In vivo stability and biocompatibility of implanted calcium alginate disks

Alginate is a commonly used biomedical hydrogel whose in vivo degradation behavior is only beginning to be understood. The use of alginate in the central nervous system is gaining popularity as an electrode coating, cell encapsulation matrix, and for duraplasty. However, it is necessary to understand how the hydrogel will behave in vivo to aid in the development of alginate for use as a neural interface material. The goal of the current study was to compare the rheological behavior of explanted alginate disks and the inflammatory response to subcutaneously implanted alginate hydrogels over a 3-month period. Specifically, the effects due to (1) in situ gelling, (2) diffusion gelling, and (3) use of a poly- l -lysine (PLL) coating were investigated. While all samples' complex moduli decreased 80% in the first day, in situ gelled alginate was more stable for the first week of implantation. The PLL coating offered some stability increases for diffusion gelled alginate, but the stability in both conditions remained significantly lower than that in in situ gelled alginate. There were no differences in biocompatibility that clearly suggested one gelation method over another. These results indicate that in situ gelation is the preferred method in neural interface applications where stability is the primary concern. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res 2007Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57402/1/31275_ftp.pd

Conducting-Polymer Nanotubes Improve Electrical Properties, Mechanical Adhesion, Neural Attachment, and Neurite Outgrowth of Neural Electrodes

An in vitro comparison of conducting-polymer nanotubes of poly(3,4-ethylenedioxythiophene) (PEDOT) and poly(pyrrole) (PPy) and to their film counterparts is reported. Impedance, charge-capacity density (CCD), tendency towards delamination, and neurite outgrowth are compared. For the same deposition charge density, PPy films and nanotubes grow relatively faster vertically, while PEDOT films and nanotubes grow more laterally. For the same deposition charge density (1.44 C cm −2 ), PPy nanotubes and PEDOT nanotubes have lower impedance (19.5 ± 2.1 kΩ for PPy nanotubes and 2.5 ± 1.4 kΩ for PEDOT nanotubes at 1 kHz) and higher CCD (184 ± 5.3 mC cm −2 for PPy nanotubes and 392 ± 6.2 mC cm −2 for PEDOT nanotubes) compared to their film counterparts. However, PEDOT nanotubes decrease the impedance of neural-electrode sites by about two orders of magnitude (bare iridium 468.8 ± 13.3 kΩ at 1 kHz) and increase capacity of charge density by about three orders of magnitude (bare iridium 0.1 ± 0.5 mC cm −2 ). During cyclic voltammetry measurements, both PPy and PEDOT nanotubes remain adherent on the surface of the silicon dioxide while PPy and PEDOT films delaminate. In experiments of primary neurons with conducting-polymer nanotubes, cultured dorsal root ganglion explants remain more intact and exhibit longer neurites (1400 ± 95 µm for PPy nanotubes and 2100 ± 150 µm for PEDOT nanotubes) than their film counterparts. These findings suggest that conducting-polymer nanotubes may improve the long-term function of neural microelectrodes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65046/1/421_ftp.pd

Complex impedance spectroscopy for monitoring tissue responses to inserted neural implants

A series of animal experiments was conducted to characterize changes in the complex impedance of chronically implanted electrodes in neural tissue. Consistent trends in impedance changes were observed across all animals, characterized as a general increase in the measured impedance magnitude at 1 kHz. Impedance changes reach a peak approximately 7 days post-implant. Reactive responses around individual electrodes were described using immuno- and histo-chemistry and confocal microscopy. These observations were compared to measured impedance changes. Several features of impedance changes were able to differentiate between confined and extensive histological reactions. In general, impedance magnitude at 1 kHz was significantly increased in extensive reactions, starting about 4 days post-implant. Electrodes with extensive reactions also displayed impedance spectra with a characteristic change at high frequencies. This change was manifested in the formation of a semi-circular arc in the Nyquist space, suggestive of increased cellular density in close proximity to the electrode site. These results suggest that changes in impedance spectra are directly influenced by cellular distributions around implanted electrodes over time and that impedance measurements may provide an online assessment of cellular reactions to implanted devices.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58178/2/jne7_4_007.pd

Use of a Bayesian maximum-likelihood classifier to generate training data for brain–machine interfaces

Brain–machine interface decoding algorithms need to be predicated on assumptions that are easily met outside of an experimental setting to enable a practical clinical device. Given present technological limitations, there is a need for decoding algorithms which (a) are not dependent upon a large number of neurons for control, (b) are adaptable to alternative sources of neuronal input such as local field potentials (LFPs), and (c) require only marginal training data for daily calibrations. Moreover, practical algorithms must recognize when the user is not intending to generate a control output and eliminate poor training data. In this paper, we introduce and evaluate a Bayesian maximum-likelihood estimation strategy to address the issues of isolating quality training data and self-paced control. Six animal subjects demonstrate that a multiple state classification task, loosely based on the standard center-out task, can be accomplished with fewer than five engaged neurons while requiring less than ten trials for algorithm training. In addition, untrained animals quickly obtained accurate device control, utilizing LFPs as well as neurons in cingulate cortex, two non-traditional neural inputs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90824/1/1741-2552_8_4_046009.pd

A finite-element model of the mechanical effects of implantable microelectrodes in the cerebral cortex

The viability of chronic neural microelectrodes for electrophysiological recording and stimulation depends on several factors, including the encapsulation of the implant by a reactive tissue response. We postulate that mechanical strains induced around the implant site may be one of the leading factors responsible for the sustained tissue response in chronic implants. The objectives of this study were to develop a finite-element model of the probe–brain tissue interface and analyze the effects of tethering forces, probe–tissue adhesion and stiffness of the probe substrate on the interfacial strains induced around the implant site. A 3D finite-element model of the probe–brain tissue microenvironment was developed and used to simulate interfacial strains created by ‘micromotion’ of chronically implanted microelectrodes. Three candidate substrates were considered: (a) silicon, (b) polyimide and (c) a hypothetical ‘soft’ material. Simulated tethering forces resulted in elevated strains both at the tip and at the sharp edges of the probe track in the tissue. The strain fields induced by a simulated silicon probe were similar to those induced by a simulated polyimide probe, albeit at higher absolute values for radial tethering forces. Simulations of poor probe–tissue adhesion resulted in elevated strains at the tip and delamination of the tissue from the probe. A tangential tethering force results in 94% reduction in the strain value at the tip of the polyimide probe track in the tissue, whereas the simulated ‘soft’ probe induced two orders of magnitude smaller values of strain compared to a simulated silicon probe. The model results indicate that softer substrates reduce the strain at the probe–tissue interface and thus may also reduce tissue response in chronic implants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49186/2/jne5_4_006.pd

Estimation of electrode location in a rat motor cortex by laminar analysis of electrophysiology and intracortical electrical stimulation

While the development of microelectrode arrays has enabled access to disparate regions of a cortex for neurorehabilitation, neuroprosthetic and basic neuroscience research, accurate interpretation of the signals and manipulation of the cortical neurons depend upon the anatomical placement of the electrode arrays in a layered cortex. Toward this end, this report compares two in vivo methods for identifying the placement of electrodes in a linear array spaced 100 µm apart based on in situ laminar analysis of (1) ketamine–xylazine-induced field potential oscillations in a rat motor cortex and (2) an intracortical electrical stimulation-induced movement threshold. The first method is based on finding the polarity reversal in laminar oscillations which is reported to appear at the transition between layers IV and V in laminar 'high voltage spindles' of the rat cortical column. Analysis of histological images in our dataset indicates that polarity reversal is detected 150.1 ± 104.2 µm below the start of layer V. The second method compares the intracortical microstimulation currents that elicit a physical movement for anodic versus cathodic stimulation. It is based on the hypothesis that neural elements perpendicular to the electrode surface are preferentially excited by anodic stimulation while cathodic stimulation excites those with a direction component parallel to its surface. With this method, we expect to see a change in the stimulation currents that elicits a movement at the beginning of layer V when comparing anodic versus cathodic stimulation as the upper cortical layers contain neuronal structures that are primarily parallel to the cortical surface and lower layers contain structures that are primarily perpendicular. Using this method, there was a 78.7 ± 68 µm offset in the estimate of the depth of the start of layer V. The polarity reversal method estimates the beginning of layer V within ±90 µm with 95% confidence and the intracortical stimulation method estimates it within ±69.3 µm. We propose that these methods can be used to estimate the in situ location of laminar electrodes implanted in the rat motor cortex.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90825/1/1741-2552_8_4_046018.pd

Poly(3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes

We investigated using poly(3,4-ethylenedioxythiophene) (PEDOT) to lower the impedance of small, gold recording electrodes with initial impedances outside of the effective recording range. Smaller electrode sites enable more densely packed arrays, increasing the number of input and output channels to and from the brain. Moreover, smaller electrode sizes promote smaller probe designs; decreasing the dimensions of the implanted probe has been demonstrated to decrease the inherent immune response, a known contributor to the failure of long-term implants. As expected, chronically implanted control electrodes were unable to record well-isolated unit activity, primarily as a result of a dramatically increased noise floor. Conversely, electrodes coated with PEDOT consistently recorded high-quality neural activity, and exhibited a much lower noise floor than controls. These results demonstrate that PEDOT coatings enable electrode designs 15 µm in diameter.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90823/1/1741-2552_8_1_014001.pd

Measuring the Electrical Stapedius Reflex with Stapedius Muscle Electromyogram Recordings

Previous studies have demonstrated a correlation between cochlear implant recipients' comfort levels ( C level, upper limit of dynamic range of stimulation) and the contralateral electrical stapedius reflex (ESR) threshold, detected by acoustic impedance change. However, the utility of the approach is limited because many recipients have no detectable impedance change. The goals of this study were to investigate the utility of the stapedial electromyogram (EMG) for estimating onset and strength of the ESR. Ketamine-anesthetized guinea pigs were implanted with Nucleus electrode arrays and stimulated with biphasic current pulse trains (250 pps) via a Cochlear Corporation CI24M stimulator. Typical EMG recordings (obtained with bipolar microwire electrodes) contained easily detectable unit potentials up to 300 μV in amplitude. Growth response curves (obtained from threshold-crossing counts or rms of the EMG signal) were typically monotonic with dynamic ranges spanning 700 μA or 8 dB. Based on adaptation and temporal properties, the stimulus protocol (500 ms duration with 4–5 s interstimulus intervals) was adequate for producing independent responses. The data presented are consistent with ESR characteristics (acoustic impedance technique) of cochlear implant recipients and with EMG properties of acoustically stimulated guinea pigs. Use of the EMG for characterizing the ESR may eventually be applied to human cochlear implant recipients as a guide in setting the upper limit of the dynamic range. © 2002 Biomedical Engineering Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43999/1/10439_2004_Article_482671.pd