neural-tissue interface

Accepted Manuscript Bioactive interpenetrating polymer networks for improving the electrode/neural-tissue interface

Cheng Zhong, Dingning Ke, Lulu Wang, Yi Lu, Liping Wang PII: DOI: Reference:

S1388-2481(17)30113-3 doi: 10.1016/j.elecom.2017.04.015 ELECOM 5928

To appear in:

Electrochemistry Communications

Received date: Revised date: Accepted date:

29 March 2017 20 April 2017 20 April 2017

Please cite this article as: Cheng Zhong, Dingning Ke, Lulu Wang, Yi Lu, Liping Wang , Bioactive interpenetrating polymer networks for improving the electrode/neural-tissue interface. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Elecom(2017), doi: 10.1016/j.elecom.2017.04.015

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ACCEPTED MANUSCRIPT Bioactive interpenetrating polymer networks for improving the electrode/neural-tissue interface

Cheng Zhong a, b, Dingning Ke c, Lulu Wang a, b , Yi Lu a, 1, Liping Wang a,1

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b University of Chinese Academy of Sciences, Beijing, China

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a CAS Center for Excellence in Brain Science and Intelligence Technology, the Brain Cognition and Brain Disease Institute (BCBDI) for Collaboration Research of SIAT at CAS and the McGovern Institute at MIT, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

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c Experiment and Innovation Center, Harbin Institute of Technology Shenzhen Graduate School, Shenzhen, China

1. Corresponding author. BCBDI, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Boulevard, Xil, Nanshan, Shenzhen 518055, China. Tel.: +86 755 86910600; fax: +86 755 86392299. E-mail address: [email protected] (Yi Lu); [email protected] (LP Wang).

ACCEPTED MANUSCRIPT Abstract

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The neural electrode is recognized as a bridge that transduces electrical signals from or into biosignals and is thus used for various experimental and therapeutic purposes. However, a major challenge that still remains is to achieve long-term effective electrical recording and stimulation in vivo. Here, we report an investigation of electrochemically co-deposited poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate)/nerve growth factor/dexamethasone phosphate/poly(vinyl alcohol)/poly(acrylic acid) interpenetrating polymer networks for improving the electrode/neural-tissue interface. After modification, the electrodes exhibit a substantially higher capacitance and lower electrochemical impedance (reduced by ~96%) at 1 kHz as compared to control electrodes. Furthermore, tissue response was evaluated after a 6-week implantation in the cortex of rats. Relative to the control group, the test group show significantly lower immunostaining intensity for glial fibrillary acidic protein and higher intensity for neuronal nuclei at the electrode/neural-tissue interface. All of these characteristics are greatly desired in chronic electrophysiological applications in vivo.

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Keywords Neural electrodes; Neural implants; Neural interfaces; Anti-inflammatory; Low-impedance; Electrophysiology

ACCEPTED MANUSCRIPT 1. Introduction Understanding the functions of brain networks and the mechanisms underlying neuropsychiatric disorders is one of the ultimate goals of scientists. Because a neural electrode enables both electrical recording and functional stimulation in a localized brain area with millisecond precision [1, 2], it serves as a key element in the dissection [3, 4] or control [5-7] of specific neural populations. However, consistent and effective recording and modulation over a requisite period in vivo continue to pose a major challenge [3, 4].

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Microelectrodes have been widely used to increase spatial precision and minimize insertion trauma. However, the impedance of the electrode increases drastically with a decrease in its geometric size, which subsequently results in high thermal background noise during recording [1]. Moreover, a miniaturized electrode has to endure considerably higher charge-injection density to reach the activation threshold required to evoke a neuronal response. Unfortunately, another major bottleneck that hinders the applications of neural electrodes is the inconsistent performance caused by the inflammatory response [3, 6, 8, 9]. The inflammatory response results in a dense astroglial encapsulation of the implant, which isolates the electrode from the surrounding neurons, and the response also leads to a loss of neurons adjacent to the electrode interface, which further deteriorates the performance of the electrode [6].

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For improving both the electrochemical performance and the biocompatibility of neural electrodes, a commonly applied strategy is surface modification with conducting polymers (CPs). It has been reported that CPs can notably increase the electrode capacitance, reduce impedance, and alleviate inflammatory responses [10-13]. However, the survival and growth of neurons around an electrode are affected by the local microenvironment after implantation, in which a chronic inflammatory response might act as a steering factor; thus, surface modification using CPs alone might be inadequate for producing a long-term functional consequence [14-18].

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In our previous studies, we have demonstrated that hydrogels can be incorporated with conducting polymers to generate conducting polymer/hydrogel interpenetrating polymer networks (CP/HY IPNs), which can improve the performance of the electrode and are highly stable after chronic implantation [19, 20]. On the basis of these results, we investigated whether immobilizing bioactive materials within CP/HY IPNs will create a comparatively more tissue-friendly interface for neural electrodes. We stabilized nerve growth factor (NGF) and dexamethasone sodium phosphate (DEX) in a composite polymer film by electrodepositing them as co-dopants with PEDOT/poly(styrenesulfonate) (PEDOT/PSS) in swollen poly(vinyl alcohol)/poly(acrylic acid) (PVA/PAA) IPN films. The surface morphology was determined by performing atomic force microscopy (AFM). Electrochemical measurements such as cyclic voltammetry (CV) and electrochemical impedance spectrum (EIS) analysis were performed. Lastly, platinum/iridium (Pt/Ir) implants modified with the composite films were implanted into the rat cortex for 6 weeks, and then the astrocyte intensity and neuronal survival around the implant sites were assessed by analyzing immunoreactivity for GFAP and neuronal nuclei (NeuN), respectively. All of these results were evaluated—and are discussed herein—in relation to the requirements of chronic application in vivo.

ACCEPTED MANUSCRIPT 2. Experimental 2.1 Electrodeposition process

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PVA/PAA IPNs were synthesized as described in previous studies [19, 20]. The substrate was coated with a thin layer of PVA/PAA film before use. To prepare the electrodeposition solution, 0.01 M 3,4-ethylenedioxythiophene monomer (EDOT; Sigma-Aldrich) was mixed with 0.25 M poly(sodium 4-styrenesulfonate) (PSSNa; MW = 70,000, Sigma-Aldrich), 10 μg/mL NGF (Sigma-Aldrich), and 10 mM DEX (National Institutes for Food and Drug Control, China). NGF and DEX were electropolymerized with PEDOT/PSS within the swollen PVA/PAA IPNs and onto the substrates to generate the PEDOT/PSS/NGF/DEX/PVA/PAA IPNs (CP/NGF/DEX/HY IPNs) at 0.9 V (vs. SCE). PEDOT/PSS/PVA/PAA (CP/HY), PEDOT/PSS/NGF/PVA/PAA (CP/NGF/HY), and PEDOT/PSS/DEX/PVA/PAA (CP/DEX/HY) IPNs were also fabricated under similar conditions.

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2.2 Physicochemical characterizations

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Pt electrodes (diameter = 100 μm) were used as the substrates in all electrochemical tests. CV and EIS measurements were performed using a potentiostat (Gamry Reference 600). The surface topographies of the films were examined using an AFM instrument (Bruker Dimension 5100).

2.3 Implantation study

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All procedures were conducted in accordance with protocols approved by the Ethics Committee for Animal Research, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences. Adult male SD rats weighing 250–300 g were used. After being anesthetized, two holes were bored at locations -4.0 mm anterior and ±3.0 mm lateral to the bregma in each animal. The brains were slowly implanted with one of 4 types of implants: Pt/Ir implants (Pt/Ir = 9/1, diameter = 200 μm) and Pt/Ir implants modified with CP/NGF/HY, CP/DEX/HY, and CP/NGF/DEX/HY films. At 6 weeks after implantation, the rats were sacrificed and immunohistological analyses were performed, following previous studies [11, 21, 22]. Fluorescence images were obtained using an Olympus IX71 inverted fluorescence microscope. Quantitative analysis was performed using custom software developed in MATLAB (MathWorks). The staining intensities of GFAP and NeuN were calculated as a function of distance up to the implant surface. The statistical significance of differences between groups (t-test p value) is also calculated.

3. Results and Discussion 3.1 Physicochemical characterizations After electrodeposition, the redox currents in the CV were significantly increased (Fig.1A), implying the modified electrode exhibited improved capacitance performance. The CP/HY-modified electrode (Fig. 1A(ii)) shows the emergence of an anodic peak and a cathodic peak at -330 and -400 mV (vs. SCE), respectively. However, the peaks were slightly shifted in the

ACCEPTED MANUSCRIPT CV of the CP/NGF/HY electrode (Fig. 1A(iii)), which might have been caused by the presence of the co-dopant NGF. Interestingly, a new oxidation peak at -120 mV appeared in the CV of the CP/DEX/HY-modified electrode (Fig. 1A(iv)), which may due to the reaction of the doped DEX anions. Notably, in the CV of the CP/NGF/DEX/HY electrode (Fig. 1A(v)), only one oxidization peak at -270 mV was observed; this indicates a relatively higher doped state of the composite film, which suggests that the co-dopants NGF and DEX in the composite films might have participated in the electrodeposition process.

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To study the detailed topography of the surfaces, we performed AFM analysis (Fig. 1B). The root mean square roughness (RRMS) and maximal heights (Hmax) of the CP/ HY film was 20.0 and 149.9 nm, respectively, suggesting a nano-scale porous structure (Fig. 1B(ii)). However, the presence of the co-dopants NGF and DEX resulted in highly different morphologies: The CP/NGF/HY film contained numerous nanoparticles that aggregated into microscale structures (Fig. 1B(iii)), whereas the CP/DEX/HY film showed increased density and markedly reduced roughness (Fig. 1B(iv)). Interestingly, the CP/NGF/DEX/HY film was composed by both nanometer-scale particles and micrometer-scale aggregated structures (Fig. 1B(v)), and this film showed a comparable roughness with the CP/DEX/HY film.

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3.2 EIS analysis

ZCPE= 1/{q(jω)n},

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The impedance at 1 kHz is acritical characteristic parameter for neural electrodes, because the frequency is relevant to the electrical activity of neurons. After deposition, the average impedance values at 1 kHz were decreased from 54.92 kΩ to ~2.0 kΩ, respectively, which is ~96% lower than the Pt electrode (Fig. 2). This drastic reduction in impedance is possibly due to the increase of the pseudo-capacitance and effective surface area at the interface. Furthermore, the equivalent circuit models of the modified interface have also been investigated (Fig. 2A), which comprises these circuit elements [12, 19]: solution resistance (RS), coating capacitance (CC), pore resistance (RP), double-layer constant-phase element (ZCPE), charge-transfer resistance (RT), and finite-length Warburg diffusion impedance (ZD). The ZCPE and ZD are described by the following equations:

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ZD = RDcoth{(jωTD)1/2}/(jωTD)1/2,

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where j = √-1, ω is the angular frequency (rad/s) = 2πf, and f is the frequency in Hz, q indicates the value of the capacitance of the CPE as n approaches 1, n reveals the micro fractal and distribution at the electrode interface, RD is the diffusional resistance, and TD is the diffusional time constant. The average CC of the electrodes modified with CP/HY, CP/NGF/HY, CP/DEX/HY, and CP/NGF/DEX/HY films increased to 0.31, 0.24, 0.22, and 0.26 μF, respectively, which implies an increase in the total amount of electroactive materials at the electrode interface. Moreover, the average CPE-p increased from 8.2 nFsn-1 to 1.79, 1.59, 1.87, and 1.68 μFsn-1, respectively, and the CPE-n values were close to 1. This result suggests that the modified electrodes show close to the optimal capacitance. The RP of these electrodes did not show notable differences. However, the

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RT, RD and TD of the CP/DEX/HY film were all markedly higher than those of other films, implying considerably slower ion transfer in the bulk film, which is consistent with the results of the CV and AFM analysis. Intriguingly, the co-dopant NGF reduced the RT and TD of the films; this result could be attributed to the structural defect of the film caused by the doped NGF, which increased the transfer rate of ions in the bulk IPNs. Furthermore, although the presence of NGF and DEX slightly lowered the CC of the films, other key parameters were not changed substantially. Considering the potential benefits offered by these deposited films during long-term implantation, the decline of the CC after the doping of NGF and DEX is a negligible loss.

3.3 Histology

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After an electrode is implanted into the brain, a host response is subsequently elicited, which results in a dense glial encapsulation (high impedance) and a subsequent loss of neurons adjacent to the electrode interface. We performed immunochemical analysis on tissue sections of rat brain after implantation to evaluate the chronic performance of the distinct films (Fig. 3A). Reactivated astrocytes (GFAP labeled) occupied the zone around the implants in both the control (Pt/Ir, n=18) and the CP/NGF/HY (n=23) groups. Statistical result shows that the GFAP intensity in both the CP/DEX/HY (n=22) and the CP/NGF/DEX/HY (n=17) groups was significantly lower (p < 0.05, t-test) than that in the non-DEX groups up to a distance of~320 µm from the implant interface (Fig. 3B), which could be attributed to the presence of DEX. Besides, neuronal loss was observed around the implants, and this loss was particularly severe in the control group and comparatively less severe in the CP/DEX/HY-modified group. However, the NeuN intensity in both the CP/NGF/HY and CP/DEX/NGF/HY groups was markedly higher than that in the control group (p < 0.05 within ~100 µm, t-test) and the CP/DEX/HY-modified group (p < 0.05 within ~50 µm, t-test). This result suggests that neuron viability was significantly enhanced at the interface of the NGF-doped composite-film-modified implants, and the findings collectively imply that the CP/NGF/DEX/HY film can improve the implant/neural-tissue interface and is suitable for long-term implantations.

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In this study, we demonstrated the feasibility and advantages of using a co-deposited CP/NGF/DEX/HY film for improving the electrode/neural-tissue interface. The composite film exhibited markedly higher capacitance and lower impedance as compared to Pt electrodes, which also showed similar diffusion impedance as compared to the pure CP film. This may be partially attributed to the porous structure of the deposited films. Furthermore, we verified the bioactive function of the deposited films and found that the films potently alleviated the inflammatory response and improved neuronal survival at the interface after implantation. All of these characteristics are crucial for the chronic implants used for precisely timed analyses or stimulation of neurons in vivo. Overall, this work has demonstrated considerable potential for combining CPs with hydrogels and bioactive materials into the neural-electrode interface. Although some of the results in this work have shown improved outcomes, neural-electrode technology is currently facing new challenges that must be overcome to meet the daunting goal

ACCEPTED MANUSCRIPT of providing consistent performance in neural circuit dissection, brain-computer interfaces, and neural prostheses.

Acknowledgments

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This research was partially sponsored by the 863 Program (2015AA020512), the NSFC Program (81100976, 31630031), the “Strategic Priority Research Program (XDB02050003)” and the "Youth Innovation Promotion Association" of the CAS, the Shenzhen Governmental Research Grants (JSGG20160429184327274, LSGG20160428140402911, JCYJ20150401145529023, JCYJ20150529143500959), and the “Shenzhen Engineering Lab for Brain Activity Mapping Technologies.”

ACCEPTED MANUSCRIPT Figure Captions Fig. 1. Physicochemical characterizations of Pt electrode (i) and Pt electrode electrodeposited with CP/HY (ii), CP/NGF/HY (iii), CP/DEX/HY (iv), and CP/NGF/DEX/HY (v) films. (A) CV measured at a scanning rate of 50 mV/s in PBS; inset: micro-Raman spectra. (B) AFM images of deposited films.

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Fig.2. The EIS of Pt electrode (i) and Pt electrode electrodeposited with CP/HY (ii), CP/NGF/HY (iii), CP/DEX/HY (iv), and CP/NGF/DEX/HY (v) films, obtained in ACSF. (A) Bode plot; inset: proposed equivalent circuit. (B) Cole-cole plot; inset: enlarged cole-cole plot; the fitting results are shown by the solid line.

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Fig. 3. Inflammatory response and neuronal survival around implants at 6 weeks after implantation in the rat brain. (A) GFAP (red) and NeuN (green) immunostaining of Pt/Ir implant (i, n=18) and Pt/Ir implant modified with CP/NGF/HY (ii, n=23), CP/DEX/HY (iii, n=22), and CP/NGF/DEX/HY (iv, n=17) films. (B, C) Quantitative comparisons of GFAP (B) and NeuN (C) immunoreactivity between control and modified implants; comparisons were performed by using intensity profiles as a function of distance from the implant interface, shown as means ± SEM.

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Graphical Abstract

ACCEPTED MANUSCRIPT Highlights We stabilized NGF and DEX in an interpenetrating polymer network by co-deposition.

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We demonstrated the advantages of the co-deposited CP/NGF/DEX/HY IPN films.

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The co-deposited IPN film exhibited markedly higher capacitance and lower impedance.

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The co-deposited film potently alleviated the inflammatory response in vivo.

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The co-deposited film notably improved neuronal survival at the implant interface.

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