Controlled release nanoparticle-embedded coatings reduce the tissue reaction to neuroprostheses

Abstract

Controlled release coatings were developed for neuroprostheses with the aim of combating the tissue reaction following implantation in the brain. The coatings consist of poly(propylene sulfide) drug-eluting nanoparticles embedded in a poly(ethylene oxide) matrix. The nanoparticles are loaded with dexamethasone, an anti-inflammatory drug known to have an effect on the cells activated during the damage caused by implantation. The nanoparticles are not affected by the coating process and the drug remains bioactive after it is released. The coating was applied to microfabricated cortical neuroprostheses consisting of platinum and polyimide. Coated drug-eluting devices were implanted in the cortex of rats. After implantation the matrix dissolves, exposing the electrode surfaces, while the nanoparticles remain in the vicinity of the tissue–implant interface. Using electrical impedance spectroscopy and comparative histology, a long-term decrease in the tissue response in comparison to control devices was observed. These coatings can therefore be used to increase the reliability and long-term efficacy of neuroprostheses.

Introduction

Microelectrodes implanted in nervous tissue can be used to stimulate or record neural activity and may one day reproduce neural functions lost to trauma or disease [1]. A limiting factor with microelectrodes chronically implanted in the brain is their loss of electrical contact with neural tissue due to the post-implantation inflammatory reaction, gliosis, and fibrosis [2], [3], [4]. Glial cells rapidly migrate to the implantation site surrounding the device, thus physically separating the microelectrode sites from the neurons they are meant to be recording from or stimulating. The efficiency of the implanted device decreases steadily with time. After approximately two to three weeks, the inflammatory response has reached its peak, electrical impedance measurements have stabilized at their maximum [5], and the number of chronically recorded single units has reached its minimum [6]. If microelectrode arrays are to be effective in neural stimulation and recording, the tissue response must be reduced or prevented in order to maintain stable microelectrode–tissue contact and neuroprostheses functionality.

Several approaches to limiting this tissue reaction have been reported, including surface modification to prevent cell adhesion [7], localized release of alpha-melanocyte stimulating hormone (α-MSH) [8] or nerve growth factor β [9], and dexamethasone injection [10]. The approach presented here involves coating microelectrode arrays with bio-resorbable drug-eluting material. We hypothesized that highly localized delivery of an anti-inflammatory drug around the implantation site would reduce the tissue response to implantation and improve recording and stimulation characteristics. The goal of this work was to determine the efficacy of these drug-eluting coatings to combat the inflammatory response to implantation.

Novel nanoparticle-embedded coatings were designed and evaluated for the controlled release of dexamethasone, which has been shown to be effective in reducing the brain response to implantable devices [10], [11]. Its release from poly(lactic-co-glycolic acid) (PLGA) nanoparticles was shown by Kim and Martin [12] using rigid silicon probes, however in this experiment the neuroprostheses were polymeric, resulting in less post-implantation injury and eventually a more straightforward translation into clinical use.

Dexamethasone was loaded into poly(propylene sulfide) (PPS) nanoparticles which were then incorporated into poly(ethylene oxide) (PEO), a bio-resorbable polymer, and applied as a coating to the neuroprosthesis. The PEO is meant to dissolve soon after implantation, thereby releasing the drug-loaded nanoparticles and exposing the electrode sites. The nanoparticles are large enough to not diffuse from the surface of the implanted device and can maintain sustained release at the implantation site. The nanoparticles were characterized before and after the coating process, to ensure that they were not damaged using scanning electron microscopy (SEM) and in vitro release rates were obtained. In vivo efficacy in the brain was evaluated using two different methods in the rat model. The first was by measuring the electrical characteristics of the tissue reaction using electrical impedance spectroscopy. The second was with immuno-fluorescence which gives qualitative insight into the cell morphology around the device.

We demonstrate with this study that the highly localized release of dexamethasone around the neuroprosthesis indeed reduces the long-term tissue reaction. In stimulation applications of neuroprostheses, a reduction in the tissue reaction will enable more efficient charge transfer during neural stimulation, reducing the current required and preventing toxic electrochemical reactions at the metal microelectrode surface [13]. In recording applications of neuroprostheses, the signal-to-noise ratio may be improved if the degree of the tissue reaction is reduced [14], [15]. These are important factors for the continued use of microelectrode based neuroprostheses in research, and may accelerate the translation of this technology into clinic applications.