fabrication-ti3c2-mxene-microelectrode-arrays-for-vivo-neural

Fabrication of Ti3C2 MXene Microelectrode Arrays for In Vivo Neural Recording

Implantable microelectrode technologies have been widely used to elucidate neural dynamics at the microscale to gain a deeper understanding of the neural ...

University of Pennsylvania

Corporal Michael J. Crescenz Veterans Affairs Medical Center

Department of Physical Medicine and Rehabilitation

Implanting subdural and penetrating electrodes in the brain causes acute trauma and inflammation that affect intracranial electroencephalographic (iEEG) recordings. This behavior and its potential impact on clinical decision-making and algorithms for implanted devices have not been assessed in detail. In this study we aim to characterize the temporal and spatial variability of continuous, prolonged human iEEG recordings.

Intracranial EEG fluctuates over months after implanting electrodes in human brain.

The chemistry that governs the dissolution of device-grade, monocrystalline silicon nanomembranes into benign end products by hydrolysis serves as the foundation for fully eco/biodegradable classes of high-performance electronics. This paper examines these processes in aqueous solutions with chemical compositions relevant to groundwater and biofluids. The results show that the presence of Si(OH) and proteins in these solutions can slow the rates of dissolution and that ion-specific effects associated with Ca can significantly increase these rates. This information allows for effective use of silicon nanomembranes not only as active layers in eco/biodegradable electronics but also as water barriers capable of providing perfect encapsulation until their disappearance by dissolution. The time scales for this encapsulation can be controlled by introduction of dopants into the Si and by addition of oxide layers on the exposed surfaces.The former possibility also allows the doped silicon to serve as an electrical interface for measuring biopotentials, as demonstrated in fully bioresorbable platforms for in vivo neural recordings. This collection of findings is important for further engineering development of water-soluble classes of silicon electronics.

Dissolution of Monocrystalline Silicon Nanomembranes and Their Use as Encapsulation Layers and Electrical Interfaces in Water-Soluble Electronics.

New devices that use targeted electrical stimulation to treat refractory localization-related epilepsy have shown great promise, although it is not well known which targets most effectively prevent the initiation and spread of seizures. To better understand how the brain transitions from healthy to seizing on a local scale, we induced focal epileptiform activity in the visual cortex of five anesthetized cats with local application of the GABA blocker picrotoxin while simultaneously recording local field potentials on a high-resolution electrocorticography array and laminar depth probes. Epileptiform activity appeared in the form of isolated events, revealing a consistent temporal pattern of ictogenesis across animals with interictal events consistently preceding the appearance of seizures. Based on the number of spikes per event, there was a natural separation between seizures and shorter interictal events. Two distinct spatial regions were seen: an epileptic focus that grew in size as activity progressed, and an inhibitory surround that exhibited a distinct relationship with the focus both on the surface and in the depth of the cortex. Epileptiform activity in the cortical laminae was seen concomitant with activity on the surface. Focus spikes appeared earlier on electrodes deeper in the cortex, suggesting that deep cortical layers may be integral to recruiting healthy tissue into the epileptic network and could be a promising target for interventional devices. Our study may inform more effective therapies to prevent seizure generation and spread in localization-related epilepsies. NEW & NOTEWORTHY We induced local epileptiform activity and recorded continuous, high-resolution local field potentials from the surface and depth of the visual cortex in anesthetized cats. Our results reveal a consistent pattern of ictogenesis, characterize the spatial spread of the epileptic focus and its relationship with the inhibitory surround, and show that focus activity within events appears earliest in deeper cortical layers. These findings have potential implications for the monitoring and treatment of refractory epilepsy.

Spatiotemporal evolution of focal epileptiform activity from surface and laminar field recordings in cat neocortex.

High-resolution neural interfaces are essential tools for studying and modulating neural circuits underlying brain function and disease. Because electrodes are miniaturized to achieve higher spatial resolution and channel count, maintaining low impedance and high signal quality becomes a significant challenge. Nanostructured materials can address this challenge because they combine high electrical conductivity with mechanical flexibility and can interact with biological systems on a molecular scale. Unfortunately, fabricating high-resolution neural interfaces from nanostructured materials is typically expensive and time-consuming and does not scale, which precludes translation beyond the benchtop. Two-dimensional (2D) TiC MXene possesses a combination of remarkably high volumetric capacitance, electrical conductivity, surface functionality, and processability in aqueous dispersions distinct among carbon-based nanomaterials. Here, we present a high-throughput microfabrication process for constructing TiC neuroelectronic devices and demonstrate their superior impedance and in vivo neural recording performance in comparison with standard metal microelectrodes. Specifically, when compared to gold microelectrodes of the same size, TiC electrodes exhibit a 4-fold reduction in interface impedance. Furthermore, intraoperative in vivo recordings from the brains of anesthetized rats at multiple spatial and temporal scales demonstrate that TiC electrodes exhibit lower baseline noise, higher signal-to-noise ratio, and reduced susceptibility to 60 Hz interference than gold electrodes. Finally, in neuronal biocompatibility studies, neurons cultured on TiC are as viable as those in control cultures, and they can adhere, grow axonal processes, and form functional networks. Overall, our results indicate that TiC MXene microelectrodes have the potential to become a powerful platform technology for high-resolution biological interfaces.

Two-Dimensional TiC MXene for High-Resolution Neural Interfaces.

Intracranial electrodes are a vital component of implantable neurodevices, both for acute diagnostics and chronic treatment with open and closed-loop neuromodulation. Their performance is hampered by acute implantation trauma and chronic inflammation in response to implanted materials and mechanical mismatch between stiff synthetic electrodes and pulsating, natural soft host neural tissue. Flexible electronics based on thin polymer films patterned with microscale conductive features can help alleviate the mechanically induced trauma; however, this strategy alone does not mitigate inflammation at the device-tissue interface. In this study, we propose a biomimetic approach that integrates microscale extracellular matrix (ECM) coatings on microfabricated flexible subdural microelectrodes. Taking advantage of a high-throughput process employing micro-transfer molding and excimer laser micromachining, we fabricate multi-channel subdural microelectrodes primarily composed of ECM protein material and demonstrate that the electrochemical and mechanical properties match those of standard, uncoated controls. In vivo ECoG recordings in rodent brain confirm that the ECM microelectrode coatings and the protein interface do not alter signal fidelity. Astrogliotic, foreign body reaction to ECM coated devices is reduced, compared to uncoated controls, at 7 and 30 days, after subdural implantation in rat somatosensory cortex. We propose microfabricated, flexible, biomimetic electrodes as a new strategy to reduce inflammation at the device-tissue interface and improve the long-term stability of implantable subdural electrodes.

Biomimetic extracellular matrix coatings improve the chronic biocompatibility of microfabricated subdural microelectrode arrays.

Intracortical neural microelectrodes, which can directly interface with local neural microcircuits with high spatial and temporal resolution, are critical for neuroscience research, emerging clinical applications, and brain computer interfaces (BCI). However, clinical applications of these devices remain limited mostly by their inability to mitigate inflammatory reactions and support dense neuronal survival at their interfaces. Herein we report the development of microelectrodes primarily composed of extracellular matrix (ECM) proteins, which act as a bio-compatible and an electrochemical interface between the microelectrodes and physiological solution. These ECM-microelectrodes are batch fabricated using a novel combination of micro-transfer-molding and excimer laser micromachining to exhibit final dimensions comparable to those of commercial silicon-based microelectrodes. These are further integrated with a removable insertion stent which aids in intracortical implantation. Results from electrochemical models and in vivo recordings from the rat's cortex indicate that ECM encapsulations have no significant effect on the electrochemical impedance characteristics of ECM-microelectrodes at neurologically relevant frequencies. ECM-microelectrodes are found to support a dense layer of neuronal somata and neurites on the electrode surface with high neuronal viability and exhibited markedly diminished neuroinflammation and glial scarring in early chronic experiments in rats.

Microfabricated intracortical extracellular matrix-microelectrodes for improving neural interfaces.

Impaired myocardial conduction is the underlying mechanism for re-entrant arrhythmias. Carbon nanotube fibers (CNTfs) combine the mechanical properties of suture materials with the conductive properties of metals and may form a restorative solution to impaired myocardial conduction.

In Vivo Restoration of Myocardial Conduction With Carbon Nanotube Fibers.

Cancer is one of the leading causes of death in the world. Therefore, the development of new advanced and targeted strategies in cancer research for early diagnosis and treatment has become essential to improve diagnosis outcomes and reduce therapy side effects. Graphene and more recently, MXene, are the main representatives of the family of two-dimensional (2D) materials and are widely studied as multimodal nanoplatforms for cancer diagnostics and treatment, in particular leveraging their potentialities as photodynamic therapeutic agents. Indeed, due to their irreplaceable physicochemical properties, they are virtuous allies for photodynamic therapy (PDT) in combination with bioimaging, photothermal therapy, as well as drug and gene delivery. In this review, the rapidly progressing literature related to the use of these promising 2D materials for cancer theranostics is described in detail, highlighting all their possible future advances in PDT.

Article	Year
Intracranial EEG fluctuates over months after implanting electrodes in human brain. Journal of neural engineering\| PubMed ID: 28862995	2017
Dissolution of Monocrystalline Silicon Nanomembranes and Their Use as Encapsulation Layers and Electrical Interfaces in Water-Soluble Electronics. ACS nano\| PubMed ID: 29178798	2017
Spatiotemporal evolution of focal epileptiform activity from surface and laminar field recordings in cat neocortex. Journal of neurophysiology\| PubMed ID: 29488838	2018
Two-Dimensional TiC MXene for High-Resolution Neural Interfaces. ACS nano\| PubMed ID: 30207690	2018
Biomimetic extracellular matrix coatings improve the chronic biocompatibility of microfabricated subdural microelectrode arrays. PloS one\| PubMed ID: 30383805	2018
Microfabricated intracortical extracellular matrix-microelectrodes for improving neural interfaces. Microsystems & nanoengineering\| PubMed ID: 31057918	2018
In Vivo Restoration of Myocardial Conduction With Carbon Nanotube Fibers. Circulation. Arrhythmia and electrophysiology\| PubMed ID: 31401852	2019
Photodynamic Therapy Based on Graphene and MXene in Cancer Theranostics. Frontiers in bioengineering and biotechnology\| PubMed ID: 31709252	2019

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