Quantitative analysis of the tissue response to chronically implanted microwire electrodes in rat cortex
Introduction
Cortically implanted microelectrode arrays are used for assessing neuronal activity. One such example is the microwire array, which has been widely used as a basic science tool, and has potential to contribute to clinical device development [1], [2], [3]. However, following implantation, chronic single unit recording and indeed, recording performance in general, is inconsistent from animal to animal with this class of devices [1], [3], [4], [5], [6], [7], [8], [9]. Available evidence suggests that the reaction the brain mounts against implanted microelectrodes contributes to recording instability, however, the factors that influence the brain tissue response to implanted electrodes remain unclear.
Evidence gathered over the last 50 years indicates that the brain tissue response to penetrating electrodes consists of several major features that are observed regardless of electrode design, species studied, or implantation method, and is similar in many respects to the foreign body response in other soft tissues [6], [10]. In particular, by 4 weeks following implantation, the reaction has a stereotypical organization consisting of hypertrophic astrocytes, fibroblasts, and meningeal cells [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23] that surrounds an activated macrophage/microglial/foreign body giant cell core found immediately adjacent to the implant [15], [17], [22]. Within this region of reactive gliosis, numerous studies have described a decrease in the neuronal population [10], [11], [12], [13], [15], [20], [21], [22], [23], [24]. Quantitative studies have shown that the response is limited to the immediate vicinity of the electrode extending a few hundred microns from the interface into surrounding brain tissue [13], [15]. While many of these features are observed at longer timepoints [10], [11], [13], [14], [15], [16], [19], [21], [23], [24], quantitative studies that examine the spatial distribution of relevant biomarkers as a function of indwelling time are lacking.
Toward this end, we employed a quantitative immunohistochemical approach to describe the spatial distribution of cell type specific markers associated with the foreign body response at 2, 4, and 12 weeks following the implantation of a microwire electrode in rat cortex. A single microwire electrode was chosen as a point of comparison with other such studies that have examined the brain tissue response to a single penetrating planar silicon electrode array [11], [13], [15], [16], [17], [25]. Specifically, the study was designed to address several questions including: a) Does inflammation persist around an implanted microwire electrode?; b) Does the pattern of reactive astrogliosis change as a function of the indwelling period?; and, c) Does the distribution of neurons at the device tissue interface change over a long indwelling period? That is, is there evidence of progressive neuronal degeneration?
Section snippets
Microelectrodes
Single shank, stainless steel microwires were provided by FHC (Bowdoinham, ME). Microwires had a 75 μm diameter shank with a sharp conical tip, approximately 1 μm in diameter, and were 5 mm in total length. The microwires were coated by the manufacturer with Epoxylite insulation, except for the last 25 μm of the tip which constituted the recording site, as is shown in Fig. 1A. All microwire electrodes were cleaned by immersion in 70% ethanol and rinsed several times in sterile DI water, followed by
Quantitative glial and neuronal response
No attached cells were observed on explanted microwires at any timepoint studied (data not shown). The activated microglia/macrophage response to implanted stainless steel microwires consisted of punctate ED-1+ immunoreactivity localized adjacent to and within the electrode track. The ED-1 immunoreactive zone was circular in shape and reflected the geometry of the implanted electrode, and was symmetric along the entire electrode shaft (Fig. 2A). There was also a large number of DAPI+ cells
Discussion
This results of our study show that inflammation persists around a single microwire electrode over a three month indwelling period in rat cortex. At no point in time or in any of the implanted animals was the implantation tract free of ED1 immunoreactivity. We consistently observed the pan-macrophage marker, ED-1, at 2, 4 and 12 weeks following implantation along the electrode tract and near the recording tip that was distributed more or less uniformly along the implant surface. We observed no
Conclusions
In this study, we observed an overall lower degree of cortical tissue reactivity near implanted insulated microwire electrodes than has been reported for planar silicon microelectrodes [10], [13], [15], [17]. We found no evidence to support a growing reactive gliotic response over time or to indicate that neuronal loss was progressive. What we found was evidence of persistent inflammation and enhanced BBB permeability that was more variable at 3 months that at 2 and 4 weeks. Whether these
Acknowledgements
The authors gratefully acknowledge Heather Kavarana for help with tissue processing.The custom LabView-based image analysis program was created by Dr. Michael J. Bridge. The authors also would like to acknowledge funding support by the National Institutes of Health (R01 NS046770).
References (48)
- et al.
A comparison of chronic multi-channel cortical implantation techniques: manual versus mechanical insertion
J Neurosci Methods
(2005) - et al.
Long-term neural recording characteristics of wire microelectrode arrays implanted in cerebral cortex
Brain Res Brain Res Protoc
(1999) - et al.
Long-term chronic recording from cortical neurons
Exp Neurol
(1976) - et al.
Dexamethasone-coated neural probes elicit attenuated inflammatory response and neuronal loss compared to uncoated neural probes
Brain Res
(2007) - et al.
Neural probe design for reduced tissue encapsulation in CNS
Biomaterials
(2007) - et al.
Dexamethasone treatment reduces astroglia responses to inserted neuroprosthetic devices in rat neocortex
Exp Neurol
(2005) - et al.
Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays
Exp Neurol
(2005) - et al.
Brain responses to micro-machined silicon devices
Brain Res
(2003) - et al.
Cerebral astrocyte response to micromachined silicon implants
Exp Neurol
(1999) - et al.
Histopathologic evaluation of prolonged intracortical electrical stimulation
Exp Neurol
(1986)