human serum albumin adsorption. PEDOT:TOS films were found superior regarding cell adhesion as compared to controls. Their nanotopography and hydrophilicity are significant factors that influence cytocompatibility. PEGylation of PEDOT:TOS increases their conductivity and hydrophilicity with similar results on cell viability with bare PEDOT:TOS. The biofunctionalized PEDOT:PSS thin films show enhanced cell proliferation.The application of PEDOT polymers has evolved as a new perspective to advance stents.In this work, nanomedicine involving nanotools and novel nanomaterials merges with bioelectronics to stimulate tissue regeneration for cardiovascular implants. This article is part of a Special Issue entitled Organic Bioelectronics — Novel Applications in Biomedicine.► Nanomedicine strategies link with bioelectronics for enhanced tissue regeneration. ► PEDOT conducting polymers are potential candidate for cardiovascular implants. ► Doping of PEDOT thin films influences the physicochemical properties and cellular response. ► Biofunctionalization of PEDOT films with RGD peptides promotes cell adhesion and proliferation. ► PEDOT-based thin films are cytocompatible and PEDOT:TOS exhibits good biological behavior.
Keywords: Bioelectronics; Conductive polymer; PEDOT; Stent; Nanomedicine; Atomic Force Microscopy;

The interaction of ECM proteins is critical in determining the performance of materials used in biomedical applications such as tissue regeneration, implantable bionics and biosensing.To improve our understanding of ECM protein–conducting polymer interactions, we have used Atomic Force Microscopy (AFM) to elucidate the interactions of fibronectin (FN) on polypyrrole (PPy) doped with different glycosaminoglycans.We were able to classify four main types of FN interactions, including those related to 1) non-specific adhesion, 2) protein unfolding and subsequent unbinding from the surface, 3) desorption and 4) interactions with no adhesion. FN adhesion on PPy/hyaluronic acid showed a significantly lower density of surface adhesion with the adhesion restricted to nodule structures, as opposed to their peripheries, of the polymer morphology. In contrast, PPy/chondroitin sulfate showed a significantly higher density of surface adhesion to the point where the distribution of adhesion effectively masked the topography. Through conductive AFM imaging, we found that the conductive regions correlated with regions of FN adhesion.Given that the conductivity requires doping of the polymer, these findings suggest that FN adhesion is mediated by interactions with chondroitin sulfate and hyaluronic acid at the polymer surface and may be indicative of specific interactions due to contributions from electrostatic attraction between the FN and sulfate/anionic groups of the dopants.This study demonstrates the ability of AFM to resolve the protein–conducting polymer interactions at the molecular and nanoscale level, which will be important for interfacing these polymer materials with biological systems. This article is part of a Special Issue entitled Organic Bioelectronics — Novel Applications in Biomedicine.
Keywords: Conducting polymer; Polypyrrole; Atomic Force Microscopy; Protein adhesion; Fibronectin;

Fibronectin conformation regulates the proangiogenic capability of tumor-associated adipogenic stromal cells by Alwin M.D. Wan; Emily M. Chandler; Maya Madhavan; David W. Infanger; Christopher K. Ober; Delphine Gourdon; George G. Malliaras; Claudia Fischbach (4314-4320).
Changes in fibronectin (Fn) matrix remodeling contribute to mammary tumor angiogenesis and are related to altered behavior of adipogenic stromal cells; yet, the underlying mechanisms remain unclear due in part to a lack of reductionist model systems that allow the inherent complexity of cell-derived extracellular matrices (ECMs) to be deciphered. In particular, breast cancer-associated adipogenic stromal cells not only enhance the composition, quantity, and rigidity of deposited Fn, but also partially unfold these matrices. However, the specific effect of Fn conformation on tumor angiogenesis is undefined.Decellularized matrices and a conducting polymer device consisting of poly(3,4-ethylenedioxythiophene) doped with poly(styrenesulfonate) (PEDOT:PSS) were used to examine the effect of Fn conformation on the behavior of 3T3-L1 preadipocytes. Changes in cell adhesion and proangiogenic capability were tested via cell counting and by quantification of vascular endothelial growth factor (VEGF) secretion, respectively. Integrin-blocking antibodies were utilized to examine varied integrin specificity as a potential mechanism.Our findings suggest that tumor-associated partial unfolding of Fn decreases adhesion while enhancing VEGF secretion by breast cancer-associated adipogenic precursor cells, and that altered integrin specificity may underlie these changes.These results not only have important implications for our understanding of tumorigenesis, but also enhance knowledge of cell-ECM interactions that may be harnessed for other applications including advanced tissue engineering approaches. This article is part of a Special Issue entitled Organic Bioelectronics — Novel Applications in Biomedicine.
Keywords: Fibronectin; Tumor angiogenesis; Integrins; Preadipocytes; Conducting polymers; Bioelectronics;

Organic bioelectronic devices consisting of alternating poly(3,4-ethylenedioxythiophene) (PEDOT) and reduced graphite oxide (rGO) striped microelectrode arrays were fabricated by lithography technology. It has been demonstrated that the organic bioelectronic devices can be used to spatially and temporally manipulate the location and proliferation of the neuron-like pheochromocytoma cells (PC-12 cells).By coating an electrically labile contact repulsion layer of poly(l-lysine-graft-ethylene glycol) (PLL-g-PEG) on the PEDOT electrode, the location and polarity of the PC-12 cells were confined to the rGO electrodes.The outgrowth of spatially confined bipolar neurites was found to align along the direction of the 20 μm wide electrode. The location of the PC-12 cells can also be manipulated temporally by applying electrical stimulation during the neurite differentiation of PC-12 cells, allowing the PC-12 cells to cross over the boundary between the PEDOT and the rGO regions and construct neurite networks in an unconfined manner where the contact repulsive coating of PLL-g-PEG was removed.This adsorption and desorption of the PLL-g-PEG without and with electrical stimulation can be attributed to the tunable surface properties of the PEDOT microelectrodes, whose surface charge can switch from being negative to positive under electrical stimulation.The electrically tunable organic bioelectronics reported here could potentially be applied to tissue engineering related to the development and regeneration of mammalian nervous systems. The spatial and temporal control in this device would also be used to study the synapse junctions of neuron–neuron contacts in both time and space domains. This article is part of a Special Issue entitled Organic Bioelectronics — Novel Applications in Biomedicine.Display Omitted► The PC-12 cells can be spatially and temporally manipulated. ► Alternating PEDOT and rGO striped microelectrode arrays were fabricated. ► The outgrowth of bipolar neurites was found to align along the electrodes. ► The electrical stimulation was used to convert the surface property of PEDOT.
Keywords: Organic bioelectronics; Lithography; Electrical simulation; Contract repulsion coating; Contract attraction coating;

Monitoring neural stem cell differentiation using PEDOT–PSS based MEA by Yuriko Furukawa; Akiyoshi Shimada; Koichi Kato; Hiroo Iwata; Keiichi Torimitsu (4329-4333).
Transplantation is one potential clinical application of neural stem cells (NSCs). However, it is very difficult to monitor/control NSCs after transplantation and so provide effective treatment. Electrical measurement using a poly(3,4-ethylenedioxythiophene)–poly(styrenesulfonate) (PEDOT–PSS) modified microelectrode array (MEA) is a biocompatible, non-invasive, non-destructive approach to understanding cell conditions. This property makes continuous monitoring available for the evaluation/assessment of the development of cells such as NSCs.A PEDOT–PSS modified MEA was used to monitor electrical signals during NSC development in a culture derived from rat embryo striatum in order to understand the NSC differentiation conditions.Electrical data indicated that NSCs with nerve growth factor (NGF) generate a cultured cortical neuron-like burst pattern while a random noise pattern was measured with epidermal growth factor (EGF) at 4 days in vitro (DIV) and a burst pattern was observed in both cases at 11 DIV indicating the successful monitoring of differentiation differences and developmental changes.The electrical analysis of cell activity using a PEDOT–PSS modified MEA could indicate neural network formation by differentiated neurons. Changes in NSC differentiation could be monitored.The method is based on non-invasive continuous measurement and so could prove a useful tool for the primary/preliminary evaluation of a pharmaceutical analysis. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.Display Omitted► A PEDOT–PSS modified MEA was used to monitor NSC differentiation. ► NSCs with NGF generate a cultured cortical neuron-like bursting pattern. ► A random noisy pattern was measured only with EGF-PSt at 4 DIV. ► A bursting pattern was observed in both cases (EGF-PSt and NGF) at 11 DIV. ► The successful monitoring of NSC differentiation difference using MEA.
Keywords: Neural stem cells; MEA (microelectrode array); PEDOT–PSS (poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate));

A major challenge when creating interfaces for the nervous system is to translate between the signal carriers of the nervous system (ions and neurotransmitters) and those of conventional electronics (electrons).Organic conjugated polymers represent a unique class of materials that utilizes both electrons and ions as charge carriers. Based on these materials, we have established a series of novel communication interfaces between electronic components and biological systems. The organic electronic ion pump (OEIP) presented in this review is made of the polymer–polyelectrolyte system poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). The OEIP translates electronic signals into electrophoretic migration of ions and neurotransmitters.We demonstrate how spatio-temporally controlled delivery of ions and neurotransmitters can be used to modulate intracellular Ca2 + signaling in neuronal cells in the absence of convective disturbances. The electronic control of delivery enables strict control of dynamic parameters, such as amplitude and frequency of Ca2 + responses, and can be used to generate temporal patterns mimicking naturally occurring Ca2 + oscillations. To enable further control of the ionic signals we developed the electrophoretic chemical transistor, an analog of the traditional transistor used to amplify and/or switch electronic signals. Finally, we demonstrate the use of the OEIP in a new “machine-to-brain” interface by modulating brainstem responses in vivo.This review highlights the potential of communication interfaces based on conjugated polymers in generating complex, high-resolution, signal patterns to control cell physiology. We foresee widespread applications for these devices in biomedical research and in future medical devices within multiple therapeutic areas. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.► We report on spatio-temporally controlled delivery of ions and neurotransmitters. ► Non-flow delivery is used to modulate intracellular Ca2 + signaling in neuronal cells. ► Electronic delivery enables control of dynamic parameters of Ca2 + responses. ► We report an electrophoretic chemical transistor to amplify and/or switch ionic signals. ► We show a “machine-to-brain” interface modulating brainstem responses in vivo.
Keywords: Organic bioelectronics; Drug delivery; Ca2 + signaling; Spatial-temporal gradient; In vivo;

Organic bioelectrodes in clinical neurosurgery by Hans von Holst (4345-4352).
Clinical neurosurgery deals with surgical procedures and intensive care of illnesses in the human central and peripheral nervous system. Neurosurgery should be looked upon as a high-tech specialty and very much dependent on new technological innovations aiming at improvements of patient's treatment and outcome. During the last decades neurosurgery has improved substantially thanks to the introduction of applied imaging technologies such as computerized tomography and magnetic resonance tomography, and new surgical modalities such as the microscope, brain navigation and neuroanesthesiology.Neurosurgical disorders, which should have the potential to benefit from conductive organic bioelectrodes, include traumatic brain and spinal cord injury and peripheral nerve injuries due to external violence in the restoration of healthy communication. This holds true also for cerebral nerves altered in their functions due to benign and malignant brain and spinal cord tumors. Further, new innovative devices in the field of functional nervous tissue disorders make the use of organic conductive electrodes attractive by considering the electrical neurochemical properties of neural interfaces.Although in its infancy, conducting organic polymers as bioelectrodes have several potential applications in clinical neurosurgery. The time it takes for new innovations and basic research to be transferred into clinical neurosurgery should not take too long. However, a prerequisite for successful implementation is the close interdisciplinary collaboration between engineers and clinicians. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.► Neuromodulation for neurosurgery disorders is a useful treatment. ► Most implants of today consist of metals with some disadvantages. ► Organic bioelectrodes are more efficient compared to metals.
Keywords: Traumatic brain injury; Stroke; Hydrocephalus; Nerve injury; Organic bioelectrodes;

Nowadays, there is a tremendous need for cheap disposable sensing devices for medical applications. Materials such as Carbon Nanotubes (CNTs) and regioregular P3HT are proven to offer a huge potential as cost-effective and solution processable semiconductors for (bio)sensing applications.CNT-based field-effect transistors (CNT-FETs) as well as regioregular P3HT-based ones (P3HT-FETs) are fabricated and operated in the so-called electrolyte-gated configuration. The active layer of the P3HT-FETs consists of a spin-coated regioregular P3HT layer, which serves on one hand as the active sensing element and on the other hand as passivation layer for the transistor's metal contacts. The active layer of the nanotube transistors consists of a randomly distributed single walled CNT-network (> 90% semiconducting tubes) deposited from a CNT-ink solution by spin-coating.We compare both devices concerning their stability in aqueous environment and their response when exposed to buffers with different pH. We found that even if P3HT shows lower stability its pH sensitivity is reproducible even after long-term measurements.CNT-FETs and P3HT-FETs offer different advantages and drawbacks concerning their stability in solution and the ease of fabrication. A discussion of their different sensing mechanisms as well as sensitivity is given here.This work reports on fast and cost-effective production of solution processable thin-film transistors based on carbon nanotubes and regioregular P3HT and demonstrates their suitability as reliable pH sensors. This article is part of a Special Issue entitled Organic Bioelectronics — Novel Applications in Biomedicine.► The performance of P3HT-FETs and CNT-FETs as pH sensors operated in an electrolyte gate mode was compared. ► The sensing mechanism was discussed for both devices. ► The stability in long-term measurements was discussed for both devices.
Keywords: Organic semiconductors; Carbon nanotubes; Field-effect transistors; Biosensors; Disposable devices;

Field effect transistor (FET) based signal-transduction (Bio-FET) is an emerging technique for label-free and real-time basis biosensors for a wide range of targets. Glucose has constantly been of interest due to its clinical relevance. Use of glucose oxidase (GOD) and a lectin protein Concanavalin A are two common strategies to generate glucose-dependent electrochemical events. However, these protein-based materials are intolerant of long-term usage and storage due to their inevitable denaturing.A phenylboronic acid (PBA) modified self-assembled monolayer (SAM) on a gold electrode with an optimized disassociation constant of PBA, that is, 3-fluoro-4-carbamoyl-PBA possessing its pKa of 7.1, was prepared and utilized as an extended gate electrode for Bio-FET.The prepared electrode showed a glucose-dependent change in the surface potential under physiological conditions, thus providing a remarkably simple rationale for the glyco-sensitive Bio-FET. Importantly, the PBA modified electrode showed tolerance to relatively severe heat and drying treatments; conditions under which protein based materials would surely be denatured.A PBA modified SAM with optimized disassociation constant (pKa) can exhibit a glucose-dependent change in the surface potential under physiological conditions, providing a remarkably simple but robust method for the glyco-sensing.This protein-free, totally synthetic glyco-sensing strategy may offer cheap, robust and easily accessible platform that may be useful in developing countries. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.
Keywords: Field effect transistors; Glucose; Phenylboronic acids; Heat tolerance;

Addressing the use of PDIF-CN2 molecules in the development of n-type organic field-effect transistors for biosensing applications by M. Barra; D. Viggiano; P. Ambrosino; F. Bloisi; F.V. Di Girolamo; M.V. Soldovieri; M. Taglialatela; A. Cassinese (4365-4373).
There is no doubt that future discoveries in the field of biochemistry will depend on the implementation of novel biosensing techniques, able to record biophysiological events with minimal biological interference. In this respect, organic electronics may represent an important new tool for the analysis of structures ranging from single molecules up to cellular events. Specifically, organic field-effect transistors (OFET) are potentially powerful devices for the real-time detection/transduction of bio-signals. Despite this interest, up to date, the experimental data useful to support the development of OFET-based biosensors are still few and, in particular, n-type (electron-transporting) devices, being fundamental to develop highly-performing circuits, have been scarcely investigated.Here, films of N,N′-1H,1H-perfluorobutyldicyanoperylene-carboxydi-imide (PDIF-CN2) molecules, a recently-introduced and very promising n-type semiconductor, have been evaporated on glass and silicon dioxide substrates to test the biocompatibility of this compound and its capability to stay electrically-active even in liquid environments.We found that PDIF-CN2 transistors can work steadily in water for several hours. Biocompatibility tests, based on in-vitro cell cultivation, remark the need to functionalize the PDIF-CN2 hydrophobic surface by extra-coating layers (i.e. poly-l-lysine) to favor the growth of confluent cellular populations.Our experimental data demonstrate that PDIF-CN2 compound is an interesting organic semiconductor to develop electronic devices to be used in the biological field.This work contributes to define a possible strategy for the fabrication of low-cost and flexible biosensors, based on complex organic complementary metal-oxide-semiconductor (CMOS) circuitry including both p- (hole-transporting) and n-type transistors. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.► Low-voltage n-type organic PDIF-CN2 transistors have been fabricated. ► Their electrical operation stability was investigated in liquid environments. ► Cell adhesion properties of PDIF-CN2 films are analyzed by using CHO cells. ► PDIF-CN2 films have been bio-functionalized by poly-l-lysine.
Keywords: Organic semiconductors; Field-effect transistors; Biosensors; Biocompatibility; Operational stability; Cellular adhesion;

Liposome sensing and monitoring by organic electrochemical transistors integrated in microfluidics by Giuseppe Tarabella; Anna Giulia Balducci; Nicola Coppedè; Simone Marasso; Pasquale D'Angelo; Stefano Barbieri; Matteo Cocuzza; Paolo Colombo; Fabio Sonvico; Roberto Mosca; Salvatore Iannotta (4374-4380).
Organic electrochemical transistors (OECTs), which are becoming more and more promising devices for applications in bioelectronics and nanomedicine, are proposed here as ideally suitable for sensing and real time monitoring of liposome-based structures. This is quite relevant since, currently, the techniques used to investigate liposomal structures, their stability in different environments as well as drug loading and delivery mechanisms, operate basically off-line and/or with pre-prepared sampling.OECTs, based on the PEDOT:PSS conductive polymer, have been employed as sensors of liposome-based nanoparticles in electrolyte solutions to assess sensitivity and monitoring capabilities based on ion-to-electron amplified transduction.We demonstrate that OECTs are very efficient, reliable and sensitive devices for detecting liposome-based nanoparticles on a wide dynamic range down to 10− 5  mg/ml (with a lowest detection limit, assessed in real-time monitoring, of 10− 7  mg/ml), thus matching the needs of typical drug loading/drug delivery conditions. They are hence particularly well suited for real-time monitoring of liposomes in solution. Furthermore, OECTs are shown to sense and discriminate successive injection of different liposomes, so that they could be good candidates in quality-control assays or in the pharmaceutical industry.Drug loading and delivery by liposome-based structures is a fast growing and very promising field that will strongly benefit from real-time, highly sensitive and low cost monitoring of their dynamics in different pharma and biomedical environments, with a particular reference to the pharmaceutical and production processes, where a major issue is monitoring and measuring the formation and concentration of liposomes and the relative drug load. The demonstrated ability to sense and monitor complex bio-structures, such as liposomes, paves the way for very promising developments in biosensing and nanomedicine. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.► Real-time sensing/monitoring liposomes by organic electrochemical transistor ► Very high sensitivity achieved for liposome-based nanoparticles sensing ► Demonstration of OECT being suitable for quality control assays ► Our studies pave the way for studying dynamics of drug-loading/delivery.
Keywords: Biosensing; Drug delivery; Liposome; Nanoparticle; Organic electrochemical transistor; Microfluidics;

Validation of the organic electrochemical transistor for in vitro toxicology by Scherrine A. Tria; Leslie H. Jimison; Adel Hama; Manuelle Bongo; Róisín M. Owens (4381-4390).
The gastrointestinal epithelium provides a physical and biochemical barrier to the passage of ions and small molecules; however this barrier may be breached by pathogens and toxins. The effect of individual pathogens/toxins on the intestinal epithelium has been well characterized: they disrupt barrier tissue in a variety of ways, such as by targeting tight junction proteins, or other elements of the junctions between adjacent cells. A variety of methods have been used to characterize disruption in barrier tissue, such as immunofluorescence, permeability assays and electrical measurements of epithelia resistance, but these methods remain time consuming, costly and ill-suited to diagnostics or high throughput toxicology.The advent of organic electronics has created a unique opportunity to interface the worlds of electronics and biology, using devices such as the organic electrochemical transistor (OECT), whose low cost materials and potential for easy fabrication in high throughput formats represent a novel solution for assessing epithelial tissue integrity.In this study, OECTs were integrated with gastro-intestinal cell monolayers to study the integrity of the gastrointestinal epithelium, providing a very sensitive way to detect minute changes in ion flow across the cell layer due to inherent amplification by the transistor.We validate the OECT against traditional methods by monitoring the effect of toxic compounds on epithelial tissue. We show a systematic characterization of this novel method, alongside existing methods used to assess barrier tissue function.The toxic compounds induce a dramatic disruption of barrier tissue, and the OECT measures this disruption with increased temporal resolution and greater or equal sensitivity when compared with existing methods. This article is part of a Special Issue entitled Organic Bioelectronics — Novel Applications in Biomedicine.► We have developed an organic electrochemical transistor to assess barrier tissue integrity ► We validate the OECT against current techniques used for assessing barrier tissue integrity. ► Toxic compounds were rapidly sensed using the OECT with better sensitivity and faster detection time than existing methods.
Keywords: Organic bioelectronics; Toxicology; Barrier tissue; Tight junctions; Paracellular transport;

Versatile characterization of thiol-functionalized printed metal electrodes on flexible substrates for cheap diagnostic applications by Petri Ihalainen; Himadri Majumdar; Anni Määttänen; Shaoxia Wang; Ronald Österbacka; Jouko Peltonen (4391-4397).
Cheap, reliable, point-of-care diagnostics is a necessity for the growing and aging population of the world. Paper substrate and printing method, combined together, are the cheapest possible method for generating high-volume diagnostic sensor platforms. Electrical transduction tools also minimize the cost and enhance the simplicity of the devices.Standard surface characterization techniques, namely contact angle measurements, atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) were used to analyze the growth of the organic thiol layers on top of the printed metal electrodes on paper substrates. The results were compared with those obtained by impedimetric electrical characterization method.This article reports the fabrication and characterization of printed metal electrodes and their functionalization by organic layers on paper and plastic substrates for biosensing and diagnostic applications. Impedimetric measurement is proposed as a simple, yet elegant, method of characterization of the organic layer growth.Very good correlation was observed between the results of organic layer growth from different measurement methods, justifying the use of paper as a substrate, printing as a method for fabricating metal and organic layers and impedance as a suitable measurement method for hand-held diagnostic devices.This result paves the way for the fabrication of more advanced bio-recognition layers for bio-affinity sensors using a printing technology that is compatible with flexible and cheap paper substrates. This article is part of a Special Issue entitled Organic Bioelectronics — Novel Applications in Biomedicine.► Suitability and use of paper as substrate for building biosensors ► Inkjet printing of metal electrodes on paper for manufacturing of cheap biosensors ► Various methods to compare growth of thiol layers on paper and plastic substrates ► Use of impedimetric (capacitance) method for electrical transduction
Keywords: Printed electronics; Flexible substrate; Nanoparticles; Inkjet printing; Self-assembled monolayer;

In biosensors with a fluid analyte, the integration of a microfluidic system, which guides the analyte into the sensing area, is critical. Quicker and economical ways to build up microfluidic systems will make point of care diagnostics viable. Printing is a low-cost technology that is increasingly used in emerging organic and flexible electronics and biosensors. In this paper, we present printed fluidic systems on flexible substrates made with pressure sensitive adhesive materials.Printable pressure sensitive adhesive materials have been used for making microfluidic systems. Flexible substrates have been used, and two types of adhesive materials, one thermally dried and another UV curable, have been tested. Top sealing layer was laminated directly on top of the printed microfluidic structure. Flow tests were done with deionized water.Flow tests with deionized water show that both adhesive materials are suitable for capillary flow driven fluidic devices. Flow test using water as dielectric material was also done successfully on a printed electrolyte gated organic field effect transistor with an integrated microfluidic system.Due to its ease of process and low cost, printed microfluidic system is believed to find more applications in biosensing devices. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.► Pressure sensitive adhesive materials were screen printed to make fluidic systems. ► Flow tests on printed microfluidic systems were successfully conducted. ► Our printed microfluidic system is easy to scale up and cost-effective.
Keywords: Pressure sensitive adhesive; Microfluidic; Printable; Electrolyte gated organic field effect transistor;

Fabrication of organic electrochemical transistor arrays for biosensing by Meng Zhang; Peng Lin; Mo Yang; Feng Yan (4402-4406).
Organic electrochemical transistors (OECT) have been used as various types of biosensors with very high sensitivity. The OECTs show advantages of easy fabrication, low operational voltage, excellent flexibility and biocompatibility.OECT arrays based on poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) were fabricated in poly(ethylene glycol) (PEG) microwells by physical delamination.The OECTs show fast response time, stable channel current and excellent transistor characteristics. The PEG microwells can be used to trap cells on top of the OECTs, which will be important for the application of the OECT arrays as cell-based biosensors.This technique provides a feasible way for high-throughput cell analysis based on transistor arrays. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.► Organic transistor microarrays were fabricated by physical delamination. ► The devices show fast response time and stable performance in electrolytes. ► Cancer cells can be trapped on the transistor arrays for cell analysis.
Keywords: Organic thin film transistor; Microarray; Cell-based biosensor;