Ion-tunable antiambipolarity in mixed ion-electron conducting polymers enables biorealistic organic electrochemical neurons.

Biointegrated neuromorphic hardware holds promise for new protocols to record/regulate signalling in biological systems. Making such artificial neural circuits successful requires minimal device/circuit complexity and ion-based operating mechanisms akin to those found in biology. Artificial spiking neurons, based on silicon-based complementary metal-oxide semiconductors or negative differential resistance device circuits, can emulate several neural features but are complicated to fabricate, not biocompatible and lack ion-/chemical-based modulation features. Here we report a biorealistic conductance-based organic electrochemical neuron (c-OECN) using a mixed ion-electron conducting ladder-type polymer with stable ion-tunable antiambipolarity. The latter is used to emulate the activation/inactivation of sodium channels and delayed activation of potassium channels of biological neurons. These c-OECNs can spike at bioplausible frequencies nearing 100 Hz, emulate most critical biological neural features, demonstrate stochastic spiking and enable neurotransmitter-/amino acid-/ion-based spiking modulation, which is then used to stimulate biological nerves in vivo. These combined features are impossible to achieve using previous technologies.

Study on the Rectification of Ionic Diode Based on Cross-Linked Nanocellulose Bipolar Membranes.

Nanocellulose-based membranes have attracted intense attention in bioelectronic devices due to their low cost, flexibility, biocompatibility, degradability, and sustainability. Herein, we demonstrate a flexible ionic diode using a cross-linked bipolar membrane fabricated from positively and negatively charged cellulose nanofibrils (CNFs). The rectified current originates from the asymmetric charge distribution, which can selectively determine the direction of ion transport inside the bipolar membrane. The mechanism of rectification was demonstrated by electrochemical impedance spectroscopy with voltage biases. The rectifying behavior of this kind of ionic diode was studied by using linear sweep voltammetry to obtain current-voltage characteristics and the time dependence of the current. In addition, the performance of cross-linked CNF diodes was investigated while changing parameters such as the thickness of the bipolar membranes, the scanning voltage range, and the scanning rate. A good long-term stability due to the high density cross-linking of the diode was shown in both current-voltage characteristics and the time dependence of current.

Enzymatically Polymerized Organic Conductors on Model Lipid Membranes.

Seamless integration between biological systems and electrical components is essential for enabling a twinned biochemical-electrical recording and therapy approach to understand and combat neurological disorders. Employing bioelectronic systems made up of conjugated polymers, which have an innate ability to transport both electronic and ionic charges, provides the possibility of such integration. In particular, translating enzymatically polymerized conductive wires, recently demonstrated in plants and simple organism systems, into mammalian models, is of particular interest for the development of next-generation devices that can monitor and modulate neural signals. As a first step toward achieving this goal, enzyme-mediated polymerization of two thiophene-based monomers is demonstrated on a synthetic lipid bilayer supported on a Au surface. Microgravimetric studies of conducting films polymerized in situ provide insights into their interactions with a lipid bilayer model that mimics the cell membrane. Moreover, the resulting electrical and viscoelastic properties of these self-organizing conducting polymers suggest their potential as materials to form the basis for novel approaches to in vivo neural therapeutics.

Exploiting mixed conducting polymers in organic and bioelectronic devices.

Efficient transport of both ionic and electronic charges in conjugated polymers (CPs) has enabled a wide range of novel electrochemical devices spanning applications from energy storage to bioelectronic devices. In this Perspective, we provide an overview of the fundamental physical processes which underlie the operation of mixed conducting polymer (MCP) devices. While charge injection and transport have been studied extensively in both ionic and electronic conductors, translating these principles to mixed conducting systems proves challenging due to the complex relationships among the individual materials properties. We break down the process of electrochemical (de)doping, the basic feature exploited in mixed conducting devices, into its key steps, highlighting recent advances in the study of these physical processes in the context of MCPs. Furthermore, we identify remaining challenges in further extending fundamental understanding of MCP-based device operation. Ultimately, a deeper understanding of the elementary processes governing operation in MCPs will drive the advancement in both materials design and device performance.

Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site.

Local control of neuronal activity is central to many therapeutic strategies aiming to treat neurological disorders. Arguably, the best solution would make use of endogenous highly localized and specialized regulatory mechanisms of neuronal activity, and an ideal therapeutic technology should sense activity and deliver endogenous molecules at the same site for the most efficient feedback regulation. Here, we address this challenge with an organic electronic multifunctional device that is capable of chemical stimulation and electrical sensing at the same site, at the single-cell scale. Conducting polymer electrodes recorded epileptiform discharges induced in mouse hippocampal preparation. The inhibitory neurotransmitter, γ-aminobutyric acid (GABA), was then actively delivered through the recording electrodes via organic electronic ion pump technology. GABA delivery stopped epileptiform activity, recorded simultaneously and colocally. This multifunctional "neural pixel" creates a range of opportunities, including implantable therapeutic devices with automated feedback, where locally recorded signals regulate local release of specific therapeutic agents.

Electronic control over detachment of a self-doped water-soluble conjugated polyelectrolyte.

Water-soluble conducting polymers are of interest to enable more versatile processing in aqueous media as well as to facilitate interactions with biomolecules. Here, we report a substituted poly(3,4-ethylenedioxythiophene) derivative (PEDOT-S:H) that is fully water-soluble and self-doped. When electrochemically oxidizing a PEDOT-S:H thin film, the film detaches from the underlying electrode. The oxidation of PEDOT-S:H starts with an initial phase of swelling followed by cracking before it finally disrupts into small flakes and detaches from the electrode. We investigated the detachment mechanism and found that parameters such as the size, charge, and concentration of ions in the electrolyte, the temperature, and also the pH influence the characteristics of detachment. When oxidizing PEDOT-S:H, the positively charged polymer backbone is balanced by anions from the electrolyte solution and also by the sulfonate groups on the side chains (more self-doping). From our experiments, we conclude that detachment of the PEDOT-S:H film upon oxidation occurs in part due to swelling caused by an inflow of solvated anions and associated water and in part due to chain rearrangements within the film, caused by more self-doping. We believe that PEDOT-S:H detachment can be of interest in a number of different applications, including addressed and active control of the release of materials such as biomolecules and cell cultures.

Drug delivery via a 3D electro-swellable conjugated polymer hydrogel.

Spatiotemporal controlled drug delivery minimizes side-effects and enables therapies that require specific dosing patterns. Conjugated polymers (CP) can be used for electrically controlled drug delivery; however so far, most demonstrations were limited to molecules up to 500 Da. Larger molecules could be incorporated only during the CP polymerization and thus limited to a single delivery. This work harnesses the record volume changes of a glycolated polythiophene p(g3T2) for controlled drug delivery. p(g3T2) undergoes reversible volumetric changes of up to 300% during electrochemical doping, forming pores in the nm-size range, resulting in a conducting hydrogel. p(g3T2)-coated 3D carbon sponges enable controlled loading and release of molecules spanning molecular weights of 800-6000 Da, from simple dyes up to the hormone insulin. Molecules are loaded as a combination of electrostatic interactions with the charged polymer backbone and physical entrapment in the porous matrix. Smaller molecules leak out of the polymer while larger ones could not be loaded effectively. Finally, this work shows the temporally patterned release of molecules with molecular weight of 1300 Da and multiple reloading and release cycles without affecting the on/off ratio.

Ion bipolar junction transistors.

Dynamic control of chemical microenvironments is essential for continued development in numerous fields of life sciences. Such control could be achieved with active chemical circuits for delivery of ions and biomolecules. As the basis for such circuitry, we report a solid-state ion bipolar junction transistor (IBJT) based on conducting polymers and thin films of anion- and cation-selective membranes. The IBJT is the ionic analogue to the conventional semiconductor BJT and is manufactured using standard microfabrication techniques. Transistor characteristics along with a model describing the principle of operation, in which an anionic base current amplifies a cationic collector current, are presented. By employing the IBJT as a bioelectronic circuit element for delivery of the neurotransmitter acetylcholine, its efficacy in modulating neuronal cell signaling is demonstrated.

Metabolite-induced in vivo fabrication of substrate-free organic bioelectronics.

Interfacing electronics with neural tissue is crucial for understanding complex biological functions, but conventional bioelectronics consist of rigid electrodes fundamentally incompatible with living systems. The difference between static solid-state electronics and dynamic biological matter makes seamless integration of the two challenging. To address this incompatibility, we developed a method to dynamically create soft substrate-free conducting materials within the biological environment. We demonstrate in vivo electrode formation in zebrafish and leech models, using endogenous metabolites to trigger enzymatic polymerization of organic precursors within an injectable gel, thereby forming conducting polymer gels with long-range conductivity. This approach can be used to target specific biological substructures and is suitable for nerve stimulation, paving the way for fully integrated, in vivo-fabricated electronics within the nervous system.

Organic bioelectronics in nanomedicine.

BACKGROUND: Nanomedicine is a research area with potential to shape, direct, and change future medical treatments in a revolutionary manner over the next decades. While the common goal with other fields of biomedicine is to solve medical problems, this area embraces an increasing number of technology platforms as they become miniaturized. Organic electronics has over the past two decades developed into an exciting and thriving area of research. SCOPE OF REVIEW: Today, the organic electronics field stands at the interface with biology. As the area of organic bioelectronics advances, it holds promise to make major contributions to nanomedicine. The progress made in this direction is the topic of this review. MAJOR CONCLUSIONS: We describe the inherent features of conducting polymers, and explain the usefulness of these materials as active scaffolds in cell biology and tissue engineering. We also explain how the combined ionic and electronic conductive nature of the polymers is used to precisely control the delivery of signal substances. This unique feature is key in novel devices for chemical communication with cells and tissues. GENERAL SIGNIFICANCE: This review highlights the results from the creative melting pot of interdisciplinary research in organic bioelectronics. This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine.

Advances in organic transistor-based biosensors: from organic electrochemical transistors to electrolyte-gated organic field-effect transistors.

Organic electronics have, over the past two decades, developed into an exciting area of research and technology to replace classic inorganic semiconductors. Organic photovoltaics, light-emitting diodes, and thin-film transistors are already well developed and are currently being commercialized for a variety of applications. More recently, organic transistors have found new applications in the field of biosensors. The progress made in this direction is the topic of this review. Various configurations are presented, with their detection principle, and illustrated by examples from the literature.

The effect of crosslinking on ion transport in nanocellulose-based membranes.

Ion selective membranes are at the heart of energy conversion and harvesting, water treatment, and biotechnologies. The currently available membranes are mostly based on expensive and non-biodegradable polymers. Here, we report a cation-selective and low-cost membrane prepared from renewable nanocellulose and 1,2,3,4-butanetetracarboxylic acid which simultaneously serves as crosslinker and source of anionic surface groups. Charge density and structure of the membranes are studied. By using different degrees of crosslinking, simultaneous control over both the nanochannel structure and surface charge concentration is achieved, which in turn determines the resulting ion transport properties. Increasing negative charge concentration via higher crosslinker content, the obtained ion conductivity reaches up to 8 mS/cm (0.1 M KCl). Optimal ion selectivity, also influenced by the solution pH, is achieved at 20 wt% crosslinker addition (with ion conductivity of 1.6 mS/cm). As regular ~1.4 nm nanochannels were formed at this composition, nanofluidic contribution to ion transport is likely.

Electrochemical control of growth factor presentation to steer neural stem cell differentiation.

Let it grow: The conjugated polymer poly(3,4-ethylenedioxythiophene) (PEDOT) was synthesized with heparin as the counterion to form a cell culture substrate. The surface of PEDOT:heparin in the neutral state associated biologically active growth factors. Electrochemical in situ oxidation of PEDOT during live cell culture decreased the bioavailability of the growth factor and created an exact onset of neural stem cell differentiation.

Spatially controlled amyloid reactions using organic electronics.

Abnormal protein aggregates, so called amyloid fibrils, are mainly known as pathological hallmarks of a wide range of diseases, but in addition these robust well-ordered self-assembled natural nanostructures can also be utilized for creating distinct nanomaterials for bioelectronic devices. However, current methods for producing amyloid fibrils in vitro offer no spatial control. Herein, we demonstrate a new way to produce and spatially control the assembly of amyloid-like structures using an organic electronic ion pump (OEIP) to pump distinct cations to a reservoir containing a negatively charged polypeptide. The morphology and kinetics of the created proteinaceous nanomaterials depends on the ion and current used, which we leveraged to create layers incorporating different conjugated thiophene derivatives, one fluorescent (p-FTAA) and one conducting (PEDOT-S). We anticipate that this new application for the OEIP will be useful for both biological studies of amyloid assembly and fibrillogenesis as well as for creating new bioelectronic nanomaterials and devices.

Capillary-Fiber Based Electrophoretic Delivery Device.

Organic electronic ion pumps (OEIPs) are versatile tools for electrophoretic delivery of substances with high spatiotemporal resolution. To date, OEIPs and similar iontronic components have been fabricated using thin-film techniques and often rely on laborious, multistep photolithographic processes. OEIPs have been demonstrated in a variety of in vitro and in vivo settings for controlling biological systems, but the thin-film form factor and limited repertoire of polyelectrolyte materials and device fabrication techniques unnecessarily constrain the possibilities for miniaturization and extremely localized substance delivery, e.g., the greater range of pharmaceutical compounds, on the scale of a single cell. Here, we demonstrate an entirely new OEIP form factor based on capillary fibers that include hyperbranched polyglycerols (dPGs) as the selective electrophoretic membrane. The dPGs enable electrophoretic channels with a high concentration of fixed charges and well-controlled cross-linking and can be realized using a simple "one-pot" fluidic manufacturing protocol. Selective electrophoretic transport of cations and anions of various sizes is demonstrated, including "large" substances that are difficult to transport with other OEIP technologies. We present a method for tailoring and characterizing the electrophoretic channels' fixed charge concentration in the operational state. Subsequently, we compare the experimental performance of these capillary OEIPs to a computational model and explain unexpected features in the ionic current for the transport and delivery of larger, lower-mobility ionic compounds. From this model, we are able to elucidate several operational and design principles relevant to miniaturized electrophoretic drug delivery technologies in general. Overall, the compactness of the capillary OEIP enables electrophoretic delivery devices with probelike geometries, suitable for a variety of ionic compounds, paving the way for less-invasive implantation into biological systems and for healthcare applications.

PEDOT:PSS-based Multilayer Bacterial-Composite Films for Bioelectronics.

Microbial electrochemical systems provide an environmentally-friendly means of energy conversion between chemical and electrical forms, with applications in wastewater treatment, bioelectronics, and biosensing. However, a major challenge to further development, miniaturization, and deployment of bioelectronics and biosensors is the limited thickness of biofilms, necessitating large anodes to achieve sufficient signal-to-noise ratios. Here we demonstrate a method for embedding an electroactive bacterium, Shewanella oneidensis MR-1, inside a conductive three-dimensional poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) matrix electropolymerized on a carbon felt substrate, which we call a multilayer conductive bacterial-composite film (MCBF). By mixing the bacteria with the PEDOT:PSS precursor in a flow-through method, we maintain over 90% viability of S. oneidensis during encapsulation. Microscopic analysis of the MCBFs reveal a tightly interleaved structure of bacteria and conductive PEDOT:PSS up to 80 µm thick. Electrochemical experiments indicate S. oneidensis in MCBFs can perform both direct and riboflavin-mediated electron transfer to PEDOT:PSS. When used in bioelectrochemical reactors, the MCBFs produce 20 times more steady-state current than native biofilms grown on unmodified carbon felt. This versatile approach to control the thickness of bacterial composite films and increase their current output has immediate applications in microbial electrochemical systems, including field-deployable environmental sensing and direct integration of microorganisms into miniaturized organic electronics.

Flexible Lamination-Fabricated Ultra-High Frequency Diodes Based on Self-Supporting Semiconducting Composite Film of Silicon Micro-Particles and Nano-Fibrillated Cellulose.

Low cost and flexible devices such as wearable electronics, e-labels and distributed sensors will make the future "internet of things" viable. To power and communicate with such systems, high frequency rectifiers are crucial components. We present a simple method to manufacture flexible diodes, operating at GHz frequencies, based on self-adhesive composite films of silicon micro-particles (Si-µPs) and glycerol dispersed in nanofibrillated cellulose (NFC). NFC, Si-µPs and glycerol are mixed in a water suspension, forming a self-supporting nanocellulose-silicon composite film after drying. This film is cut and laminated between a flexible pre-patterned Al bottom electrode and a conductive Ni-coated carbon tape top contact. A Schottky junction is established between the Al electrode and the Si-µPs. The resulting flexible diodes show current levels on the order of mA for an area of 2 mm(2), a current rectification ratio up to 4 × 10(3) between 1 and 2 V bias and a cut-off frequency of 1.8 GHz. Energy harvesting experiments have been demonstrated using resistors as the load at 900 MHz and 1.8 GHz. The diode stack can be delaminated away from the Al electrode and then later on be transferred and reconfigured to another substrate. This provides us with reconfigurable GHz-operating diode circuits.

Development and Characterization of Organic Electronic Scaffolds for Bone Tissue Engineering.

Bones have been shown to exhibit piezoelectric properties, generating electrical potential upon mechanical deformation and responding to electrical stimulation with the generation of mechanical stress. Thus, the effects of electrical stimulation on bone tissue engineering have been extensively studied. However, in bone regeneration applications, only few studies have focused on the use of electroactive 3D biodegradable scaffolds at the interphase with stem cells. Here a method is described to combine the bone regeneration capabilities of 3D-printed macroporous medical grade polycaprolactone (PCL) scaffolds with the electrical and electrochemical capabilities of the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT). PCL scaffolds have been highly effective in vivo as bone regeneration grafts, and PEDOT is a leading material in the field of organic bioelectronics, due to its stability, conformability, and biocompatibility. A protocol is reported for scaffolds functionalization with PEDOT, using vapor-phase polymerization, resulting in a conformal conducting layer. Scaffolds' porosity and mechanical stability, important for in vivo bone regeneration applications, are retained. Human fetal mesenchymal stem cells proliferation is assessed on the functionalized scaffolds, showing the cytocompatibility of the polymeric coating. Altogether, these results show the feasibility of the proposed approach to obtain electroactive scaffolds for electrical stimulation of stem cells for regenerative medicine.

Electronic control of platelet adhesion using conducting polymer microarrays.

We hereby report a method to fabricate addressable micropatterns of e-surfaces based on the conducting polymer poly(3,4-ethylenedioxythiophene) doped with the anion tosylate (PEDOT:Tos) to gain dynamic control over the spatial distribution of platelets in vitro. With thin film processing and microfabrication techniques, patterns down to 10 µm were produced to enable active regulation of platelet adhesion at high spatial resolution. Upon electronic addressing, both reduced and oxidized surfaces were created within the same device. This surface modulation dictates the conformation and/or orientation, rather than the concentration, of surface proteins, thus indirectly regulating the adhesion of platelets. The reduced electrode supported platelet adhesion, whereas the oxidized counterpart inhibited adhesion. PEDOT:Tos electrode fabrication is compatible with most of the classical patterning techniques used in printing as well as in the electronics industry. The first types of tools promise ultra-low-cost production of low-resolution (>30 µm) electrode patterns that may combine with traditional substrates and dishes used in a classical analysis setup. Platelets play a pronounced role in cardiovascular diseases and have become an important drug target in order to prevent thrombosis. This clinical path has in turn generated a need for platelet function tests to monitor and assess platelet drug efficacy. The spatial control of platelet adherence presented here could prove valuable for blood cell separation or biosensor microarrays, e.g. in diagnostic applications where platelet function is evaluated.

Detection of glutamate and acetylcholine with organic electrochemical transistors based on conducting polymer/platinum nanoparticle composites.

The aim of the study is to open a new scope for organic electrochemical transistors based on PEDOT:PSS, a material blend known for its stability and reliability. These devices can leverage molecular electrocatalysis by incorporating small amounts of nano-catalyst during the transistor manufacturing (spin coating). This methodology is very simple to implement using the know-how of nanochemistry and results in efficient enzymatic activity transduction, in this case utilizing choline oxidase and glutamate oxidase.