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. 2017 Feb;14(1):016008.
doi: 10.1088/1741-2552/14/1/016008. Epub 2016 Dec 9.

Rodent Model for Assessing the Long Term Safety and Performance of Peripheral Nerve Recording Electrodes

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Free PMC article

Rodent Model for Assessing the Long Term Safety and Performance of Peripheral Nerve Recording Electrodes

Srikanth Vasudevan et al. J Neural Eng. .
Free PMC article

Abstract

Objective: In the US alone, there are approximately 185 000 cases of limb amputation annually, which can reduce the quality of life for those individuals. Current prosthesis technology could be improved by access to signals from the nervous system for intuitive prosthesis control. After amputation, residual peripheral nerves continue to convey motor signals and electrical stimulation of these nerves can elicit sensory percepts. However, current technology for extracting information directly from peripheral nerves has limited chronic reliability, and novel approaches must be vetted to ensure safe long-term use. The present study aims to optimize methods to establish a test platform using rodent model to assess the long term safety and performance of electrode interfaces implanted in the peripheral nerves.

Approach: Floating Microelectrode Arrays (FMA, Microprobes for Life Sciences) were implanted into the rodent sciatic nerve. Weekly in vivo recordings and impedance measurements were performed in animals to assess performance and physical integrity of electrodes. Motor (walking track analysis) and sensory (Von Frey) function tests were used to assess change in nerve function due to the implant. Following the terminal recording session, the nerve was explanted and the health of axons, myelin and surrounding tissues were assessed using immunohistochemistry (IHC). The explanted electrodes were visualized under high magnification using scanning electrode microscopy (SEM) to observe any physical damage.

Main results: Recordings of axonal action potentials demonstrated notable session-to-session variability. Impedance of the electrodes increased upon implantation and displayed relative stability until electrode failure. Initial deficits in motor function recovered by 2 weeks, while sensory deficits persisted through 6 weeks of assessment. The primary cause of failure was identified as lead wire breakage in all of animals. IHC indicated myelinated and unmyelinated axons near the implanted electrode shanks, along with dense cellular accumulations near the implant site. Scanning electron microscopy (SEM) showed alterations of the electrode insulation and deformation of electrode shanks.

Significance: We describe a comprehensive testing platform with applicability to electrodes that record from the peripheral nerves. This study assesses the long term safety and performance of electrodes in the peripheral nerves using a rodent model. Under this animal test platform, FMA electrodes record single unit action potentials but have limited chronic reliability due to structural weaknesses. Future work will apply these methods to other commercially-available and novel peripheral electrode technologies.

Figures

Figure 1
Figure 1. Implant design and surgical procedure
(A) The connector mount was secured to the lumbar fascia and the FMA array and EMG wires were tunneled to the implant site. FMA electrode is shown implanted into the sciatic nerve and the ground wire is inserted into an adjacent muscle. (B) Custom designed connector mount designed to support two Omnetics connectors, for the FMA and for the EMG wires. (C) A schematic depicting the FMA array layout with 16 electrodes, a reference (R) and ground (G). (D) Implant assembly with blue arrows indicating observed breakage points for both EMG wires and FMA lead wire.
Figure 2
Figure 2. Electrochemical impedance spectroscopy of electrodes before and during implantation
(A) Heat map reflecting impedance at 1 kHz of individual electrodes before implantation (PRE), one hour after implantation (POST), and weekly, starting two weeks post-implantation until device failure. (B) Average data plot showing impedance of functional channels in each electrode over time (The bars for each animal signify measurements taken PRE, POST, and weekly until device failure, as in part A). (C) The number of functional channels over time for all 5 implanted FMAs. Functional channels are defined as those with impedance between 10 kΩ and 2 MΩ.
Figure 3
Figure 3. Recorded action potential signal to noise ratio (SNR) and recording yield over time
(A) Heat maps for individual electrodes showing SNR calculated from the peak-to-peak voltage of the average waveforms during awake state. Variability in SNR over time is seen for all channels. White areas indicate channels with impedance greater than 2 MΩ (non-functional). (B) Trace recorded in FMA-4, channel 16 at two weeks post-implantation and sorted waveform (below) showing neural activity (green) and noise (red). (C) Recording yield was calculated as the ratio of the number of channels with neural activity over the number functional channels for a given recording session. All arrays display session-to-session variation in recording yield, with an overall average of 9% yield across all arrays and recording sessions in the awake state.
Figure 4
Figure 4. Functional changes associated with implantation
(A) Walking track analysis was used to compute the sciatic function index (SFI). The FMA implant cohort shows deficits at 1 week with recovery at 2 weeks. (B) Von Frey test was employed to measure mechanical allodynia shows hypersensitivity in both Sham and FMA implant cohorts, as compared to Control. Hypersensitivity recovers in the Sham cohort by 6 weeks, while full recovery is not achieved for the FMA implant cohort in this time. Data on the graph represented as Mean ± S.E. Statistical differences represented as *P ≤ 0.05, **P ≤ 0.01 and ***P ≤ 0.001.
Figure 5
Figure 5. Tissue response to chronic FMA implantation
Thin sections (~15 μm) of nerve were stained for axons (β-Tubulin), myelin (P0) and cellular nuclei (DAPI). Uninjured nerve (left) provides a control for comparison with nerve from beneath the implanted array from animal FMA-3 (right). One electrode shank is visible inside a fascicle (right of dotted line) and the other one outside of it (left of dotted line) are indicated with a star. While both myelinated (yellow; green+red) and unmyelinated axons (green) surround the intrafascicular electrode shank, the overall axon density is lower than in the uninjured control. Multiple layers of cellular nuclei are accumulated around the shanks and nearby extrafascicular space, as indicated by DAPI staining.
Figure 6
Figure 6. Physical alterations of harvested electrodes with scanning electron microscopy
In all five implanted electrodes (FMA-1 through FMA-5), gross deformation of the electrode shanks is visible. In addition, gaps between metal and insulation and damaged insulation are apparent (white arrows), as are bent electrode tips (yellow arrows). Ground and reference shanks within the electrode are indicated with blue arrows in FMA-5. An unimplanted electrode of slightly different shank length is shown to demonstrate that on receipt from the manufacturer, the electrode shanks are straight, insulation is intact and electrode tips are unbent.

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