Vertical organic electrochemical transistor platforms for efficient electropolymerization of thiophene based oligomers.

Organic electrochemical transistors (OECTs) have emerged as promising candidates for various fields, including bioelectronics, neuromorphic computing, biosensors, and wearable electronics. OECTs operate in aqueous solutions, exhibit high amplification properties, and offer ion-to-electron signal transduction. The OECT channel consists of a conducting polymer, with PEDOT:PSS receiving the most attention to date. While PEDOT:PSS is highly conductive, and benefits from optimized protocols using secondary dopants and detergents, new p-type and n-type polymers are emerging with desirable material properties. Among these, low-oxidation potential oligomers are highly enabling for bioelectronics applications, however the polymers resulting from their polymerization lag far behind in conductivity compared with the established PEDOT:PSS. In this work we show that by careful design of the OECT geometrical characteristics, we can overcome this limitation and achieve devices that are on-par with transistors employing PEDOT:PSS. We demonstrate that the vertical architecture allows for facile electropolymerization of a family of trimers that are polymerized in very low oxidation potentials, without the need for harsh chemicals or secondary dopants. Vertical and planar OECTs are compared using various characterization methods. We show that vOECTs are superior platforms in general and propose that the vertical architecture can be expanded for the realization of OECTs for various applications.

Neural probe system for behavioral neuropharmacology by bi-directional wireless drug delivery and electrophysiology in socially interacting mice.

Assessing the neurological and behavioral effects of drugs is important in developing pharmacological treatments, as well as understanding the mechanisms associated with neurological disorders. Herein, we present a miniaturized, wireless neural probe system with the capability of delivering drugs for the real-time investigation of the effects of the drugs on both behavioral and neural activities in socially interacting mice. We demonstrate wireless drug delivery and simultaneous monitoring of the resulting neural, behavioral changes, as well as the dose-dependent and repeatable responses to drugs. Furthermore, in pairs of mice, we use a food competition assay in which social interaction was modulated by the delivery of the drug, and the resulting changes in their neural activities are analyzed. During modulated food competition by drug injection, we observe changes in neural activity in mPFC region of a participating mouse over time. Our system may provide new opportunities for the development of studying the effects of drugs on behaviour and neural activity.

Noninvasive Stimulation of Peripheral Nerves using Temporally-Interfering Electrical Fields.

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation (PNS) noninvasively without surgically implanted devices are enabling for fundamental research and clinical translation. Here, it is demonstrated how relatively high-frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. This principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model is validated. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve is demonstrated. This method is simple, relying on the repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.

An Intrafascicular Neural Interface With Enhanced Interconnection for Recording of Peripheral Nerve Signals.

For implantable devices, Parylene C (hereafter referred to as Parylene) has shown promising properties such as flexibility, biocompatibility, biostability, and good barrier properties. Parylene-based flexible interconnection cable (FIC) was previously developed to connect a flexible penetrating microelectrode array (FPMA) with a recording system. However, Parylene-based FIC was difficult to handle and prone to damage during the implantation surgery because of its low mechanical strength. To improve the mechanical properties of the FIC, we suggest a mechanically enhanced flexible interconnection cable (enhanced FIC) obtained using a combination of Parylene and polyimide. To investigate the long-term stability of the enhanced FIC, Parylene-only FIC, and enhanced FIC were tested and their mechanical properties were compared under an accelerated aging condition. During the course of six months of soaking, the maximum strength of the enhanced FIC remained twice as high as that of the Parylene-only FIC throughout the experiment, although the mechanical strength of both FICs decreased over time. To show the capability of the enhanced FIC in the context of nerve signal recording as a part of a neural interfacing device, it was assembled together with the FPMA and custom-made wireless recording electronics. We demonstrated the feasibility of the enhanced FIC in an in vivo application by recording acute nerve signals from canine sciatic nerves.

Simplified adaptor for stereotactic surgery in non-human primates.

BACKGROUND: It is challenging for researchers performing stereotactic procedures to transition from small animals to non-human primate (NHP) experiments. The NHP stereotactic atlas is based on ear-bar zero (EBZ), which is an anatomical reference frame that is not visible during surgery. Most current NHP stereotactic systems require high-cost MRI or CT imaging and complex computer processing to determine the stereotactic coordinates, limiting the procedure to those with significant expertise. NEW METHOD: We have designed a simplified adaptor consisting of a circular arc for coronal tilt, a carrier for electrodes or cannulas, and an anchor to attach the adaptor to a conventional stereotactic frame. Our adaptor allows easy identification of the EBZ with the help of an anchor notch, and provides digital distance sensors without the need for imaging data or computer processing. Our system enables the use of trajectories that avoid injury to important structures and vessels. RESULTS: We tested the accuracy of our system using simulated targeting with phantoms, and demonstrated sub-millimeter accuracy. Infusion of methylene blue also showed satisfactory staining in target structures deep in the brain. COMPARISON WITH EXISTING METHODS: This system does not require high-cost imaging and extra training to determine EBZ. Once EBZ is set automatically by the system itself, targeting is similar to that in small animal stereotactic procedure. CONCLUSION: Our simple adaptor will aid researchers who plan to conduct experiments involving stereotactic surgery in NHPs.

A 3D-Printed Sensor for Monitoring Biosignals in Small Animals.

Although additive manufacturing technologies, also known as 3D printing, were first introduced in the 1980s, they have recently gained remarkable popularity owing to decreased costs. 3D printing has already emerged as a viable technology in many industries; in particular, it is a good replacement for microfabrication technology. Microfabrication technology usually requires expensive clean room equipment and skilled engineers; however, 3D printing can reduce both cost and time dramatically. Although 3D printing technology has started to emerge into microfabrication manufacturing and medical applications, it is typically limited to creating mechanical structures such as hip prosthesis or dental implants. There have been increased interests in wearable devices and the critical part of such wearable devices is the sensing part to detect biosignals noninvasively. In this paper, we have built a 3D-printed sensor that can measure electroencephalogram and electrocardiogram from zebrafish. Despite measuring biosignals noninvasively from zebrafish has been known to be difficult due to that it is an underwater creature, we were able to successfully obtain electrophysiological information using the 3D-printed sensor. This 3D printing technique can accelerate the development of simple noninvasive sensors using affordable equipment and provide an economical solution to physiologists who are unfamiliar with complicated microfabrication techniques.

Author Correction: Zebrafish as an animal model in epilepsy studies with multichannel EEG recordings.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Correction to: Polymer-based interconnection cables to integrate with flexible penetrating microelectrode arrays.

The original version of this article unfortunately contained a mistake. In Eqs. (1) to (3), the gas constant 'R' should be replaced with Boltzmann constant 'k B.' This change accompanies the change in the paragraph following Eq. (3) as below.

Polymer-based interconnection cables to integrate with flexible penetrating microelectrode arrays.

There have been various types of interconnection methods for neural interfacing electrodes, such as silicon ribbon cables, wire bonding and polymer-based cables. In this study, interconnection cables were developed for integration with a Flexible Penetrating Microelectrode Array (FPMA) that was previously developed for neural signal recording or stimulation. Polyimide and parylene C were selected as base materials for the interconnection cables as both materials can preserve the flexibility of the FPMA better than other interconnection methods such as silicon ribbon cable or wire bonding. We conducted durability tests to determine if the interconnection cables were suitable for in-vivo implantation, by long-term soaking of the cables in phosphate buffered saline solution. We measured the changes in impedance over time, and equivalent circuit models were used to analyze the electrochemical phenomena on the surface of the cables. Lastly, we implanted the cable-integrated electrodes device onto rabbit's sciatic nerve and recorded neural signals to prove the feasibility of the developed FPMA integration system.

Development of an intrafascicular neural interface for peripheral nerve implantation.

This paper describes an intrafascicular neural interface for peripheral nerve implantation. The flexible penetrating microelectrode array with varying lengths (vl-FPMA), interconnection cable, wireless recording and stimulator modules were designed and fabricated to detect neural signals from the peripheral nerves or to stimulate them. The vl-FPMA consisted of silicon needles and polydimethylsiloxane (PDMS) platform supporting the needles. The length of electrode needles varied from 600 to 1000 µm. The interconnection cable was fabricated as parylene-metal-parylene sandwiched structure. The wireless recording/stimulation modules were also developed and connected with the electrodes. The integrated system was implanted in the sciatic nerve of beagles and the recording capability of the integrated system was demonstrated successfully.

Recording nerve signals in canine sciatic nerves with a flexible penetrating microelectrode array.

OBJECTIVE: Previously, we presented the fabrication and characterization of a flexible penetrating microelectrode array (FPMA) as a neural interface device. In the present study, we aim to prove the feasibility of the developed FPMA as a chronic intrafascicular recording tool for peripheral applications. APPROACH: For recording from the peripheral nerves of medium-sized animals, the FPMA was integrated with an interconnection cable and other parts that were designed to fit canine sciatic nerves. The uniformity of tip exposure and in vitro electrochemical properties of the electrodes were characterized. The capability of the device to acquire in vivo electrophysiological signals was evaluated by implanting the FPMA assembly in canine sciatic nerves acutely as well as chronically for 4 weeks. We also examined the histology of implanted tissues to evaluate the damage caused by the device. MAIN RESULTS: Throughout recording sessions, we observed successful multi-channel recordings (up to 73% of viable electrode channels) of evoked afferent and spontaneous nerve unit spikes with high signal quality (SNR > 4.9). Also, minor influences of the device implantation on the morphology of nerve tissues were found. SIGNIFICANCE: The presented results demonstrate the viability of the developed FPMA device in the peripheral nerves of medium-sized animals, thereby bringing us a step closer to human applications. Furthermore, the obtained data provide a driving force toward a further study for device improvements to be used as a bidirectional neural interface in humans.

Zebrafish as an animal model in epilepsy studies with multichannel EEG recordings.

Despite recent interest in using zebrafish in human disease studies, sparked by their economics, fecundity, easy handling, and homologies to humans, the electrophysiological tools or methods for zebrafish are still inaccessible. Although zebrafish exhibit more significant larval-adult duality than any other animal, most electrophysiological studies using zebrafish are biased by using larvae these days. The results of larval studies not only differ from those conducted with adults but also are unable to delicately manage electroencephalographic montages due to their small size. Hence, we enabled non-invasive long-term multichannel electroencephalographic recording on adult zebrafish using custom-designed electrodes and perfusion system. First, we exploited demonstration of long-term recording on pentylenetetrazole-induced seizure models, and the results were quantified. Second, we studied skin-electrode impedance, which is crucial to the quality of signals. Then, seizure propagations and gender differences in adult zebrafish were exhibited for the first time. Our results provide a new pathway for future neuroscience research using zebrafish by overcoming the challenges for aquatic organisms such as precision, serviceability, and continuous water seepage.

Zebrafish needle EMG: a new tool for high-throughput drug screens.

Zebrafish models have recently been highlighted as a valuable tool in studying the molecular basis of neuromuscular diseases and developing new pharmacological treatments. Needle electromyography (EMG) is needed not only for validating transgenic zebrafish models with muscular dystrophies (MD), but also for assessing the efficacy of therapeutics. However, performing needle EMG on larval zebrafish has not been feasible due to the lack of proper EMG sensors and systems for such small animals. We introduce a new type of EMG needle electrode to measure intramuscular activities of larval zebrafish, together with a method to hold the animal in position during EMG, without anesthetization. The silicon-based needle electrode was found to be sufficiently strong and sharp to penetrate the skin and muscles of zebrafish larvae, and its shape and performance did not change after multiple insertions. With the use of the proposed needle electrode and measurement system, EMG was successfully performed on zebrafish at 30 days postfertilization (dpf) and at 5 dpf. Burst patterns and spike morphology of the recorded EMG signals were analyzed. The measured single spikes were triphasic with an initial positive deflection, which is typical for motor unit action potentials, with durations of ∼10 ms, whereas the muscle activity was silent during the anesthetized condition. These findings confirmed the capability of this system of detecting EMG signals from very small animals such as 5 dpf zebrafish. The developed EMG sensor and system are expected to become a helpful tool in validating zebrafish MD models and further developing therapeutics.

Effect of bone cement volume and stiffness on occurrences of adjacent vertebral fractures after vertebroplasty.

OBJECTIVE: The purpose of this study is to find the optimal stiffness and volume of bone cement and their biomechanical effects on the adjacent vertebrae to determine a better strategy for conducting vertebroplasty. METHODS: A three-dimensional finite-element model of a functional spinal unit was developed using computed tomography scans of a normal motion segment, comprising the T11, T12 and L1 vertebrae. Volumes of bone cement, with appropriate mechanical properties, were inserted into the trabecular core of the T12 vertebra. Parametric studies were done by varying the volume and stiffness of the bone cement. RESULTS: When the bone cement filling volume reached 30% of the volume of a vertebral body, the level of stiffness was restored to that of normal bone, and when higher bone cement exceeded 30% of the volume, the result was stiffness in excess of that of normal bone. When the bone cement volume was varied, local stress in the bony structures (cortical shell, trabecular bone and endplate) of each vertebra monotonically increased. Low-modulus bone cement has the effect of reducing strain in the augmented body, but only in cases of relatively high volumes of bone cement (>50%). Furthermore, varying the stiffness of bone cement has a negligible effect on the stress distribution of vertebral bodies. CONCLUSION: The volume of cement was considered to be the most important determinant in endplate fracture. Changing the stiffness of bone cement has a negligible effect on the stress distribution of vertebral bodies.

Finite element analysis of the biomechanical effect of coflex™ on the lumbar spine.

OBJECTIVE: The biomechanical properties of the Coflex™ (Paradigm Spine, NY, USA), a device designed to provide dynamic stabilization without lumbar fusion, have not been clearly defined. The purpose of this study was to determine the efficacy and biomechanical effect of Coflex™ using finite element model (FEM). METHODS: A 3D geometric model of the L3-L5 was created by integrating computerized tomography (CT) images. Based on the geometric model, a 3D FEM was created and the Coflex™ model was incorporated into the base model. Mechanical load dependent on the postural changes and boundary conditions, were imposed to simulate various 3D physiological states. The simulation analysis included stress and strain distributions, intervertebral disc deformation, and the range of motion of the facet joint and lumbar spinous process. RESULTS: Coflex™ significantly restrained displacement in extension, lateral bending and compression of joint between the L4-5 as one in the experimental group was observed -1.3% of flexion, -24.5% of extension, -44.5% of lateral bending and -37.2%. The average intradiscal pressure of the L4-5 decreased by 63% and the average facet contract force of the L4-5 decreased markedly by 34% in the experimental group. A load of 120 MPa from extension was observed at the base of spinous process in the experimental group. CONCLUSION: The Coflex™ can be safely used for achieving functional dynamic stabilization of the lumbar vertebral column while preserving the intactness of the other components. However, the fatigue fracture of the L4 spinous process should be carefully monitored.