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Accurate neuronal tracing of microelectrodes based on PEDOT-dye coatings
Abstract and Figures
Penetrating microelectrode probes offer the opportunity to precisely monitor neuronal signals over several months. After the experimental end point, histological methods are used to analyze the tissue and to correlate recorded signals to histological findings. However, accurate retroactive tracing of the position of individual microelectrodes is currently hampered by the lack of suitable techniques to mark their positions. Here we describe a poly (3, 4-ethylene dioxythiophene) (PEDOT) based microelectrode coating, which is optimized for an active, electrochemically controllable release of the neuronal tracer DiI. The tracer is incorporated into the polymer coating by an ion exchange mechanism. Active cycling showed a 3.6 times higher dye incorporation rate compared to reference samples which were solely immersed in the dye. A bi-layer system was used to optimize drug storage ability and could suppress passive leakage of DiI from the film by more than a factor 6. The PEDOT/dye system was characterized in vitro in terms of its ability to store the dye over the time course of the experiment, deliver a precise quantity upon electroactivation and continuously support stable recordings throughout an implantation.
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... By introducing a bilayer system with a second PEDOT/PSS layer on top of a dye filled electrode coating, it was possible to decrease passive leakage ( Fig. 3 (b)) without preventing an active release of the dye. Similar results were reported previously with the neurotracer DiI [21]. The lipophilic character of the neurotracer is expected to limit its possibility to passively diffuse into the aqueous environment in vivo, but it is assumed that the direct contact with a lipophilic membrane is necessary to allow dye to leave the electrode surface. ...
Penetrating neural probes comprising arrays of microelectrodes are commonly used to monitor local field potentials and multi-unit activity in animal brain over time frames of weeks. To correlate these recorded signals to specific tissue areas, histological analysis is performed after the experimental endpoint. Even if the lesion of the penetrating probe shaft can be observed, a precise reconstruction of the exact electrode positions is still challenging. To overcome these experimental difficulties, we developed a new concept, whereupon recording electrodes are coated with a poly (3, 4-ethylenedioxythiophene/ polystyrenesulfonate) (PEDOT/PSS)-based film. The conducting polymer acts as dye reservoir over several weeks and afterwards provides controlled delivery of neurotracers. This paper presents a recording electrode based on a PEDOT/PSS bilayer optimized for dye delivery and with reduced impedance. Controlled exchange of neurotracer dye is successfully demonstrated in vitro using spectrofluorometry and in neuroblastoma cell cultures. A second PEDOT/PSS capping layer on top of the dye reservoir lowers the passive leakage of dye by a factor of 6.4 and prevents a direct contact of the dye filled layer with the cells. Stability tests over four weeks demonstrate the electrochemical stability of the PEDOT coating, as well as retained functionality of the dye delivery system.
On-demand release of bioactive substances with high spatial and temporal control offers ground-breaking possibilities in the field of life sciences. However, available strategies for developing such release systems lack the possibility of combining efficient control over release with adequate storage capability in a reasonably compact system. In this study we present a new approach to target this deficiency by the introduction of a hybrid material. This organic-inorganic material was fabricated by atomic layer deposition of ZnO into thin films of polyethylene glycol, forming the carrier matrix for the substance to be released. Sub-surface growth mechanisms during this process converted the liquid polymer into a solid, yet water-soluble, phase. This layer permits extended storage for various substances within a single film of only a few micrometers in thickness, and hence demands minimal space and complexity. Improved control over release of the model substance Fluorescein was achieved by coating the hybrid material with a conducting polymer film. Single dosage and repetitive dispensing from this system was demonstrated. Release was controlled by applying a bias potential of ±0.5 V to the polymer film enabling or respectively suppressing the expulsion of the model drug. In vitro tests showed excellent biocompatibility of the presented system.
Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50-60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7-9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour.
The possibility to release drugs from conducting polymers, like polypyrrole (PPy) or poly(3,4-ethylenedioxythiophene) (PEDOT), has been described and investigated for a variety of different substances during the last years, showing a wide interest in these release systems. A point that has not been looked at so far however is the possibility of other substances, next to the intended ones, leaving the polymer film under the high voltage excursions during redox sweeping. In this study we target this weakness of commonly used detection methods by implementing a high precision analytical method (HPLC) that allows a separation and subsequently a detailed quantification of all possible release products. We could identify a significantly more complex release behavior for a PEDOT:Dex system than has been assumed so far, revealing the active release of the monomer upon redox activation. The released EDOT could thereby be shown to result from the bulk material, causing a considerable loss of polymer (> 10% during 6 release events) that could partly account for the observed degradation or delamination effects of drug-eluting coatings. The monomer leakage was found to be substantially higher for a PEDOT:Dex film compared to a PEDOT:PSS sample. This finding indicates an overestimation of drug release if side-products are mistaken for the actual drug mass. Moreover the full picture of released substances implements the need for further studies to reduce the monomer leakage and identify possible adverse effects, especially in the perspective of releasing an anti-inflammatory substance for attenuation of the foreign body reaction towards implanted electrodes.
Electrodes intended for neural communication must be designed to meet both the electrochemical and biological requirements essential for long term functionality. Metallic electrode materials have been found inadequate to meet these requirements and therefore conducting polymers for neural electrodes have emerged as a field of interest. One clear advantage with polymer electrodes is the possibility to tailor the material to have optimal biomechanical and chemical properties for certain applications. To identify and evaluate new materials for neural communication electrodes, three charged biomolecules, fibrinogen, hyaluronic acid (HA), and heparin are used as counterions in the electrochemical polymerization of poly(3,4-ethylenedioxythiophene) (PEDOT). The resulting material is evaluated electrochemically and the amount of exposed biomolecule on the surface is quantified. PEDOT:biomolecule surfaces are also studied with static contact angle measurements as well as scanning electron microscopy and compared to surfaces of PEDOT electrochemically deposited with surfactant counterion polystyrene sulphonate (PSS). Electrochemical measurements show that PEDOT:heparin and PEDOT:HA, both have the electrochemical properties required for neural electrodes, and PEDOT:heparin also compares well to PEDOT:PSS. PEDOT:fibrinogen is found less suitable as neural electrode material.
Development of electroactive conjugated polymers, for the purpose of recording and eliciting signals in the neural systems in humans, can be used to fashion the interfaces between the two signalling systems of electronics and neural systems. The design of desirable chemical, mechanical and electrical properties in the electroactive polymerelectrodes, and the means of integration of these into biological systems, are here reviewed.
Preparation of conducting-polymer nanotubes for application in controlled drug release was investigated. The process involved electrospinning of a biodegradable drug incorporated polymer followed by electrochemical deposition of a conducting polymer. The conducting-polymer nanotubes were found to decrease the impedance and increase the charge capacity of the recording electrode sites on microfabricated neural prosthetic devices. It was observed that microelectrode neural probes facilitate the function stimulation of neurons in the central nervous system. The enhanced charge-transfer capacity of electrodes after surface treatment by PEDOT nanotubes was also investigated and confirmed by cyclic voltammetry.
A complementary-metal-oxide-semiconductor-compatible fabrication technique for ultrathin silicon chips of arbitrary shape is reported. It combines deep reactive ion etching and wafer grinding to define the in-plane geometry and thickness of the chips, respectively. Neural probes with shaft lengths up to 12 mm and thicknesses down to 25 μm were fabricated.
This paper reviews the application of intrinsically conducting polymers (ICPs) in drug delivery. ICPs are organic polymers with electrical, magnetic and optical properties usually associated with metals, whilst retaining the advantageous mechanical properties and ease of processing usually associated with polymers. Due to the inherent properties of these unique materials, electrical stimulation can be used to alter the redox state of ICPs, which in turn can modify the release rate of drug. The controlled release of drugs from ICPs has been reported in the literature since the 1980s. Following continued development, clinical applications of ICP-based drug delivery systems (DDS) have been reported recently. The next generation of controlled release technologies could utilise the biosensing properties of ICPs combined with their drug delivering abilities to develop an intelligent drug delivery system from a single material where the release rate of drug self adjusts in response to a sensed change in local body environment. This article provides an overview of ICP synthesis and properties relevant to their use as DDS, including biodegradability and biocompatibility, followed by literature on ICP-based DDS examining different methods of drug incorporation and release. The pharmaceutical applications of these systems have also been discussed. It is concluded that ICPs hold great promise in drug delivering implants where the dose can be adjusted through application of external stimulus, thus optimising benefit to side effect ratio while simultaneously ensuring patient adherence.
Chronic recordings from micromachined neural electrode arrays often fail a few weeks after implantation primarily due to the formation of an astro-glial sheath around the implant. We propose a drug delivery system, from conducting polymer (CP) coatings on the electrode sites, to modulate the inflammatory implant-host tissue reaction. In this study, polypyrrole (PPy) based coatings for electrically controlled and local delivery of the ionic form of an anti-inflammatory drug, dexamethasone (Dex), was investigated. The drug was incorporated in PPy via electropolymerization of pyrrole and released in PBS using cyclic voltammetry (CV). FTIR analysis of the surface showed the presence of Dex and polypyrrole on the coated electrode. The thickness of the coated film was estimated to be approximately 50 nm by ellipsometry. We are able to release 0.5 mug/cm(2) Dex in 1 CV cycle and a total of almost 16 mug/cm(2) Dex after 30 CV cycles. In vitro studies and immunocytochemistry on murine glial cells suggest that the released drug lowers the count of reactive astrocytes to the same extent as the added drug. In addition, the released drug is not toxic to neurons as seen by healthy neuronal viability in the released drug treated cells.
- N A Donnelly
- T Holtzman
- P D Rich
- A J Nevado-Holgado
- A B J Fernando
- G V Dijck
- . T Holzhammer
- O Paul
- P Ruther
- O Paulsen
- T W Robbins
- J W Dalley
N. A. Donnelly, T. Holtzman, P. D. Rich, A. J. Nevado-Holgado, A. B.
J. Fernando, G. V. Dijck,. T. Holzhammer, O. Paul, P. Ruther, O.
Paulsen, T. W. Robbins & J. W. Dalley. Oscillatory Activity in the
Medial Prefrontal Cortex and Nucleus Accumbens Correlates with
Impulsivity and Reward Outcome. PLoS ONE, 9(10): e111300, 2014