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. 2021 Nov 5:15:761525.
doi: 10.3389/fnins.2021.761525. eCollection 2021.

Improving Deep Brain Stimulation Electrode Performance in vivo Through Use of Conductive Hydrogel Coatings

Tomoko Hyakumura  1   2 , Ulises Aregueta-Robles  3 , Wenlu Duan  3 , Joel Villalobos  1   2 , Wendy K Adams  1 , Laura Poole-Warren  3   4 , James B Fallon  1   2
Affiliations

Improving Deep Brain Stimulation Electrode Performance in vivo Through Use of Conductive Hydrogel Coatings

Tomoko Hyakumura et al. Front Neurosci. .

Abstract

Active implantable neurological devices like deep brain stimulators have been used over the past few decades to treat movement disorders such as those in people with Parkinson's disease and more recently, in psychiatric conditions like obsessive compulsive disorder. Electrode-tissue interfaces that support safe and effective targeting of specific brain regions are critical to success of these devices. Development of directional electrodes that activate smaller volumes of brain tissue requires electrodes to operate safely with higher charge densities. Coatings such as conductive hydrogels (CHs) provide lower impedances and higher charge injection limits (CILs) than standard platinum electrodes and support safer application of smaller electrode sizes. The aim of this study was to examine the chronic in vivo performance of a new low swelling CH coating that supports higher safe charge densities than traditional platinum electrodes. A range of hydrogel blends were engineered and their swelling and electrical performance compared. Electrochemical performance and stability of high and low swelling formulations were compared during insertion into a model brain in vitro and the formulation with lower swelling characteristics was chosen for the in vivo study. CH-coated or uncoated Pt electrode arrays were implanted into the brains of 14 rats, and their electrochemical performance was tested weekly for 8 weeks. Tissue response and neural survival was assessed histologically following electrode array removal. CH coating resulted in significantly lower voltage transient impedance, higher CIL, lower electrochemical impedance spectroscopy, and higher charge storage capacity compared to uncoated Pt electrodes in vivo, and this advantage was maintained over the 8-week implantation. There was no significant difference in evoked potential thresholds, signal-to-noise ratio, tissue response or neural survival between CH-coated and uncoated Pt groups. The significant electrochemical advantage and stability of CH coating in the brain supports the suitability of this coating technology for future development of smaller, higher fidelity electrode arrays with higher charge density requirement.

Keywords: conductive hydrogel; deep brain stimulation; electrical properties; electrode coating; neural stimulation; tissue response.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Rat DBS electrode arrays, uncoated (top) and CH-coated (bottom) (scale bar, 1 mm).
FIGURE 2
FIGURE 2
(A) Flow chart of tests and treatment performed on DBS arrays. Four arrays were tested in total, two coated with the low swelling formulation (LS), and two coated with the high swelling formulation (HS). The electrochemical performance of uncoated DBS arrays was assessed before and after insertion into the agarose gel to generate baseline Pt Data (1–2). Arrays were then CH-coated and swollen to provide baseline CH properties (3). Following ethylene oxide sterilisation (4) the in-agarose gel testing consisted of assessing changes in electrochemical properties following insertion of dry and swollen CH-coated electrodes in agarose gels (5 and 7) compared to baseline (3). Arrays were removed from the agarose gel and assessed in PBS (6 and 8). (B) Biphasic electrode pulse (top) and voltage transient of Pt in reference to Ag/AgCl electrode (bottom).
FIGURE 3
FIGURE 3
Effect of number MA groups per PVA chain and PVA-Tau content on hydrogels diameter (A), and volumetric selling ratio (B). Dashed lines represent the HS variant, 100% PVA-Tau 95% confidence intervals (n = 3, N = 9). (C) Polarisation impedance (Zp) and (D) charge storage capacity (CSC) of CH coated MEs. The dotted lines show the 95% confidence intervals for the Zp and CSC levels of uncoated Pt MEs. *0.05 > p > 0.01, ***p < 0.001. Error bars are ± 1 SEM.
FIGURE 4
FIGURE 4
Baseline electrochemical properties of DBS arrays uncoated (n = 4), LS CH-coated (n = 2) and HS CH-coated (n = 2) under equilibrium swelling conditions. The measurements represent the average of the arrays (each array is the average of four electrode sites). Electrochemical testing regime consisted of (A) polarisation impedance (Zp), (B) voltage transient (VT) impedance, (C) charges storage capacity (CSC), and (D) charge injection limit (CIL) determined with a 100 μs biphasic, charge-balanced pulse (D). Error bars are ± 1 SD.
FIGURE 5
FIGURE 5
Electrochemical properties of CH-coated electrode arrays in different conditions. Pt electrode arrays (n = 4) were CH-coated with the low swelling (LS) formulation (n = 2) (blue) or with the high swelling (HS) reference formulation (n = 2) (green). Each data point represent the average of arrays (each array is the average of four electrode sites). (A) polarisation impedance (Zp), (B) voltage transient (VT) impedance, (C) charges storage capacity (CSC), and (D) charge injection limit (CIL). The electrochemical properties were assessed following ethylene oxide sterilisation, (ETO) then upon insertion in agarose gels with the CH coating dry (Inserted Dry). Arrays were removed, assessed (Removed) and then inserted with the CH coating swollen (Inserted Swollen) in a new agarose gel and removed for a final test.
FIGURE 6
FIGURE 6
Voltage transient (VT) impedance and charge injection limit (CIL) measured in the rat brain. Conductive hydrogel-coated electrodes (CH) or uncoated platinum electrodes (Pt) were implanted in rat brains and electrochemical testing was performed weekly for 8 weeks. The maximum current that can be applied before reaching the potential for water reduction (Emc = –0.6 V) was measured as CIL. VT impedance was calculated from the peak voltage in the first phase of response to fixed current of 100 μA delivered at 100 μs pulse width. Both graphs represent mean ± SD. (A) VT impedance was significantly lower in CH compared with Pt (p < 0.001, three-way ANOVA, 36 CH electrodes, 48 Pt electrodes) across all electrode contacts for the duration of the study. There was significant effect of duration of implantation in Pt (p < 0.001), increasing in the first 2 weeks and decreasing in the final 2 weeks. (B) CIL was significantly higher in CH compared with Pt (p < 0.001, three-way ANOVA, 24 CH electrodes, 28 Pt electrodes) across all electrode contacts for the duration of the study.
FIGURE 7
FIGURE 7
Electrochemical impedance spectroscopy (EIS) measurement in the rat brain. EIS was measured within the frequency range from 100 Hz to 100 kHz using a potentiostat. (A,B) Representative impedance and phase angle measurement of conductive hydrogel-coated (CH) and uncoated platinum (Pt) electrodes at the start (w1, week 1) and end (w8) of chronic implantation. (C–E) All graphs represent mean ± SD. CH electrodes had significantly lower impedance at 100 Hz, 1 kHz, and 10 kHz throughout the duration of the study (p’s < 0.001, three-way ANOVAs, 28 Pt electrodes, 24 CH electrodes). There was no significant effect of duration of implantation or electrode contacts at all three frequencies (p’s > 0.4).
FIGURE 8
FIGURE 8
Charge storage capacity (CSC) of conductive hydrogel-coated (CH) and uncoated platinum (Pt) electrodes tested weekly in the rat brain. Cyclic voltammetry was measured between –0.6 and 0.8 V for six cycles using a potentiostat. CSC was calculated as the average area inside the cyclic voltammetry traces. (A) Representative cyclic voltammetry traces of CH and Pt electrodes at the start (w1) and the end (w8) of chronic implantation. (B) Mean charge storage capacity ± SD measured in vivo. CH had significantly higher charge storage capacity (p < 0.001, three-way ANOVA, 28 Pt electrodes, 24 CH electrodes) across all the electrode contacts for the duration of the study. There was no significant effect of duration of implantation (p = 0.106), or interaction between coating and duration of implantation (p = 0.108).
FIGURE 9
FIGURE 9
Evoked potential threshold measured weekly and signal to noise ratio at the start and end of the study. Rats implanted with DBS electrode arrays with conductive hydrogel-coated (CH) or uncoated platinum (Pt) electrodes were stimulated with burst of 10 pulses at 80 Hz at different current levels (100–650 μA) to record evoked responses (A′). Graphs represent mean ± SD. (A) Evoked response threshold was not significantly affected by CH coating throughout the duration of the study (p = 0.206, two-way ANOVA, 3–4 rats for Pt and CH). There was no significant effect of duration of implantation (p = 0.470), or interaction between coating and week (p = 0.636). (B) Signal to noise ratio was calculated from the amplitude of evoked response at 650 μA stimulation compare to a sub-threshold stimulus. Signal to noise ratio was not significantly affected by CH coating (p = 0.443, two-way ANOVA, 7 rats for Pt, 4 rats for CH). There was no significant difference between start and end signal to noise ratio (p = 0.189).
FIGURE 10
FIGURE 10
Tissue response and neural survival at the site of implantation in the rat brain implanted with conductive hydrogel-coated (CH) or uncoated platinum (Pt) electrodes. The brains were sectioned and immunostained for glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) to assess tissue response and neural survival (10 rats for Pt and 6 rats for CH). All graphs represent mean ± SD. (A) Representative images of GFAP and NeuN immunostaining in the rat brains implanted with Pt and CH electrodes. Scale bar, 200 μm. (B) GFAP fluorescence was significantly higher near the implant (p < 0.001), but was not significantly affected by CH coating (I, implanted; N, non-implanted; p = 0.387, two-way ANOVA). (C) The relative number of NeuN positive cells (neurons) to non-implanted were significantly reduced near the implant compared to the area further away from the implant (p < 0.001), but was not significantly affected by CH coating (p = 0.352, two-way ANOVA).
FIGURE 11
FIGURE 11
Delaminated CH coating in the rat brain. After tissue fixation and electrode array removal, the brains were sectioned and stained with cresyl violet. This is an example of delaminated CH coating remaining in the brain after electrode array removal (A, red arrows). Higher magnification images (B,C) show that the CH coating delaminated in large pieces. Scale bar (A) = 1 mm (applies to A), scale bar (B) = 200 μm (applies to B,C).
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