Multilayer Arrays for Neurotechnology Applications (MANTA): Chronically Stable Thin-Film Intracortical Implants.

Flexible implantable neurointerfaces show great promise in addressing one of the major challenges of implantable neurotechnology, namely the loss of signal connected to unfavorable probe tissue interaction. The authors here show how multilayer polyimide probes allow high-density intracortical recordings to be combined with a reliable long-term stable tissue interface, thereby progressing toward chronic stability of implantable neurotechnology. The probes could record 10-60 single units over 5 months with a consistent peak-to-peak voltage at dimensions that ensure robust handling and insulation longevity. Probes that remain in intimate contact with the signaling tissue over months to years are a game changer for neuroscience and, importantly, open up for broader clinical translation of systems relying on neurotechnology to interface the human brain.

A Subdural Bioelectronic Implant to Record Electrical Activity from the Spinal Cord in Freely Moving Rats.

Bioelectronic devices have found use at the interface with neural tissue to investigate and treat nervous system disorders. Here, the development and characterization of a very thin flexible bioelectronic implant inserted along the thoracic spinal cord in rats directly in contact with and conformable to the dorsal surface of the spinal cord are presented. There is no negative impact on hind-limb functionality nor any change in the volume or shape of the spinal cord. The bioelectronic implant is maintained in rats for a period of 12 weeks. The first subdural recordings of spinal cord activity in freely moving animals are presented; rats are plugged in via a recording cable and allowed to freely behave and move around on a raised platform. Recordings contained multiple distinct voltage waveforms spatially localize to individual electrodes. This device has great potential to monitor electrical signaling in the spinal cord after an injury and in the future, this implant will facilitate the identification of biomarkers in spinal cord injury and recovery, while enabling the delivery of localized electroceutical and chemical treatments.

On the longevity of flexible neural interfaces: Establishing biostability of polyimide-based intracortical implants.

Flexible neural implants are extremely favored, as the most successful strategy to promote probe-tissue integration and avoid severe gliosis relies on reducing the mechanical mismatch between probe and brain tissue. But what are the realistic requirements for achieving chronic recording stability? What are the critical dimensions and main factors determining glial scar-free device integration? To answer these questions, two types of hair-sized polyimide-based flexible intracortical (PIXI) arrays were fabricated, differing only in their cross-sectional area. Chronic tissue reaction to both types was evaluated in rats, and in different implantation setups. Interfacial stresses were found to play a critical role in long-term tissue integration. Still, all the devices provided high quality chronic recordings of single units and inflammatory gene expression was not significantly upregulated for larger devices. Our study points out that the most relevant factor in eliciting FBR is played by mechanical probe-tissue interactions, that polyimide is well tolerated by the tissue, and that a holistic design - considering material properties, geometrical dimensions and assembling techniques - is the key towards longevity and long-term performance of intracortical probes. The optimization of only one parameter did not yet lead to the successful translation of research accomplishments into chronic preclinical and clinical applications.

Biomedical Microtechnologies Beyond Scholarly Impact.

The recent tremendous advances in medical technology at the level of academic research have set high expectations for the clinical outcomes they promise to deliver. To the demise of patient hopes, however, the more disruptive and invasive a new technology is, the bigger the gap is separating the conceptualization of a medical device and its adoption into healthcare systems. When technology breakthroughs are reported in the biomedical scientific literature, news focus typically lies on medical implications rather than engineering progress, as the former are of higher appeal to a general readership. While successful therapy and diagnostics are indeed the ultimate goals, it is of equal importance to expose the engineering thinking needed to achieve such results and, critically, identify the challenges that still lie ahead. Here, we would like to provoke thoughts on the following questions, with particular focus on microfabricated medical devices: should research advancing the maturity and reliability of medical technology benefit from higher accessibility and visibility? How can the scientific community encourage and reward academic work on the overshadowed engineering aspects that will facilitate the evolution of laboratory samples into clinical devices?

Carbon-based neural electrodes: promises and challenges.

Neural electrodes are primary functional elements of neuroelectronic devices designed to record neural activity based on electrochemical signals. These electrodes may also be utilized for electrically stimulating the neural cells, such that their response can be simultaneously recorded. In addition to being medically safe, the electrode material should be electrically conductive and electrochemically stable under harsh biological environments. Mechanical flexibility and conformability, resistance to crack formation and compatibility with common microfabrication techniques are equally desirable properties. Traditionally, (noble) metals have been the preferred for neural electrode applications due to their proven biosafety and a relatively high electrical conductivity. Carbon is a recent addition to this list, which is far superior in terms of its electrochemical stability and corrosion resistance. Carbon has also enabled 3D electrode fabrication as opposed to the thin-film based 2D structures. One of carbon's peculiar aspects is its availability in a wide range of allotropes with specialized properties that render it highly versatile. These variations, however, also make it difficult to understand carbon itself as a unique material, and thus, each allotrope is often regarded independently. Some carbon types have already shown promising results in bioelectronic medicine, while many others remain potential candidates. In this topical review, we first provide a broad overview of the neuroelectronic devices and the basic requirements of an electrode material. We subsequently discuss the carbon family of materials and their properties that are useful in neural applications. Examples of devices fabricated using bulk and nano carbon materials are reviewed and critically compared. We then summarize the challenges, future prospects and next-generation carbon technology that can be helpful in the field of neural sciences. The article aims at providing a common platform to neuroscientists, electrochemists, biologists, microsystems engineers and carbon scientists to enable active and comprehensive efforts directed towards carbon-based neuroelectronic device fabrication.

Prediction of Speech Onset by Micro-Electrocorticography of the Human Brain.

Recent technological advances show the feasibility of offline decoding speech from neuronal signals, paving the way to the development of chronically implanted speech brain computer interfaces (sBCI). Two key steps that still need to be addressed for the online deployment of sBCI are, on the one hand, the definition of relevant design parameters of the recording arrays, on the other hand, the identification of robust physiological markers of the patient's intention to speak, which can be used to online trigger the decoding process. To address these issues, we acutely recorded speech-related signals from the frontal cortex of two human patients undergoing awake neurosurgery for brain tumors using three different micro-electrocorticographic ([Formula: see text]ECoG) devices. First, we observed that, at the smallest investigated pitch (600[Formula: see text][Formula: see text]m), neighboring channels are highly correlated, suggesting that more closely spaced electrodes would provide some redundant information. Second, we trained a classifier to recognize speech-related motor preparation from high-gamma oscillations (70-150[Formula: see text]Hz), demonstrating that these neuronal signals can be used to reliably predict speech onset. Notably, our model generalized both across subjects and recording devices showing the robustness of its performance. These findings provide crucial information for the design of future online sBCI.

Conformable polyimide-based µECoGs: Bringing the electrodes closer to the signal source.

Structural biocompatibility is a fundamental requirement for chronically stable bioelectronic devices. Newest neurotechnologies are increasingly focused on minimizing the foreign body response through the development of devices that match the mechanical properties of the implanted tissue and mimic its surface composition, often compromising on their robustness. In this study, an analytical approach is proposed to determine the threshold of conformability for polyimide-based electrocorticography devices. A finite element model was used to quantify the depression of the cortex following the application of devices mechanically above or below conformability threshold. Findings were validated in vivo on rat animal models. Impedance measurements were performed for 40 days after implantation to monitor the status of the biotic/abiotic interface with both conformable and non-conformable implants. Multi-unit activity was then recorded for 12 weeks after implantation using the most compliant device type. It can therefore be concluded that conformability is an essential prerequisite for steady and reliable implants which does not only depend on the Young's modulus of the device material: it strongly relies on the relation between tissue curvature at the implantation site and corresponding device's thickness and geometry, which eventually define the moment of inertia and the interactions at the material-tissue interface.

Integration of Micro-Patterned Carbon Fiber Mats into Polyimide for the Development of Flexible Implantable Neural Devices.

Polymer-derived carbon as neural electrode material has recently been subject of interest due to its ability to act as a multimodal platform for simultaneous recording and stimulation of neural activity and neurotransmitter detection. Its mechanical properties and the inverse fabrication protocol commonly used for the manufacturing of pyrolyzed carbon thin-film devices, however, only allow for its use as the electrode material and not as material for interconnects and other conductive components. In this study -for the first time-a process to fabricate flexible neural devices entirely made of carbon fibers (CFs) and polyimide (PI) was developed. The devices consist of carbonized polyacrylonitrile (PAN) fiber mats embedded in polyimide, which were patterned into the desired shapes using reactive ion etching (RIE). This method allowed for the fabrication of miniaturized, flexible and conductive carbon components with critical dimensions of 12.5 µm. Tensile tests were performed to evaluate the mechanical stability of the CF/PI composite, to detect potential electrical resistance changes due to bending and to study the adhesion of different PI layers onto each other. A strong mechanical interlock between CFs and PI was demonstrated and no significant change in the resistance of the CFs was detected after 100k cycles of tensile bending (r = 3 mm). The fabrication approach proposed here successfully yielded entirely metal-free and entirely flexible electrodes. It opens the door to further studies with the guarantee of highly stable electrodes, both mechanically and electrically.

Glassy Carbon Electrocorticography Electrodes on Ultra-Thin and Finger-Like Polyimide Substrate: Performance Evaluation Based on Different Electrode Diameters.

Glassy carbon (GC) has high potential to serve as a biomaterial in neural applications because it is biocompatible, electrochemically inert and can be incorporated in polyimide-based implantable devices. Miniaturization and applicability of GC is, however, thought to be partially limited by its electrical conductivity. For this study, ultra-conformable polyimide-based electrocorticography (ECoG) devices with different-diameter GC electrodes were fabricated and tested in vitro and in rat models. For achieving conformability to the rat brain, polyimide was patterned in a finger-like shape and its thickness was set to 8 µm. To investigate different electrode sizes, each ECoG device was assigned electrodes with diameters of 50, 100, 200 and 300 µm. They were electrochemically characterized and subjected to 10 million biphasic pulses-for achieving a steady-state-and to X-ray photoelectron spectroscopy, for examining their elemental composition. The electrodes were then implanted epidurally to evaluate the ability of each diameter to detect neural activity. Results show that their performance at low frequencies (up to 300 Hz) depends on the distance from the signal source rather than on the electrode diameter, while at high frequencies (above 200 Hz) small electrodes have higher background noises than large ones, unless they are coated with poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS).

Achieving Ultra-Conformability With Polyimide-Based ECoG Arrays.

Micro-electrode arrays for electrocorticography (ECoG) represent the best compromise between invasiveness and signal quality, as they are surface devices that still allow high sensitivity recordings. In this work, an assessment of different technical aspects determining the ultimate performance of ultra-conformable polyimide-based µECoG arrays is conducted via a finite element model, impedance spectroscopy measurements and recordings of sensorimotor evoked potentials (SEPs) in rats. The finite element model proves that conformability of thin-film arrays can be achieved with polyimide, a non-stretchable material, by adjusting its thickness according to the curvature of the targeted anatomical area. From the electrochemical characterization of the devices, intrinsic thermal noise of platinum and gold electrodes is estimated to be 3-5 µV. Results show that electrode size and in vitro impedance do not influence the amplitude of the recorded SEPs. However, the use of a reference on-skull (a metal screw), as compared to reference on-array (a metal electrode surrounding the recording area), provides higher-amplitude SEPs. Additionally, the incorporation of a grounded metal shield in the thin-film devices limits crosstalk between tracks and does not compromise the recording capabilities of the arrays.

Integrity Assessment of a Hybrid DBS Probe that Enables Neurotransmitter Detection Simultaneously to Electrical Stimulation and Recording.

Deep brain stimulation (DBS) is a successful medical therapy for many treatment resistant neuropsychiatric disorders such as movement disorders; e.g., Parkinson's disease, Tremor, and dystonia. Moreover, DBS is becoming more and more appealing for a rapidly growing number of patients with other neuropsychiatric diseases such as depression and obsessive compulsive disorder. In spite of the promising outcomes, the current clinical hardware used in DBS does not match the technological standards of other medical applications and as a result could possibly lead to side effects such as high energy consumption and others. By implementing more advanced DBS devices, in fact, many of these limitations could be overcome. For example, a higher channels count and smaller electrode sites could allow more focal and tailored stimulation. In addition, new materials, like carbon for example, could be incorporated into the probes to enable adaptive stimulation protocols by biosensing neurotransmitters in the brain. Updating the current clinical DBS technology adequately requires combining the most recent technological advances in the field of neural engineering. Here, a novel hybrid multimodal DBS probe with glassy carbon microelectrodes on a polyimide thin-film device assembled on a silicon rubber tubing is introduced. The glassy carbon interface enables neurotransmitter detection using fast scan cyclic voltammetry and electrophysiological recordings while simultaneously performing electrical stimulation. Additionally, the presented DBS technology shows no imaging artefacts in magnetic resonance imaging. Thus, we present a promising new tool that might lead to a better fundamental understanding of the underlying mechanism of DBS while simultaneously paving our way towards better treatments.

Graphitic Carbon Electrodes on Flexible Substrate for Neural Applications Entirely Fabricated Using Infrared Nanosecond Laser Technology.

Neural interfaces for neuroscientific research are nowadays mainly manufactured using standard microsystems engineering technologies which are incompatible with the integration of carbon as electrode material. In this work, we investigate a new method to fabricate graphitic carbon electrode arrays on flexible substrates. The devices were manufactured using infrared nanosecond laser technology for both patterning all components and carbonizing the electrode sites. Two laser pulse repetition frequencies were used for carbonization with the aim of finding the optimum. Prototypes of the devices were evaluated in vitro in 30 mM hydrogen peroxide to mimic the post-surgery oxidative environment. The electrodes were subjected to 10 million biphasic pulses (39.5 µC/cm2) to measure their stability under electrical stress. Their biosensing capabilities were evaluated in different concentrations of dopamine in phosphate buffered saline solution. Raman spectroscopy and x-ray photoelectron spectroscopy analysis show that the atomic percentage of graphitic carbon in the manufactured electrodes reaches the remarkable value of 75%. Results prove that the infrared nanosecond laser yields activated graphite electrodes that are conductive, non-cytotoxic and electrochemically inert. Their comprehensive assessment indicates that our laser-induced carbon electrodes are suitable for future transfer into in vivo studies, including neural recordings, stimulation and neurotransmitters detection.

Multilayer poly(3,4-ethylenedioxythiophene)-dexamethasone and poly(3,4-ethylenedioxythiophene)-polystyrene sulfonate-carbon nanotubes coatings on glassy carbon microelectrode arrays for controlled drug release.

The authors present an electrochemically controlled, drug releasing neural interface composed of a glassy carbon (GC) microelectrode array combined with a multilayer poly(3,4-ethylenedioxythiophene) (PEDOT) coating. The system integrates the high stability of the GC electrode substrate, ideal for electrical stimulation and electrochemical detection of neurotransmitters, with the on-demand drug-releasing capabilities of PEDOT-dexamethasone compound, through a mechanically stable interlayer of PEDOT-polystyrene sulfonate (PSS)-carbon nanotubes (CNT). The authors demonstrate that such interlayer improves both the mechanical and electrochemical properties of the neural interface, when compared with a single PEDOT-dexamethasone coating. Moreover, the multilayer coating is able to withstand 10 × 106 biphasic pulses and delamination test with negligible change to the impedance spectra. Cross-section scanning electron microscopy images support that the PEDOT-PSS-CNT interlayer significantly improves the adhesion between the GC substrate and PEDOT-dexamethasone coating, showing no discontinuities between the three well-interconnected layers. Furthermore, the multilayer coating has superior electrochemical properties, in terms of impedance and charge transfer capabilities as compared to a single layer of either PEDOT coating or the GC substrate alone. The authors verified the drug releasing capabilities of the PEDOT-dexamethasone layer when integrated into the multilayer interface through repeated stimulation protocols in vitro, and found a pharmacologically relevant release of dexamethasone.

Highly Stable Glassy Carbon Interfaces for Long-Term Neural Stimulation and Low-Noise Recording of Brain Activity.

We report on the superior electrochemical properties, in-vivo performance and long term stability under electrical stimulation of a new electrode material fabricated from lithographically patterned glassy carbon. For a direct comparison with conventional metal electrodes, similar ultra-flexible, micro-electrocorticography (µ-ECoG) arrays with platinum (Pt) or glassy carbon (GC) electrodes were manufactured. The GC microelectrodes have more than 70% wider electrochemical window and 70% higher CTC (charge transfer capacity) than Pt microelectrodes of similar geometry. Moreover, we demonstrate that the GC microelectrodes can withstand at least 5 million pulses at 0.45 mC/cm2 charge density with less than 7.5% impedance change, while the Pt microelectrodes delaminated after 1 million pulses. Additionally, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) was selectively electrodeposited on both sets of devices to specifically reduce their impedances for smaller diameters (<60 µm). We observed that PEDOT-PSS adhered significantly better to GC than Pt, and allowed drastic reduction of electrode size while maintaining same amount of delivered current. The electrode arrays biocompatibility was demonstrated through in-vitro cell viability experiments, while acute in vivo characterization was performed in rats and showed that GC microelectrode arrays recorded somatosensory evoked potentials (SEP) with an almost twice SNR (signal-to-noise ratio) when compared to the Pt ones.

Electrical and mechanical characterisation of single wall carbon nanotubes based composites for tissue engineering applications.

This paper presents the realisation of conductive matrices for application to tissue engineering research. We used poly(L-lactide (PLLA)), poly(epsilon-caprolactone) (PCL), and poly(lactide-co-glycolide) (PLGA) as polymer matrix, because they are biocompatible and biodegradable. The conductive property was integrated to them by adding single wall carbon nanotubes (SWNTs) into the polymer matrix. Several SWNTs concentrations were introduced aiming to understand how they influence and modulate mechanical properties, impedance features and electric percolation threshold of polymer matrix. It was observed that a concentration of 0.3% was able to transform insulating matrix into conductive one. Furthermore, a conductive model of the SWNT/polymer was developed by applying power law of percolation threshold.