Neuroelectronic interfacing with cultured multielectrode arrays toward a cultured probe

Efficient and selective electrical stimulation and recording of neural activity in peripheral, spinal, or central pathways requires multielectrode arrays at micrometer scale. ¿Cultured probe¿ devices are being developed, i.e., cell-cultured planar multielectrode arrays (MEAs). They may enhance efficiency and selectivity because neural cells have been grown over and around each electrode site as electrode-specific local networks. If, after implantation, collateral sprouts branch from a motor fiber (ventral horn area) and if they can be guided and contacted to each ¿host¿ network, a very selective and efficient interface will result. Four basic aspects of the design and development of a cultured probe, coated with rat cortical or dorsal root ganglion neurons, are described. First, the importance of optimization of the cell-electrode contact is presented. It turns out that impedance spectroscopy, and detailed modeling of the electrode-cell interface, is a very helpful technique, which shows whether a cell is covering an electrode and how strong the sealing is. Second, the dielectrophoretic trapping method directs cells efficiently to desired spots on the substrate, and cells remain viable after the treatment. The number of cells trapped is dependent on the electric field parameters and the occurrence of a secondary force, a fluid flow (as a result of field-induced heating). It was found that the viability of trapped cortical cells was not influenced by the electric field. Third, cells must adhere to the surface of the substrate and form networks, which are locally confined, to one electrode site. For that, chemical modification of the substrate and electrode areas with various coatings, such as polyethyleneimine (PEI) and fluorocarbon monolayers promotes or inhibits adhesion of cells. Finally, it is shown how PEI patterning, by a stamping technique, successfully guides outgrowth of collaterals from a neonatal rat lumbar spinal cord explant, after six days in cultur

W:Ti flexible transversal electrode array for peripheral nerve stimulation: a feasibility study

The development of hardware for neural interfacing remains a technical challenge. We introduce a flexible, transversal intraneural tungsten:titanium electrode array for acute studies. We characterize the electrochemical properties of this new combination of tungsten and titanium using cyclic voltammetry and electrochemical impedance spectroscopy. With an in-vivo rodent study, we show that the stimulation of peripheral nerves with this electrode array is possible and that more than half of the electrode contacts can yield a stimulation selectivity index of 0.75 or higher at low stimulation currents. This feasibility study paves the way for the development of future cost-effective and easy-to-fabricate neural interfacing electrodes for acute settings, which ultimately can inform the development of technologies that enable bi-directional communication with the human nervous system

Bringing sensation to prosthetic hands—chronic assessment of implanted thin-film electrodes in humans

Direct stimulation of peripheral nerves with implantable electrodes successfully provided sensory feedback to amputees while using hand prostheses. Longevity of the electrodes is key to success, which we have improved for the polyimide-based transverse intrafascicular multichannel electrode (TIME). The TIMEs were implanted in the median and ulnar nerves of three trans-radial amputees for up to six months. We present a comprehensive assessment of the electrical properties of the thin-film metallization as well as material status post explantationem. The TIMEs stayed within the electrochemical safe limits while enabling consistent and precise amplitude modulation. This lead to a reliable performance in terms of eliciting sensation. No signs of corrosion or morphological change to the thin-film metallization of the probes was observed by means of electrochemical and optical analysis. The presented longevity demonstrates that thin-film electrodes are applicable in permanent implant systems

Mechanism of peripheral nerve modulation and recent applications

Neuromodulation is a multi-interdisciplinary field of neuroscience, neural engineering, and medicine in a complex, but a way of understanding. Recently, the interest and researches in this field have been attracted due to its promising applications such as bionic limbs and bioelectronic medicine. For easier entry into this field, in this review, we approach the basic mechanism, methods, and applications of peripheral neuromodulation sequentially. Firstly, the overall structure and functions of the human nervous system are introduced, especially in the peripheral nervous system (PNS). Specifically, the fundamental neurophysiology regarding action potentials and neural signals is introduced to understand the communication between the neurons. Thereafter, two main methods for peripheral neuromodulation, which are electrical and optogenetic approaches, are introduced with the principles of the state-of-art devices. Finally, advanced applications of neuromodulation combined with the sensor, stimulator, and controller, called a closed-loop system are introduced with an example of bionic limbs. © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.1

Neural Interfacing with Dorsal Root Ganglia: Anatomical Characterization and Electrophysiological Recordings with Novel Electrode Arrays

Dorsal root ganglia (DRG), the hubs of neurons conducting sensory information into the spinal cord, are promising targets for clinical and investigative neural interface technologies. DRG stimulation is currently a tertiary therapy for chronic pain patients, which has an estimated prevalence of 11-40% of adults in the United States. In pre-clinical studies, combined neural recording and stimulation at DRG has been used as part of closed-loop systems to drive activity of the limbs and the urinary system. This suggests a role for clinical DRG interfaces to assist, among other patient groups, the nearly 300,000 spinal cord injured patients in the United States. To maximize the utility of DRG interfaces, however, there remains a strong need to improve our understanding of DRG structure. Neural interface technologies for both stimulation and recording rely heavily on the spatial organization of their neural targets. To record high-fidelity neural signals, a microelectrode must be placed within about 200 µm of a neural cell body. Likewise, effective neural stimulation is believed to act on a subset of DRG axons based on their size and target. The spatial organization of DRG, however, has not been previously quantified. In this thesis, I demonstrate a novel algorithm to transform histological cross-sections of DRG to a normalized circular region for quantifying trends across many samples. Using this algorithm on 26 lumbosacral DRG from felines, a common preclinical DRG model, I found that the highest density of neural cell bodies was in the outer 24% radially, primarily at the dorsal aspect. I extended this analysis to a semi-automated cross-DRG analysis in 33 lower lumbar DRG from 10 human donors. I found that the organization of human DRG was similar to felines, with the highest density of cell bodies found in the outer 20-25% of the DRG, depending on spinal level. I also found a trend toward lower small-axon density at the dorsal aspect of L5 DRG, a key region for stimulation applications. To take advantage of this quantitative knowledge of DRG organization, future neural interfaces with DRG will require more advanced technologies. Standard silicon-based electrode arrays, while useful for short-term DRG recordings, ultimately fail in chronic use after several weeks as a result of mechanical mismatch with neural tissue. In this thesis, I demonstrate sensory recording from the surface and interior of sacral DRG during acute surgery using a variety of flexible polyimide microelectrode arrays 4-μm thick and minimum site separation 25 to 40 μm. Using these arrays, I recorded from bladder and somatic afferents with high fidelity. The high density of sites allowed for neural source localization from surface recordings to depths 25 to 107 µm. This finding supports the anatomical analysis suggesting a high density of cell bodies in the dorsal surface region where the surface array was applied. The high site density also allowed for the use of advanced signal processing to decrease analysis time and track neural sources during movement of the array which may occur during future behavioral experiments. This thesis represents significant advances in our understanding of DRG and how to interface with them, particularly related to the way anatomy can inform development of future technologies. Going forward, it will be important to expand the anatomical maps based on organ function and to test the novel flexible arrays in chronic implant experiments.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/153477/1/zsperry_1.pd

An Investigation of Sensory Percepts Elicited by Macro-Sieve Electrode Stimulation of the Rat Sciatic Nerve

Intuitive control of conventional prostheses is hampered by their inability to replicate the rich tactile and proprioceptive feedback afforded by natural sensory pathways. Electrical stimulation of residual nerve tissue is a promising means of reintroducing sensory feedback to the central nervous system. The macro-sieve electrode (MSE) is a candidate interface to amputees’ truncated peripheral nerves whose unique geometry enables selective control of the complete nerve cross-section. Unlike previously studied interfaces, the MSE’s implantation entails transection and subsequent regeneration of the target nerve. Therefore, a key determinant of the MSE’s suitability for this task is whether it can elicit sensations at low current levels in the face of altered axon morphology and caliber distribution inherent to nerve regeneration. This dissertation describes a combined rat sciatic nerve and behavioral model that was developed to answer this question. Four rats learned a go/no-go detection task with auditory stimuli and then underwent surgery to implant the MSE in the sciatic nerve. After healing, they returned to behavioral training and transferred their attention to monopolar electrical stimuli presented in one multi-channel and eight single-channel stimulus configurations. Current amplitudes varied based on the method of constant stimuli (MCS). A subset of single-channel configurations was tested longitudinally at two timepoints spaced three weeks apart. Psychometric curves generated for each dataset enabled the calculation of 50% detection thresholds and associated slopes. For a given rat, the multi-channel configuration’s per-channel current requirement for stimulus detection was lower than all corresponding single-channel thresholds. Single-channel thresholds for leads located near the nerve’s center were, on average, half those of leads located more peripherally. Of the five leads tested longitudinally, three had thresholds that decreased or remained stable over the three-week span. The remaining two leads’ thresholds showed a significant increase, possibly due to scarring or device failure. Overall, thresholds for stimulus detection were comparable with more traditional penetrative electrode implants, suggesting that the MSE is indeed viable as a sensory feedback interface. These results represent an important first step in establishing the MSE’s suitability as a sensory feedback interface for integration with prosthetic systems. More broadly, it lays the groundwork for future experiments that will extend the described model to the study of other devices, stimulus parameters, and task paradigms