Electrochemically actuated microelectrodes for minimally invasive peripheral nerve interfaces.

Electrode arrays that interface with peripheral nerves are used in the diagnosis and treatment of neurological disorders; however, they require complex placement surgeries that carry a high risk of nerve injury. Here we leverage recent advances in soft robotic actuators and flexible electronics to develop highly conformable nerve cuffs that combine electrochemically driven conducting-polymer-based soft actuators with low-impedance microelectrodes. Driven with applied voltages as small as a few hundreds of millivolts, these cuffs allow active grasping or wrapping around delicate nerves. We validate this technology using in vivo rat models, showing that the cuffs form and maintain a self-closing and reliable bioelectronic interface with the sciatic nerve of rats without the use of surgical sutures or glues. This seamless integration of soft electrochemical actuators with neurotechnology offers a path towards minimally invasive intraoperative monitoring of nerve activity and high-quality bioelectronic interfaces.

Prevention of the foreign body response to implantable medical devices by inflammasome inhibition.

SignificanceImplantable electronic medical devices (IEMDs) are used for some clinical applications, representing an exciting prospect for the transformative treatment of intractable conditions such Parkinson's disease, deafness, and paralysis. The use of IEMDs is limited at the moment because, over time, a foreign body reaction (FBR) develops at the device-neural interface such that ultimately the IEMD fails and needs to be removed. Here, we show that macrophage nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity drives the FBR in a nerve injury model yet integration of an NLRP3 inhibitor into the device prevents FBR while allowing full healing of damaged neural tissue to occur.

Hole-limited electrochemical doping in conjugated polymers.

Simultaneous transport and coupling of ionic and electronic charges is fundamental to electrochemical devices used in energy storage and conversion, neuromorphic computing and bioelectronics. While the mixed conductors enabling these technologies are widely used, the dynamic relationship between ionic and electronic transport is generally poorly understood, hindering the rational design of new materials. In semiconducting electrodes, electrochemical doping is assumed to be limited by motion of ions due to their large mass compared to electrons and/or holes. Here, we show that this basic assumption does not hold for conjugated polymer electrodes. Using operando optical microscopy, we reveal that electrochemical doping speeds in a state-of-the-art polythiophene can be limited by poor hole transport at low doping levels, leading to substantially slower switching speeds than expected. We show that the timescale of hole-limited doping can be controlled by the degree of microstructural heterogeneity, enabling the design of conjugated polymers with improved electrochemical performance.

Operando NMR electrochemical gating studies of ion dynamics in PEDOT:PSS.

Although organic mixed ionic-electronic conductors are widely proposed for use in bioelectronics, energy generation/storage and neuromorphic computing, our fundamental understanding of the charge-compensating interactions between the ionic and electronic carriers and the dynamics of ions remains poor, particularly for hydrated devices and on electrochemical cycling. Here we show that operando 23Na and 1H nuclear magnetic resonance (NMR) spectroscopy can quantify cation and water movement during the doping/dedoping of films comprising the widely used mixed conductor poly(3,4-ethylene dioxythiophene) poly(styrene sulfonate) (PEDOT:PSS). A distinct 23Na quadrupolar splitting is observed due to the partial ordering of the PSS chains within the PEDOT:PSS-rich domains, with respect to the substrate. Operando 23Na NMR studies reveal a close-to-linear correlation between the quadrupolar splitting and the charge stored, which is quantitatively explained by a model in which the holes on the PEDOT backbone are bound to the PSS SO3- groups; an increase in hole concentration during doping inversely correlates with the number of Na+ ions bound to the PSS chains within the PEDOT-rich ordered domains, leading to a decrease in ions within the ordered regions and a decrease in quadrupolar splitting. The Na+-to-electron coupling efficiency, measured via 23Na NMR intensity changes, is close to 100% when using a 1 M NaCl electrolyte. Operando 1H NMR spectroscopy confirms that the Na+ ions injected into/extracted from the wet films are hydrated. These findings shed light on the working principles of organic mixed conductors and demonstrate the utility of operando NMR spectroscopy in revealing structure-property relationships in electroactive polymers.

Semiconducting Polymers for Neural Applications.

Electronically interfacing with the nervous system for the purposes of health diagnostics and therapy, sports performance monitoring, or device control has been a subject of intense academic and industrial research for decades. This trend has only increased in recent years, with numerous high-profile research initiatives and commercial endeavors. An important research theme has emerged as a result, which is the incorporation of semiconducting polymers in various devices that communicate with the nervous system─from wearable brain-monitoring caps to penetrating implantable microelectrodes. This has been driven by the potential of this broad class of materials to improve the electrical and mechanical properties of the tissue-device interface, along with possibilities for increased biocompatibility. In this review we first begin with a tutorial on neural interfacing, by reviewing the basics of nervous system function, device physics, and neuroelectrophysiological techniques and their demands, and finally we give a brief perspective on how material improvements can address current deficiencies in this system. The second part is a detailed review of past work on semiconducting polymers, covering electrical properties, structure, synthesis, and processing.

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.

The rise of plastic bioelectronics.

Plastic bioelectronics is a research field that takes advantage of the inherent properties of polymers and soft organic electronics for applications at the interface of biology and electronics. The resulting electronic materials and devices are soft, stretchable and mechanically conformable, which are important qualities for interacting with biological systems in both wearable and implantable devices. Work is currently aimed at improving these devices with a view to making the electronic-biological interface as seamless as possible.

Recent advances in neural interfaces-Materials chemistry to clinical translation.

Implantable neural interfaces are important tools to accelerate neuroscience research and translate clinical neurotechnologies. The promise of a bidirectional communication link between the nervous system of humans and computers is compelling, yet important materials challenges must be first addressed to improve the reliability of implantable neural interfaces. This perspective highlights recent progress and challenges related to arguably two of the most common failure modes for implantable neural interfaces: (1) compromised barrier layers and packaging leading to failure of electronic components; (2) encapsulation and rejection of the implant due to injurious tissue-biomaterials interactions, which erode the quality and bandwidth of signals across the biology-technology interface. Innovative materials and device design concepts could address these failure modes to improve device performance and broaden the translational prospects of neural interfaces. A brief overview of contemporary neural interfaces is presented and followed by recent progress in chemistry, materials, and fabrication techniques to improve in vivo reliability, including novel barrier materials and harmonizing the various incongruences of the tissue-device interface. Challenges and opportunities related to the clinical translation of neural interfaces are also discussed.

Transparent, conformable, active multielectrode array using organic electrochemical transistors.

Mechanically flexible active multielectrode arrays (MEA) have been developed for local signal amplification and high spatial resolution. However, their opaqueness limited optical observation and light stimulation during use. Here, we show a transparent, ultraflexible, and active MEA, which consists of transparent organic electrochemical transistors (OECTs) and transparent Au grid wirings. The transparent OECT is made of Au grid electrodes and has shown comparable performance with OECTs with nontransparent electrodes/wirings. The transparent active MEA realizes the spatial mapping of electrocorticogram electrical signals from an optogenetic rat with 1-mm spacing and shows lower light artifacts than noise level. Our active MEA would open up the possibility of precise investigation of a neural network system with direct light stimulation.

Conjugated Polymers in Bioelectronics.

The emerging field of organic bioelectronics bridges the electronic world of organic-semiconductor-based devices with the soft, predominantly ionic world of biology. This crosstalk can occur in both directions. For example, a biochemical reaction may change the doping state of an organic material, generating an electronic readout. Conversely, an electronic signal from a device may stimulate a biological event. Cutting-edge research in this field results in the development of a broad variety of meaningful applications, from biosensors and drug delivery systems to health monitoring devices and brain-machine interfaces. Conjugated polymers share similarities in chemical "nature" with biological molecules and can be engineered on various forms, including hydrogels that have Young's moduli similar to those of soft tissues and are ionically conducting. The structure of organic materials can be tuned through synthetic chemistry, and their biological properties can be controlled using a variety of functionalization strategies. Finally, organic electronic materials can be integrated with a variety of mechanical supports, giving rise to devices with form factors that enable integration with biological systems. While these developments are innovative and promising, it is important to note that the field is still in its infancy, with many unknowns and immense scope for exploration and highly collaborative research. The first part of this Account details the unique properties that render conjugated polymers excellent biointerfacing materials. We then offer an overview of the most common conjugated polymers that have been used as active layers in various organic bioelectronics devices, highlighting the importance of developing new materials. These materials are the most popular ethylenedioxythiophene derivatives as well as conjugated polyelectrolytes and ion-free organic semiconductors functionalized for the biological interface. We then discuss several applications and operation principles of state-of-the-art bioelectronics devices. These devices include electrodes applied to sense/trigger electrophysiological activity of cells as well as electrolyte-gated field-effect and electrochemical transistors used for sensing of biochemical markers. Another prime application example of conjugated polymers is cell actuators. External modulation of the redox state of the underlying conjugated polymer films controls the adhesion behavior and viability of cells. These smart surfaces can be also designed in the form of three-dimensional architectures because of the processability of conjugated polymers. As such, cell-loaded scaffolds based on electroactive polymers enable integrated sensing or stimulation within the engineered tissue itself. A last application example is organic neuromorphic devices, an alternative computing architecture that takes inspiration from biology and, in particular, from the way the brain works. Leveraging ion redistribution inside a conjugated polymer upon application of an electrical field and its coupling with electronic charges, conjugated polymers can be engineered to act as artificial neurons or synapses with complex, history-dependent behavior. We conclude this Account by highlighting main factors that need to be considered for the design of a conjugated polymer for applications in bioelectronics-although there can be various figures of merit given the broad range of applications, as emphasized in this Account.

Controlling the mode of operation of organic transistors through side-chain engineering.

Electrolyte-gated organic transistors offer low bias operation facilitated by direct contact of the transistor channel with an electrolyte. Their operation mode is generally defined by the dimensionality of charge transport, where a field-effect transistor allows for electrostatic charge accumulation at the electrolyte/semiconductor interface, whereas an organic electrochemical transistor (OECT) facilitates penetration of ions into the bulk of the channel, considered a slow process, leading to volumetric doping and electronic transport. Conducting polymer OECTs allow for fast switching and high currents through incorporation of excess, hygroscopic ionic phases, but operate in depletion mode. Here, we show that the use of glycolated side chains on a thiophene backbone can result in accumulation mode OECTs with high currents, transconductance, and sharp subthreshold switching, while maintaining fast switching speeds. Compared with alkylated analogs of the same backbone, the triethylene glycol side chains shift the mode of operation of aqueous electrolyte-gated transistors from interfacial to bulk doping/transport and show complete and reversible electrochromism and high volumetric capacitance at low operating biases. We propose that the glycol side chains facilitate hydration and ion penetration, without compromising electronic mobility, and suggest that this synthetic approach can be used to guide the design of organic mixed conductors.

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.

Developing Next-generation Brain Sensing Technologies - A Review.

Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients.

Molecular Design of Semiconducting Polymers for High-Performance Organic Electrochemical Transistors.

The organic electrochemical transistor (OECT), capable of transducing small ionic fluxes into electronic signals in an aqueous environment, is an ideal device to utilize in bioelectronic applications. Currently, most OECTs are fabricated with commercially available conducting poly(3,4-ethylenedioxythiophene) (PEDOT)-based suspensions and are therefore operated in depletion mode. Here, we present a series of semiconducting polymers designed to elucidate important structure-property guidelines required for accumulation mode OECT operation. We discuss key aspects relating to OECT performance such as ion and hole transport, electrochromic properties, operational voltage, and stability. The demonstration of our molecular design strategy is the fabrication of accumulation mode OECTs that clearly outperform state-of-the-art PEDOT-based devices, and show stability under aqueous operation without the need for formulation additives and cross-linkers.

Nanostructured conducting polymers for stiffness controlled cell adhesion.

We propose a facile and reproducible method, based on ultra thin porous alumina membranes, to produce cm(2) ordered arrays of nano-pores and nano-pillars on any kind of substrates. In particular our method enables the fabrication of conducting polymers nano-structures, such as poly[3,4-ethylenedioxythiophene]:poly[styrene sulfonate] ( PEDOT: PSS). Here, we demonstrate the potential interest of those templates with controlled cell adhesion studies. The triggering of the eventual fate of the cell (proliferation, death, differentiation or migration) is mediated through chemical cues from the adsorbed proteins and physical cues such as surface energy, stiffness and topography. Interestingly, as well as through material properties, stiffness modifications can be induced by nano-topography, the ability of nano-pillars to bend defining an effective stiffness. By controlling the diameter, length, depth and material of the nano-structures, one can possibly tune the effective stiffness of a (nano) structured substrate. First results indicate a possible change in the fate of living cells on such nano-patterned devices, whether they are made of conducting polymer (soft material) or silicon (hard material).

Organic bioelectronics: a new era for organic electronics.

BACKGROUND: 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. SCOPE OF REVIEW: This is a perspective on the history and current status of the field. MAJOR CONCLUSIONS: 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. GENERAL SIGNIFICANCE: Organic bioelectronics is a young and exciting interdisciplinary field. This article is part of a Special Issue entitled Organic Bioelectronics - Novel Applications in Biomedicine.

Fibronectin conformation regulates the proangiogenic capability of tumor-associated adipogenic stromal cells.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS AND GENERAL SIGNIFICANCE: 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.

Engineering hydrophilic conducting composites with enhanced ion mobility.

Ion mobility has a direct influence on the performance of conducting polymers in a number of applications as it dictates the operational speed of the devices. We report here the enhanced ion mobility of poly(3,4-ethylene dioxythiophene) after incorporation of gelatin. The gelatin-rich domains were seen to provide an ion pathway through the composites.